Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices.

The cardiotoxicity risk of hydroxychloroquine (HCQ) and azithromycin (AZM) has been the subject of intensive research triggered by safety concerns in COVID-19 patients. HCQ and AZM have been associated with QT interval prolongation and drug-induced arrhythmias, however other cardiotoxicity mechanisms remain largely unexplored. Our group has pioneered the living heart slice preparation, an ex-vivo platform that maintains native cardiac tissue architecture and physiological electrical and contractile properties. Here, we evaluated the cardiotoxic effect of HCQ and AZM applied alone or in combination on cardiac contractility by measuring contractile force and contraction kinetics in heart slices prepared from porcine hearts. Our results show that clinically relevant concentrations of HCQ monotherapy (1-10 µM) reduced contractile force and contraction kinetics in porcine slices in a dose-dependent manner. However, AZM monotherapy decreased contractile force and contraction kinetics only at higher concentrations (30 µM). Combination of HCQ and AZM induced a dose-dependent effect similar to HCQ alone. Furthermore, pre-treating porcine heart slices with the L-type calcium channel agonist Bay K8644 prevented the effect of both drugs, while administration of Bay K8644 after drugs interventions largely reversed the effects, suggesting a mechanism involving inhibition of L-type calcium channels. These findings indicate that HCQ and AZM alter cardiac function beyond QT prolongation with significant contractile dysfunction in intact cardiac tissue. Our porcine heart slices provide a powerful platform to investigate mechanisms of drug cardiotoxicity.

Hydroxychloroquine induces long QT syndrome by blocking hERG channel

In March 2022, more than 600 million cases of Corona Virus Disease 2019 (COVID-19) and about 6 million deaths have been reported worldwide. Unfortunately, while effective antiviral therapy has not yet been available, chloroquine (CQ)/hydroxychloroquine (HCQ) has been considered an option for the treatment of COVID-19. While many studies have demonstrated the potential of HCQ to decrease viral load and rescue patients' lives, controversial results have also been reported. One concern associated with HCQ in its clinical application to COVID-19 patients is the potential of causing long QT interval (LQT), an electrophysiological substrate for the induction of lethal ventricular tachyarrhythmias. Yet, the mechanisms for this cardiotoxicity of HCQ remained incompletely understood. Adult New Zealand white rabbits were used for investigating the effects of HCQ on cardiac electrophysiology and expression of ion channel genes. HEK-293T cells with sustained overexpression of human-ether-a-go-go-related gene (hERG) K+ channels were used for whole-cell patch-clamp recordings of hERG K+ channel current (IhERG). Quantitative RT-PCR analysis and Western blot analysis were employed to determine the expression of various genes at mRNA and protein levels, respectively. electrocardiogram (ECG) recordings revealed that HCQ prolonged QT and RR intervals and slowed heart rate in rabbits. Whole-cell patch-clamp results showed that HCQ inhibited the tail current of hERG channels and slowed the reactivation process from inactivation state. HCQ suppressed the expression of hERG and hindered the formation of the heat shock protein 90 (Hsp90)/hERG complex. Moreover, the expression levels of connexin 43 (CX43) and Kir2.1, the critical molecular/ionic determinants of cardiac conduction thereby ventricular arrythmias, were decreased by HCQ, while those of Cav1.2, the main Ca2+ handling proteins, remained unchanged and SERCA2a was increased. HCQ could induce LQT but did not induce arrhythmias, and whether it is suitable for the treatment of COVID-19 requires more rigorous investigations and validations in the future. [ FROM AUTHOR] Copyright of Frigid Zone Medicine is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Eastern Regional Meeting 2021

The proceedings contain 63 papers. The topics discussed include: doxorubicin cardiotoxicity in human organotypic cardiac slices is modulated by P38 MAPK inhibition in a sex- and isoform-specific manner;validation of a modified response evaluation criteria in solid tumors after stereotactic ablative radiosurgery for lung cancer;safer use of aspirin in older adults, need for a consensus;efficacy of facemasks in prevention of COVID-19: a systematic review;practice patterns of rapid influenza diagnostic test;equity and inclusion in patient centered outcomes research: lessons from the adaptable study at Montefiore site;a solution to decrease potentially inappropriate medications (PIM) use during hospitalization;predictors of misperceptions, risk perceptions, and personal risk perceptions about COVID-19 by country, education and income;cognitive function and the consumption of probiotic foods in older adults: an NHANES study;and registered dietitian nutritionist care impacts nutrition-related outcomes for patients with cancer in the outpatient setting.

Corrigendum: Cardio-oncology in the COVID Era (Co & Co): The never-ending story.

[This corrects the article DOI: 10.3389/fcvm.2022.821193.].

Analysis of fatal cardiac adverse events caused by chloroquine: a study based on the related data from the WHO global database of individual case safety reports. TT -:Who.

Objective: To analyze the clinical characteristics of fatal cardiac adverse events associated with chloroquine, which was recommended for the antiviral treatment of novel coronavirus pneumonia, and provide reference for clinical safe drug use. Method(s): The fatal cardiac adverse events associated with chloroquine were searched from the World Health Organization global database of individual case safety reports (VigiBase). The clinical characteristics of the individual cases with well-documented reports (VigiGrade completeness score >=0.80 or with detailed original reports) were analyzed. The adverse events were coded using the systematic organ classification (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA) version 22.1 of International Conference on Harmonization (ICH). Result(s): Up to 23 February 2020, a total of 45 reports of fatal heart injuries related to chloroquine were reported in VigiBase, which were from 16 countries. Of them, 30 reports were fully informative. Among the 30 reports,20 cases developed fatal cardiac adverse events after a single large dose of chloroquine. Of them, 17 cases' fatal cardiac adverse events were caused by overdose of chloroquine (15 cases were suicide or suspected suicide, and 2 children took chloroquine by mistake);3 cases' fatal cardiac adverse events were caused in clinical treatment;18 cases showed arrhythmia and cardiac arrest;6 cases showed prolonged QRS wave or QT interval;6 cases were with hypokalemia, including 4 severe ones. Among the 30 reports, 10 cases developed fatal cardiac adverse events after multiple administration of chloroquine, of which 4 cases were treated with chloroquine for 23 days to 2 months and died of heart failure, cardiac arrest or myocardial infarction;6 cases were treated with chloroquine for 20 months to 29 years and all of them had cardiomyopathy, which were confirmed by endomyocardial biopsy to be caused by chloroquine in 3 cases. Conclusion(s): Cardiac toxicity was the primary cause of fatal adverse events caused by chloroquine;the main manifestation of single large dose of chloroquine was arrhythmia and the manifestation of multiple administration was cardiomyopathy.Copyright © 2020 by the Chinese Medical Association.

COVID-19 pandemic is a pandemic of antimicrobial therapy.

The article presents a critical analysis of antibiotic usage tactics in the treatment of patients with COVID-19 existing in Russian and foreign healthcare, and discusses the possible causes of unjustified antibiotic aggression in this category of patients. The potential negative consequences of the widespread use of antibiotics in patients carrying a new coronavirus infection are analyzed: life-threatening cardiotoxicity in patients with the simultaneous administration of such a "popular" candidate etiologic therapy as a combination of azithromycin and hydroxychloroquine, the potential development of other serious adverse drug reactions (in particular, the development of an antibiotic-associated pseudomembranous colitis, etc.), the expected dramatic increase in the secondary drug resistance of potentially pathogenic microorganisms to widely and often prescribed antibiotics.Copyright © 2021, Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. All rights reserved.

Cardiotoxicity of chloroquine and hydroxychloroquine through mitochondrial pathway.

BACKGROUND: Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes. METHODS: Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling. RESULTS: Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC50 concentration for CQ is 20 µM and for HCQ is 50 µM. Based on two-way ANOVA analysis, the highest effect of CQ and HCQ on the generation of ROS, collapse in the MMP, and mitochondrial swelling were observed at 40 µM and 100 µM concentrations, respectively (p < 0.05). Also, the highest effect of these two drugs has been observed in 60 min (p < 0.05). The statistical results showed that compared to CQ, HCQ is able to cause the release of cytochrome c from mitochondria in all applied concentrations (p < 0.05). CONCLUSIONS: The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

Effect Of Rosuvastatin In The Protection Against Azithromycin Induced Cardiotoxicity In Covid-19 Patients: A One-Year Prospective Study

Background Azithromycin is a widely used broad-spectrum antibiotic that was recently used in the treatment protocol of COVID-19 but its cardiac side effects became a more prominent concern. Rosuvastatin is a synthetic statin that showed anti-inflammatory, antioxidant and autonomic nervous system regulatory effects in addition, there is increasing evidence supporting that it could play a beneficial role in patients with COVID-19. Objective To evaluate the protective effect of Rousvastatin against Azithromycin-induced cardiotoxicity in Covid-19 patients. Patients and Methods This is a prospective study that was conducted on adult patients diagnosed with COVID-19 who were admitted to isolation centres in Minia Governorate, Egypt for the period of one year (June 2021 to May 2022). The study included a total of 80 COVID-19 patients who were divided into 2 groups (n=40 each), group (I) "Azithromycin group" that included patients received Azithromycin (500 mg/day for 5 days) orally and group (II) "Azithromycin + Rosuvastatin group" that included patients received Azithromycin by oral route as group (I) plus Rosuvastatin 20 mg/day orally. All included cases were subjected to full history taking, clinical examination and laboratory investigations and after treatment, the outcome measures were reported and compared. Results No significant differences were observed between groups regarding demographic and baseline characteristics. Also, the two groups were comparable with no significant differences in pulse rate, blood sugar, CBC, electrolyte elements, liver enzymes, and kidney function (a slight reduction was noticed in group II). While, Ferritin level was significantly lower in group (II) compared to group (I), (830 ± 72.5 vs. 865 ± 69.5, p=0.03). No significant differences were observed among groups as regards Troponin level (p=0.56) "Only one case was positive in group (I)". Both groups were almost comparable without significant differences in both stages of infection and mortality (p=0.38 and 1.0, respectively). Conclusion Rosuvastatin did not have a significant role in the protection of Azithromycin-induced cardiotoxicity, it slightly ameliorates the biochemical and stress markers alterations of Azithromycin. Further larger studies are warranted for investigating this issue. [ FROM AUTHOR] Copyright of Journal of Pharmaceutical Negative Results is the property of ResearchTrentz and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Mechanism of Cardiac Pathogenesis and Cardiotoxicity of Anti-COVID-19 Drugs

Novel coronavirus (nCoV-19) infection has been declared a pandemic by WHO. More than 223 countries are under the attack of this emergency situation. Primarily, pneumocytes encountered by the nCoV-19 via ACE-2 receptor cause pulmonary edema, damage to alveolar cells, production of inflammatory cells, and hypoxia. It has been found that patients with co-existing cardiovascular diseases are more prone to the infection, and severe cardiovascular dysfunction was further observed when infected with nCoV-19. There is no substantial mechanism available for the pathogenesis of this cardiovascular dysfunction;therefore, we herein present a possible mechanistic approach of cardiotoxicity by nCov-19 infection. The hypothesis of this study is based on immunopathology of nCoV-19 in pneumocytes, presence of ACE-2 on cardiomyocytes membrane, cytokine storm, genomic analysis of virus in cardiac tissue, and several reports published on the cardiovascular complications in nCoV-19 across the globe. We have also analyzed the cardiotoxic profile of recently used repurposed and investigational drugs and highlighted their possible cardiotoxic consequences and drug interactions with cardiovascular medicines, such as statins and anti-coagulants.Copyright © 2021 Bentham Science Publishers.

Anti-COVID-19 Sulfonamides: A DFT, Docking and ADMET Study

Background: The development of a specific curative drug or prophylactic and vaccine is urgently required to cure COVID-19. Sulfonamide and its derivatives are famous for their multi-faceted antibiotic and antiviral activities against verities of a pathogen. Objective(s): The objective of this study is to find new potential molecules for COVID-19 treatment. We tested some sulfonamide molecules (including antiviral compounds) as SARS CoV-2 Mpro in-hibitors. Method(s): In this study, the Density Functional Theory (DFT) and Docking study have been util-ized for protein-small molecule affinity prediction. The SwissADME server was used for pharma-cokinetics and drug-like likeness prediction, and the Pred-hERG server was employed for cardio-toxicity prediction. Result(s): In this study, sixteen sulfonamides have been investigated in silico, with a perspective to obtaining a potential anti-covid compound. The sulfonamides have been subjected to molecular docking with SARS CoV-2 Mpro, mainly responsible for viral infection and replication. We discov-er the molecular flexibility and charge distribution profoundly affecting the binding of the compounds to the protein. Moderately flexible (six rotatable bond) and less polar (sufficient hydropho-bic) sulfonamide are favorable for strong binding with the enzyme. Here, the bioavailability proper-ties like adsorption, distribution, metabolism, excretion, pharmacokinetics, and potential toxicity of these compounds have also been checked. Conclusion(s): Low cardio-toxicity and high bioavailability make these sulfonamides a good anti-COVID-19 drug option. The sulfonamide 16 was found to be the best.Copyright © 2022 Bentham Science Publishers.

High-intensity exercise prescription guided by heart rate variability in breast cancer patients: a study protocol for a randomized controlled trial.

BACKGROUND: Breast cancer is a chronic disease with a large growth in its treatments, prognosis, improvements, side effects and rehabilitation therapies research. These advances have also highlighted the need to use physical exercise as a countermeasure to reduce the cardiotoxicity of pharmacological treatments, increase patients' strength and quality of life and improve body composition, physical condition and mental health. However, new investigations show the need for a closed exercise individualisation to produce higher physiological, physical and psychological benefits in remote exercise programs. To this end, the present study will use, in a novel way in this population, heart rate variability (HRV) as a measure for prescribing high-intensity training. Thus, the primary objective of this randomised clinical trial is to analyse the effects of a high-intensity exercise program daily guided by HRV, a preplanned moderate to high-intensity exercise intervention and a usual care group, in breast cancer patients after chemotherapy and radiotherapy treatments. METHODS: For this purpose, a 16-week intervention will be carried out with 90 breast cancer patients distributed in 3 groups (a control group, a moderate to high-intensity preplanned exercise group and a high-intensity exercise group guided by HRV). Both physical exercise interventions will be developed remotely and supervised including strength and cardiovascular exercises. Physiological variables, such as cardiotoxicity, biomarkers, lipid profile, glucose, heart rate and blood pressure; physical measures like cardiorespiratory capacity, strength, flexibility, agility, balance and body composition; and psychosocial variables, as health-related quality of life, fatigue, functionality, self-esteem, movement fear, physical exercise level, anxiety and depression will be measure before, after the intervention and 3 and 6 months follow up. DISCUSSION: Personalized high-intensity exercise could be a promising exercise intervention in contrast to moderate-intensity or usual care in breast cancer patients to reach higher clinical, physical and mental effects. In addition, the novelty of controlling HRV measures daily may reflect exercise effects and patients' adaptation in the preplanned exercise group and a new opportunity to adjust intensity. Moreover, findings may support the effectiveness and security of physical exercise remotely supervised, although with high-intensity exercise, to reach cardiotoxicity improvements and increase physical and psychosocial variables after breast cancer treatments. Trial registration ClinicalTrials.gov nº NCT05040867 ( https://clinicaltrials.gov/ct2/show/record/NCT05040867 ).

Myocardial infarction or myocarditis? A case report and review of a myocardial adverse event associated with mRNA vaccine.

A 23-year-old man started with chest pain 8 h after his first Pfizer-BioNTech COVID-19 vaccination. ECG evaluation showed sinus tachycardia with ST-segment elevation in D1, AVL, V5, and V6, the findings compatible with acute subepicardial myocardial damage. However, cardiac MRI documented myocardial fibrosis, with cardiac late enhancement non-ischemic pattern with diffuse edema. He had no other symptoms to suggest another etiology than the vaccination. The patient was hospitalized and received corticosteroid (prednisolone) daily. Then, 2 weeks after hospitalization, all laboratory parameters and ECG were normal and the patient was discharged from the hospital. The patient had a history of Wolf-Parkinson White that was corrected with ablation when he was 11 years old. This report calls attention to myocardial adverse reaction risk for mRNA COVID-19 vaccines for people with a previous cardiac disease history.

Incidence and potential risk factors for remdesivir-associated bradycardia in hospitalized patients with COVID-19: A retrospective cohort study.

Background: Remdesivir is widely used for the management of COVID-19 and several studies have reported bradycardia as a potential side effect associated with this agent. The aim of the present study was to evaluate the incidence rate, severity, and potential risk factors of remdesivir-associated bradycardia. Methods: We performed a retrospective cohort study among hospitalized adult patients with COVID-19 who were treated with remdesivir from March 2020 to October 2021. Our primary outcome of interest was the incidence rate and severity of bradycardia after remdesivir administration. We defined mild bradycardia as a heart rate of 51-59 beats per minute, moderate bradycardia as a heart rate of 41-50 beats per minute, and severe bradycardia as a heart rate of ≤40 beats per minute. We also performed univariable and multivariable regression analyses to determine potential bradycardia risk factors. Baseline characteristics were reported as means with standard deviations or medians with interquartile ranges (IQRs). All the statistical tests are shown as odds ratios (ORs) with 95% confidence intervals (CIs). Results: In total, 1,635 patients were included in this study. The median age with IQR was 68 (57-79) years and 51.7% of the patients were male. In total, 606 (37.1%) patients developed bradycardia. Among them, 437 patients (26.7%) developed mild bradycardia, 158 patients (9.7%) moderate bradycardia, while 11 patients (0.7%) experienced severe bradycardia. In our adjusted multivariate logistic regression, the odds of bradycardia development after remdesivir administration were higher among patients with age ≥65 years (OR 1.76, 95% CI: 1.04-2.99, p = 0.04), those with hypertension (OR 1.37, 95% CI: 1.07-1.75, p = 0.01), and obesity (OR 1.32, 95% CI: 1.02-1.68, p = 0.03). Conclusion: More than 1 out of 3 patients (37%) who received remdesivir for COVID-19 developed bradycardia with the majority of these patients developing mild or moderate bradycardia that is usually a benign manifestation not needing treatment in most cases. Age ≥65 years, hypertension, and obesity were potential risk factors for remdesivir-associated bradycardia among hospitalized COVID-19 patients. Clinicians should be aware of this adverse event and consider close clinical monitoring for patients at high risk for this adverse event.

Safety considerations of chloroquine in the treatment of patients with diabetes and COVID-19.

Patients with underlying diseases and coronavirus disease 2019 (COVID-19) are at increased risk of death. Using the recommended anti-COVID-19 drug, chloroquine phosphate (CQ), to treat patients with severe cases and type 2 diabetes (T2D) could potentially cause harm. We aimed to understand the safety of CQ in patients with T2D by administrating the recommended dose (63 mg/kg twice daily for 7 days) and a high dose (126 mg/kg twice daily for 7 days) of CQ in T2D rats. We found that CQ increased the total mortality of the T2D rats from 27.3% to 72.7% in the recommended and high-dose groups during the whole period. CQ also induced hematotoxicity of T2D rats in the high-dose group; the hepatic enzymes in T2D rats were significantly elevated. CQ also changed the electrocardiograms, prolonged the QTc intervals, and produced urinary leukocytes and proteins in the T2D rats. Histopathological observations revealed that CQ caused severe damage to the rats' heart, jejunum, liver, kidneys, spleen, and retinas. Furthermore, CQ significantly decreased the serum IL-1ß and IL-6 levels. In conclusion, the CQ dosage and regimen used to treat COVID-19 induced adverse effects in diabetic rats, suggesting the need to reevaluate the effective dose of CQ in humans.

How toxic is an old friend? A review of the safety of hydroxychloroquine in clinical practice.

Hydroxychloroquine (HCQ) and its close relative chloroquine (CQ) were initially used as antimalarial agents but are now widely prescribed in rheumatology, dermatology and immunology for the management of autoimmune diseases. HCQ is considered to have a better long-term safety profile than CQ and is therefore more commonly used. HCQ has a key role in the treatment of connective tissue diseases including systemic lupus erythematosus (SLE), where it provides beneficial immunomodulation without clinically significant immunosuppression. HCQ can also assist in managing inflammatory arthritis, including rheumatoid arthritis (RA). Debate around toxicity of HCQ in COVID-19 has challenged those who regularly prescribe HCQ to discuss its potential toxicities. Accordingly, we have reviewed the adverse effect profile of HCQ to provide guidance about this therapeutic agent in clinical practice.

Cardio-Oncology in the COVID Era (Co & Co): The Never Ending Story.

The pathophysiology of some non-communicable diseases (NCDs) such as hypertension, cardiovascular disease (CVD), diabetes, and cancer includes an alteration of the endothelial function. COVID-19 is a pulmonary and vascular disease with a negative impact on patients whose damaged endothelium is particularly vulnerable. The peculiar SARS-CoV-2-induced "endothelitis" triggers an intriguing immune-thrombosis that affects both the venous and arterial vascular beds. An increased liability for infection and an increased likelihood of a worse outcome have been observed during the pandemic in patients with active cancer and in cancer survivors. "Overlapping commonalities" between COVID-19 and Cardio-Oncology have been described that include shared phenotypes of cardiovascular toxicities such as left ventricular dysfunction, ischemic syndromes, conduction disturbances, myocarditis, pericarditis and right ventricular failure; shared pathophysiologic mechanisms such as inflammation, release of cytokines, the renin-angiotensin-aldosterone-pathway, coagulation abnormalities, microthrombosis and endothelial dysfunction. For these features and for the catalyst role of NCDs (mainly CVD and cancer), we should refer to COVID-19 as a "syndemic." Another challenging issue is the persistence of the symptoms, the so-called "long COVID" whose pathogenesis is still uncertain: it may be due to persistent multi-organ viral attacks or to an abnormal immune response. An intensive vaccination campaign is the most successful pharmacological weapon against SARS-CoV-2, but the increasing number of variants has reduced the efficacy of the vaccines in controlling SARS-CoV-2 infections. After a year of vaccinations we have also learned more about efficacy and side-effects of COVID-19 vaccines. An important byproduct of the COVID-19 pandemic has been the rapid expansion of telemedicine platforms across different care settings; this new modality of monitoring cancer patients may be useful even in a post pandemic era. In this paper we analyze the problems that the cardio-oncologists are facing in a pandemic scenario modified by the extensive vaccination campaign and add actionable recommendations derived from the ongoing studies and from the syndemic nature of the infection.

Synergistic action of organophosphates and COVID-19 on inflammation, oxidative stress, and renin-angiotensin system can amplify the risk of cardiovascular maladies.

Organophosphates (OPs) are ubiquitous environmental contaminants, widely used as pesticides in agricultural fields. In addition, they serve as flame-retardants, plasticizers, antifoaming or antiwear agents in lacquers, hydraulic fluids, and floor polishing agents. Therefore, world-wide and massive application of these compounds have increased the risk of unintentional exposure to non-targets including the human beings. OPs are neurotoxic agents as they inhibit the activity of acetylcholinesterase at synaptic cleft. Moreover, they can fuel cardiovascular issues in the form of myocardities, cardiac oedema, arrhythmia, systolic malfunction, infarction, and altered electrophysiology. Such pathological outcomes might increase the severity of cardiovascular diseases which are the leading cause of mortality in the developing world. Coronavirus disease-19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. Similar to OPs, SARS-CoV-2 disrupts cytokine homeostasis, redox-balance, and angiotensin-II/AT1R axis to promote cardiovascular injuries. Therefore, during the current pandemic milieu, unintentional exposure to OPs through several environmental sources could escalate cardiac maladies in patients with COVID-19.

Remdesivir associated sinus bradycardia in patients with COVID-19: A prospective longitudinal study.

Background: Remdesivir is effective against SARS-Cov-2 with little evidence of its adverse effect on the cardiac system. The aim of the present study is investigating the incidence of bradycardia in COVID-19 patients treated with Remdesivir. Methods: This prospective longitudinal study was conducted in a tertiary center on COVID-19 patients for Remdesivir therapy. The objectives were to investigate the incidence of sinus bradycardia, and also the association between their demographics, underlying diseases, and the disease severity with developing bradycardia in COVID-19 patients treated with Remdesivir. Results: Of 177 patients, 44% were male. The mean (±standard deviation) age of patients was 49.79 ± 15.16 years old. Also, 33% were hospitalized due to more severe symptoms. Oxygen support was required for all hospitalized subjects. A total of 40% of the patients had comorbidities, with the most common comorbidity being hypertension. The overall incidence of bradycardia (heart rate<60 bpm) in patients receiving Remdesivir was 27%, of whom 70% had extreme bradycardia (heart rate <50 bpm). There was also a statistically significant reduction in heart rate after five doses of Remdesivir compared to the baseline heart rates. In the multivariable model, none of the covariates including age above 60 years, female sex, CRP>50 mg/L, O2 saturation<90%, underlying cardiovascular disease, hypertension and diabetes mellitus, and beta-blockers were associated with Remdesivir-induced bradycardia. No association was found between the COVID-19 severity indicators and bradycardia. Conclusion: As sinus bradycardia is a prevalent adverse cardiac effect of Remdesivir, it is recommended that all COVID-19 patients receiving Remdesivir, be evaluated for heart rate based on examination; and in the case of bradyarrhythmia, cardiac monitoring should be performed during administration to prevent adverse drug reactions.

Effect of Rosuvastatin in the Protection against Azithromycin Induced Cardiotoxicity in Covid-19 Patients: A One-Year Prospective Study

Background Azithromycin is a widely used broad-spectrum antibiotic that was recently used in the treatment protocol of COVID-19 but its cardiac side effects became a more prominent concern. Rosuvastatin is a synthetic statin that showed anti-inflammatory, antioxidant and autonomic nervous system regulatory effects in addition, there is increasing evidence supporting that it could play a beneficial role in patients with COVID-19. Objective To evaluate the protective effect of Rousvastatin against Azithromycin-induced cardiotoxicity in Covid-19 patients. Patients and Methods This is a prospective study that was conducted on adult patients diagnosed with COVID-19 who were admitted to isolation centres in Minia Governorate, Egypt for the period of one year (June 2021 to May 2022). The study included a total of 80 COVID-19 patients who were divided into 2 groups (n=40 each), group (I) "Azithromycin group" that included patients received Azithromycin (500 mg/day for 5 days) orally and group (II) "Azithromycin + Rosuvastatin group" that included patients received Azithromycin by oral route as group (I) plus Rosuvastatin 20 mg/day orally. All included cases were subjected to full history taking, clinical examination and laboratory investigations and after treatment, the outcome measures were reported and compared. Results No significant differences were observed between groups regarding demographic and baseline characteristics. Also, the two groups were comparable with no significant differences in pulse rate, blood sugar, CBC, electrolyte elements, liver enzymes, and kidney function (a slight reduction was noticed in group II). While, Ferritin level was significantly lower in group (II) compared to group (I), (830 +/- 72.5 vs. 865 +/- 69.5, p=0.03). No significant differences were observed among groups as regards Troponin level (p=0.56) "Only one case was positive in group (I)". Both groups were almost comparable without significant differences in both stages of infection and mortality (p=0.38 and 1.0, respectively). Conclusion Rosuvastatin did not have a significant role in the protection of Azithromycin-induced cardiotoxicity, it slightly ameliorates the biochemical and stress markers alterations of Azithromycin. Further larger studies are warranted for investigating this issue. Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.

P17-03 New approach methodologies to evaluate botanical safety

Natural products, such as botanical dietary supplements, are used globally and in some regions growing in their popularity and use, especially in the current COVID-19 pandemic. Ensuring the safety of these products is an important public health priority. Botanicals are naturally complex, with varying chemical compositions due to factors such as differences in growing conditions, extraction processes, and/or changes to the finished product. Globally, conventional in vivo and in vitro testing schemes are built on single chemicals, not on complex mixtures such as botanical products. Because of the chemical variability and a reliance on history of use data, toxicity data for many botanical mixtures are lacking and few tools have been tested for their suitability for these complex mixtures. A cross-sector collaboration between scientists in industry, government, and academia for botanical safety has been initiated with the goal of providing a sound scientific basis for integrating existing data with new approach methodologies to evaluate botanical safety. Thirteen botanicals with existing toxicity and/or clinical information available were chosen as initial candidates to evaluate various in silico and in vitro assays for their suitability to detect toxicological endpoints. Characterization of all thirteen botanicals was completed in early 2022, with quantification information obtained for selected individual constituents. Using this information as well as already available constituent details in the literature, the suitability of various in silico models and their use in various aspects of botanical safety evaluation were explored;as a screening step in an overall safety assessment for specific toxicological endpoints (e.g., genotoxicity, DART), to predict pharmacokinetic properties for use in PBPK modeling, and to predict formation of potentially toxic metabolites. Planned in vitro studies targeting specific endpoints of interest (hepatotoxicity, genotoxicity, developmental and reproductive toxicity, neurotoxicity, cardiotoxicity, and systemic toxicity) will be initiated mid-2022. This presentation will provide an overview of work completed to-date as well as a summary of the test materials, planned assays, and learnings to-date regarding advancements available for botanical safety assessment. Copyright © 2022 Elsevier B.V.