zithromax and Cardiotoxicity

Topics: Azithromycin; Cardiotoxicity; Cardiotoxins; Cell Survival; Cells, Cultured; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac

Coronavirus disease 2019 (COVID-19), which began in China, caused a global pandemic. Few studies have shown the benefit of hydroxychloroquine (HY) ± azithromycin (AZ) for treating COVID-19. Concerns of QT prolongation and increased risks of torsade's de pointes (TdP) with this combination have been raised since each agent can individually prolong the QT interval. This retrospective, observational study included hospitalized patients treated with HY and AZ from March 2020 to May 2020 at a large community hospital. Serial assessments of the QT interval were performed. Our aim is to evaluate the safety and characterize the change in QTc interval and arrhythmic events in COVID-19 patients treated with HY/AZ. A total of 21 COVID patients who received at least four days of HY and AZ were included in this study. Mean baseline was QTc 403 ms, mean maximum QTc was 440 ms, mean change in QTc was 36 ms. Only one patient (4.8%) developed prolonged QTc > 500 ms. No patient had a change in QTc of 60 ms or more. No patient developed TdP. Fifteen patients (71.4%) had hypoxia on admission, with only two patients (9.5%) required oxygen of 1-2 L at discharge. 80.9% of patients have been discharged home or inpatient rehabilitation.

Topics: Azithromycin; Cardiotoxicity; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Retrospective Studies; SARS-CoV-2

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; COVID-19 Drug Treatment; Drug Therapy, Combination; Humans; Hydroxychloroquine; SARS-CoV-2; Treatment Outcome

Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity.. Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH).. The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results.. We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Apoptosis; Azithromycin; Cardiotoxicity; COVID-19 Drug Treatment; Disease Models, Animal; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium

Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.

Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Azithromycin; Cardiotoxicity; Chloroquine; COVID-19 Drug Treatment; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Myocytes, Cardiac; Risk Assessment; SARS-CoV-2; United States

Only a handful of US Food and Drug Administration (FDA) Emergency Use Authorizations exist for drug and biologic therapeutics that treat severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements, such as QT interval (action potential duration) and drug-biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onward, and arrhythmias were observed at days 8 and 10. Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients' serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe coronavirus disease 2019 (COVID-19) therapeutics.

Topics: Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Clinical Trials as Topic; COVID-19 Drug Treatment; Drug Therapy, Combination; Humans; Hydroxychloroquine; Long QT Syndrome; SARS-CoV-2

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Chloroquine; Coronavirus Infections; COVID-19; Dehydration; Drug Interactions; Electrocardiography; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Risk Assessment; Water-Electrolyte Imbalance

Topics: Azithromycin; Cardiotoxicity; COVID-19; COVID-19 Drug Treatment; Databases, Factual; Electrocardiography; Heart Diseases; Humans; Hydroxychloroquine; Pharmacovigilance; Public Health Surveillance; World Health Organization

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID-19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5-day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5-day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Azithromycin; Cardiotoxicity; Cardiovascular Diseases; Child; Child, Preschool; COVID-19 Drug Treatment; Databases, Factual; Drug Therapy, Combination; Female; Humans; Hydroxychloroquine; Infant; Infant, Newborn; Male; Middle Aged; Risk Factors; Sex Factors; Young Adult

Conflicting evidence exists on the association between azithromycin use and cardiac events.. To compare the odds of cardiac events among new users of azithromycin relative to new users of amoxicillin using real-world data.. This retrospective cohort study used data from Truven Health Analytics MarketScan database from January 1, 2009, to June 30, 2015. Patients receiving either amoxicillin or azithromycin and enrolled in a health care plan 365 days before (baseline period) the dispensing date (index date) were included in the study. Patients were matched 1:1 on high-dimensional propensity scores. Data were analyzed from October 1, 2018, to December 31, 2019.. New use of azithromycin compared with new use of amoxicillin.. The primary outcome consisted of cardiac events, including syncope, palpitations, ventricular arrhythmias, cardiac arrest, or death as a primary diagnosis for hospitalization at 5, 10, and 30 days from the index date. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs.. After matching, the final cohort included 2 141 285 episodes of each index therapy (N = 4 282 570) (mean [SD] age of patients, 35.7 [22.3] years; 52.6% female). Within 5 days after therapy initiation, 1474 cardiac events (0.03%) occurred (708 in the amoxicillin cohort and 766 in the azithromycin cohort). The 2 most frequent events were syncope (1032 [70.0%]) and palpitations (331 [22.5%]). The odds of cardiac events with azithromycin compared with amoxicillin were not significantly higher at 5 days (OR, 1.08; 95% CI, 0.98-1.20), 10 days (OR, 1.05; 95% CI, 0.97-1.15), and 30 days (OR, 0.98; 95% CI, 0.92-1.04). Among patients receiving any concurrent QT-prolonging drug, the odds of cardiac events with azithromycin were 1.40 (95% CI, 1.04-1.87) greater compared with amoxicillin. Among patients 65 years or older and those with a history of cardiovascular disease and other risk factors, no increased risk of cardiac events with azithromycin was noted.. This study found no association of cardiac events with azithromycin compared with amoxicillin except among patients using other QT-prolonging drugs concurrently. Although azithromycin is a safe therapy, clinicians should carefully consider its use among patients concurrently using other QT-prolonging drugs.

Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Cohort Studies; Drug Interactions; Drug Therapy, Combination; Female; Heart Arrest; Humans; Logistic Models; Long QT Syndrome; Male; Middle Aged; Mortality; Odds Ratio; Retrospective Studies; Risk Factors; Syncope; Tachycardia, Ventricular

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Azithromycin; Cardiotoxicity; Cell Differentiation; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Embryonic Stem Cells; Humans; Mice; Myocytes, Cardiac; Pandemics; Pneumonia, Viral

The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment.. Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest.. The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced.. The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.

Topics: Action Potentials; Adolescent; Adult; Aged; Antiviral Agents; Azithromycin; Cardiotoxicity; COVID-19; COVID-19 Drug Treatment; Delivery of Health Care; Female; Heart Conduction System; Heart Rate; Hospitalization; Humans; Hydroxychloroquine; Male; Middle Aged; New York; Patient Safety; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Torsades de Pointes; Treatment Outcome; Young Adult

The Food and Drug Administration recently warned of the fatal cardiovascular risks of azithromycin in humans. In addition, a recently published study documented azithromycin-induced cardiotoxicity in rats. This study aimed to justify the exact cardiovascular events accompanying azithromycin administration in rats, focusing on electrocardiographic, biochemical, and histopathological changes. In addition, the underlying mechanisms were studied regarding reactive oxygen species production, cytokine release, and apoptotic cell-death. Finally, the supposed protective effects of both carvedilol and vitamin C were assessed. Four groups of rats were used: (1) control, (2) azithromycin, (3) azithromycin + carvedilol, and (4) azithromycin + vitamin C. Azithromycin resulted in marked atrophy of cardiac muscle fibers and electrocardiographic segment alteration. It increased the heart rate, lactate dehydrogenase, creatine phosphokinase, malondialdehyde, nitric oxide, interleukin-1 beta (IL1-β), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-κB), and caspase-3. It decreased reduced glutathione, glutathione peroxidase, and superoxide dismutase. Carvedilol and vitamin C prevented most of the azithromycin-induced electrocardiographic and histopathological changes. Carvedilol and vitamin C decreased lactate dehydrogenase, malondialdehyde, IL1-β, TNF-α, NF-κB, and caspase-3. Both agents increased glutathione peroxidase. This study shows that both carvedilol and vitamin C protect against azithromycin-induced cardiotoxicity through antioxidant, immunomodulatory, and antiapoptotic mechanisms.

Topics: Animals; Anti-Bacterial Agents; Ascorbic Acid; Azithromycin; Carbazoles; Cardiotoxicity; Carvedilol; Caspase 3; Electrocardiography; Interleukin-1beta; Male; NF-kappa B; Propanolamines; Random Allocation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tumor Necrosis Factor-alpha