Cardiotoxic Properties Research Articles

Comprehensive assessment of subchronic low-dose exposure to doxorubicin in the Wistar rat model

Rationale. Doxorubicin is a chemotherapeutic antibiotic from the anthracycline class that has cumulative and dose-dependent cardiotoxic effects. The cardiotoxic properties of doxorubicin are manifested in characteristic pathologies of the heart and its microenvironment. Doxorubicin also exhibits genotoxic properties and is often used to model acute genotoxic effects in small laboratory animal models.Aim: To evaluate chronic low-dose exposure to doxorubicin in a Wistar rat model using cytogenetic methods and electron microscopy.Material and Methods. The study included two groups of 10 male Wistar rats: an experimental group (weekly doxorubicin in the tail vein 2 mg/kg for 4 weeks) and a control group (0.9% NaCl). A micronucleus test was used to evaluate genotoxic effects. Visualization of the myocardial structure was carried out using scanning electron microscopy in back-scattered electrons on an electron microscope.Results. The analysis showed a significant difference between the control (0.8%) and experimental groups (3.2%) in the level of polychrome erythrocytes with a micronucleus. It was found that rats from the experimental group were characterized by a significant decrease in the number of polychromatic red blood cells compared to the control group. In the experimental group, pronounced heterogeneity of the morphological structure of the myocardium was noted. Electron micrographs of hepatocytes from rats treated with doxorubicin showed degenerative changes in the structure of liver cells.Conclusion. The results of our study provide insight into the subacute effect of a small dose of doxorubicin on the heart, liver and hematopoietic system of normolipidemic Wistar rats. We have proposed mechanisms of interaction between important organs and systems of the body exposed to doxorubicin against the background of a general pathological condition. In the future, the nature of the toxic effects of lower and optimal doses of the mutagen in the context of subchronic cumulative exposure should be determined.

Fasting: A Complex, Double-Edged Blade in the Battle Against Doxorubicin-Induced Cardiotoxicity.

In recent years, there has been a surge in the popularity of fasting as a method to enhance one's health and overall well-being. Fasting is a customary practice characterized by voluntary refraining from consuming food and beverages for a specified duration, ranging from a few hours to several days. The potential advantages of fasting, including enhanced insulin sensitivity, decreased inflammation, and better cellular repair mechanisms, have been well documented. However, the effects of fasting on cancer therapy have been the focus of recent scholarly investigations. Doxorubicin (Dox) is one of the most widely used chemotherapy medications for cancer treatment. Unfortunately, cardiotoxicity, which may lead to heart failure and other cardiovascular issues, has been linked to Dox usage. This study aims to comprehensively examine the possible advantages and disadvantages of fasting concerning Dox-induced cardiotoxicity. Researchers have investigated the potential benefits of fasting in lowering the risk of Dox-induced cardiac damage to solve this problem. Nevertheless, new studies indicate that prolonged alternate-day fasting may adversely affect the heart's capacity to manage the cardiotoxic properties of Dox. Though fasting may benefit overall health, it is essential to proceed cautiously and consider the potential risks in certain circumstances.

Total Synthesis of (+)‐Kalmanol

AbstractKalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. We have achieved the efficient total synthesis of (+)‐kalmanol in 22 steps with 2.3 % yield. The synthesis featured a Rh‐catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton.

Total Synthesis of (+)-Kalmanol.

Kalmanol, the flagship member of the kalmane diterpene family, possesses a complex and highly oxidized 5/5/8/5 tetracyclic skeleton with nine contiguous stereocenters and exhibits significant analgesic effects and cardiotoxic properties. We have achieved the efficient total synthesis of (+)-kalmanol in 22 steps with 2.3 % yield. The synthesis featured a Rh-catalyzed [5+2+1] cycloaddition reaction to construct 5/5/8 tricyclic skeleton, and a meticulously designed sequence of stereoselective oxidations of the 5/5/8/5 tetracyclic skeleton.

COMBINATORIAL IMMUNE CHECKPOINT BLOCKADE INCREASES MYOCARDIAL SECRETION OF H–FABP, NT–PRO–BNP, NLRP–3 INFLAMMASOME, INTERLEUKIN–1Β AND INTERLEUKIN–6: BIOCHEMICAL IMPLICATIONS IN CARDIO–IMMUNO–ONCOLOGY

Abstract Background Immune checkpoint blockade have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA–4 or PD–1 or PDL–1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti–LAG3 monoclonal antibody, Relatlimab, has been approved by FDA for combinatorial treatment with Nivolumab for metastatic melanoma. Moreover, anti PD–L1 blocking agent Atezolizumab is actually under study in association with Ipilimumab as innovative thearpy for metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies and the use of new targets in immunotherapy could expose patients to more adverse cardiovascular events. Purpose In this study, we highlighted the cardiotoxic properties of new Combinatorial immune checkpoint blockade therapies. Methods Human cardiomyocytes co–cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD–L1 and CTLA–4 or PD–1 and LAG–3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H–FABP, NT–Pro–BNP), NLRP3–inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Results Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co–cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD–L1/CTLA–4 blocking agents, and 35.7% higher in PD–1/LAG–3 blocking agents compared to monotherapies. NT–Pro–BNP and H–FABP, were also strongly increased in combination therapy with respect to monotherapies. NLRP3, IL–6 and IL–1β levels were also increased by PDL–1/CTLA–4 and PD–1/LAG–3 combined blocking agents compared to untreated cells and monotherapies. Conclusion Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro– inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Abstract LB180: Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison

Abstract Introduction. Cardiotoxicity is an important side effect limiting the clinical use of all anthracyclines, including doxorubicin (DOX). DOX targets topoisomerase II alpha (Top2α) and beta (Top2β), two enzymes that regulate DNA topology. Top2β is present in cardiomyocytes and has been proposed as a major contributor to DOX-induced cardiotoxicity. Annamycin (ANN), a novel clinically evaluated DOX analog, displays suppressed or no cardiotoxic properties in preclinical in vivo experiments. The objective of this study was to directly assess and compare the potency of DOX and ANN against Top2α and Top2β and determine their impact on physiology of human cardiomyocytes and mice hearts following chronic exposure. Our initial data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Methods. The potency of ANN and DOX to inhibit Top2 was tested in DNA relaxation assays using recombinant Top2α and Top2β with kinetoplast as the DNA substrate. ANN and DOX cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models. Cardiotoxicity of liposome formulated ANN (L-ANN) is currently being examined in ongoing clinical studies of subjects with acute myeloid leukemia (NCT05319587) or soft tissue sarcoma with metastases to the lungs (NCT04887298). Results. The nanomolar range potency of ANN in tested cancer cell lines was 2-10 times greater than that of DOX. The DNA relaxation assay demonstrated high potency of ANN against recombinant Top2α and Topβ with IC50 values 0.23±0.06 and 0.22± 0.06 µM, respectively, whereas the IC50 for DOX was 0.65± 0.22 and 0.34± 0.31µM, respectively. Importantly, ANN did not significantly affect electric potential, contractility, and viability of human cardiomyocytes up to highest tested dose of 1,500 nM (72h exposure). In contrast, DOX caused a dramatic change in heart beating rate and decreased in contractility and field potential amplitude. In rat cardiomyocyte culture (H92C), ANN was 14-fold less cytotoxic than DOX (IC50 1,264 nM for ANN vs. 88 nM for DOX). No cardiotoxicity of L-ANN was detected in myocardium of nude mice exposed weekly for 12 weeks to therapeutic doses of L-ANN (4 mg/kg, 40% of LD10). Finally, data from ongoing clinical trials revealed no drug related cardiac events in patients receiving L-ANN (confirmed by an independent review of the Duke’s ECHO core laboratory, USA). Conclusions. Our preclinical studies demonstrate non-cardiotoxic properties of ANN. These data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Interestingly, ANN appeared to be a significantly more potent inhibitor of Top2β than DOX, suggesting that Top2β may not be a universal mediator of cardiotoxicity of anthracyclines. Additional studies are needed to reevaluate the role of Top2β in anthracycline-induced cardiotoxicity. Citation Format: Rafal J. Zielinski, Krzysztof Grela, Roberto Cardenas-Zuniga, Stanislaw Skora, Izabela Fokt, Mihai Gagea, Wolfram Dempke, Waldemar Priebe. Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB180.

Statins and highly sensitive cardiac troponins: cardiotoxicity or cross-reactivity?

To date, hypolipidemic drugs of the statin group are among the most popular therapeutic agents used for the prevention and treatment of the most common worldwide atherosclerotic cardiovascular diseases (CVD). Therefore, considerable attention of researchers is focused on statins to study the additional effects of these drugs, which is accompanied by the discovery of new mechanisms of action and properties that should be taken into account to optimize the tactics of managing patients with CVD. In addition to the key lipid-lowering effect of statins associated with the inhibition of the ratelimiting enzyme (3-hydroxy-3-methylglutaryl-coenzyme A reductase), researchers report a variety of other properties of these drugs. Important circumstances contributing to the disclosure of new effects of statins are: improvement of research methods, and first of all, their sensitivity and specificity; the discovery of new molecules and molecular pathways that may be affected by statins. In general, the currently established numerous non-lipid effects of statin drugs can be divided into two groups: favorable and side effects, which must be taken into account when managing patients with CVD and comorbid diseases. Thanks to recent studies using modern clinical diagnostic cardiomarkers (highly sensitive cardiac troponins (CT)), molecular genetic and morphological methods, potential cardiotoxic properties of statin group drugs have been identified. Of particular concern are the data on a statininduced increase in the concentration of highly sensitive CT, which are a key and generally recognized criterion for myocardial damage. In this article we discuss possible mechanisms of increasing the concentration of CT and cardiotoxic effects when using statins.

Machine-learning-based similarity meets traditional QSAR: “q-RASAR” for the enhancement of the external predictivity and detection of prediction confidence outliers in an hERG toxicity dataset

Recently, the concept of quantitative Read-Across Structure-Activity Relationship (q-RASAR) has been introduced by using various Machine Learning (ML) - derived similarity functions in the traditional quantitative structure-activity relationship (QSAR) modeling framework with the objective of enhancing the external predictivity of models while using the same available chemical information content. The present study uses the hERG K+ channel inhibition cardiotoxicity, a pharmaceutically relevant endpoint, as the modeling set for making predictions using the novel q-RASAR approach, as the approach combines the merits of QSAR and Read-Across, and generates simple and interpretable models using various similarity and error-based measures as descriptors. The cardiotoxicity data (in terms of pIC50 values) were collected from the literature. The curated data set was then divided into training and test sets using the sorted response-based division algorithm. The important set of features was identified based on the internal validation metrics of initial genetic algorithm models. Based on the features selected in the final Multiple Linear Regression (MLR) model, RASAR descriptors were computed using a tool available from https://sites.google.com/jadavpuruniversity.in/dtc-lab-software/home. The RASAR descriptors were then merged with the previously selected features, and an MLR q-RASAR model was generated using the grid search approach. The prediction outliers were then identified using the novel DTC Applicability Domain Plot, and the q-RASAR models were used for predictions after the removal of prediction outliers. A final Partial Least Squares (PLS) q-RASAR model was generated to obviate inter-correlation among descriptors. Various other Machine Learning approaches were also employed with the optimization of relevant hyperparameters based on the cross-validation approach, and the final test set prediction results were compared. Based on the performance in the test set predictions and interpretability, the PLS q-RASAR model was chosen as the final model which provided enhanced predictivity in comparison to previously reported models even without using 3-D descriptors. This model can thus be used for the quick screening of molecules, even before their synthesis, to estimate their cardiotoxic potential thus prioritizing molecules for further experimental testing in the drug discovery pipeline. A Java-based prediction tool has also been developed for the quick screening of cardiotoxic properties of query compounds and made available from https://sites.google.com/jadavpuruniversity.in/dtc-lab-software/home.

Selenium alleviates endoplasmic reticulum calcium depletion-induced endoplasmic reticulum stress and apoptosis in chicken myocardium after mercuric chloride exposure.

Mercury is a highly toxic heavy metal with definite cardiotoxic properties and can affect the health of humans and animals through diet. Selenium (Se) is a heart-healthy trace element and dietary Se has the potential to attenuate heavy metal-induced myocardial damage in humans and animals. This study was designed to explore antagonistic effect of Se on the cardiotoxicity of mercuric chloride (HgCl2) in chickens. Hyline brown hens received a normal diet, a diet containing 250mg/L HgCl2, or a diet containing 250mg/L HgCl2 and 10mg/kg Na2SeO3 for 7weeks, respectively. Histopathological observations demonstrated that Se attenuated HgCl2-induced myocardial injury, which was further confirmed by the results of serum creatine kinase and lactate dehydrogenase levels assay and myocardial tissues oxidative stress indexes assessment. The results showed that Se prevented HgCl2-induced cytoplasmic calcium ion (Ca2+) overload and endoplasmic reticulum (ER) Ca2+ depletion mediated by Ca2+-regulatory dysfunction of ER. Importantly, ER Ca2+ depletion led to unfolded protein response and endoplasmic reticulum stress (ERS), resulting in apoptosis of cardiomyocytes via PERK/ATF4/CHOP pathway. In addition, heat shock protein expression was activated by HgCl2 through these stress responses, which was reversed by Se. Moreover, Se supplementation partially eliminated the effects of HgCl2 on the expression of several ER-settled selenoproteins, including selenoprotein K (SELENOK), SELENOM, SELENON, and SELENOS. In conclusion, these results suggested that Se alleviated ER Ca2+ depletion and oxidative stress-induced ERS-dependent apoptosis in chicken myocardium after HgCl2 exposure.

Review of Recent Laboratory and Experimental Data on Cardiotoxicity of Statins.

Due to the fact that statins are among the most high-demand therapeutic agents used for the treatment and prevention of the most common cardiovascular diseases, a significant amount of research is focused on these drugs. As a result, the study and discovery of new effects in statin drugs continues. Research methods are constantly being improved in terms of their sensitivity and specificity, which leads to a change in ideas. In addition to the main lipid-lowering effect, statins have a number of additional effects, which can be conditionally divided into positive (pleiotropic) and negative (side effects). Moreover, information about many of the pleiotropic effects of statins is controversial and may subsequently change as new data become available. To a large extent, this is due to the introduction of new and the improvement of old methods of study: clinical, laboratory and morphological ones. Recent studies report the possibility of statins having potential cardiotoxic properties, which is expressed by an increase in the concentration of highly sensitive cardiac troponins, as well as various adverse changes in cardiac myocytes at the ultrastructural and molecular levels. This paper discusses possible mechanisms of statin cardiotoxicity. This narrative review is based on an analysis of publications in the Medline, PubMed, PubMed Central and Embase databases. The terms "statins", "troponin", "troponin I", "troponin T" in combination with "cardiotoxicity", "false positive", "mechanisms of increase", "pathophysiological mechanisms", "oxidative stress" and "cardiomyocyte apoptosis" were used to search publications.

Repeated and On-Demand Intracellular Recordings of Cardiomyocytes Derived from Human-Induced Pluripotent Stem Cells.

Pharmaceutical compounds may have cardiotoxic properties, triggering potentially life-threatening arrhythmias. To investigate proarrhythmic effects of drugs, the patch clamp technique has been used as the gold standard for characterizing the electrophysiology of cardiomyocytes in vitro. However, the applicability of this technology for drug screening is limited, as it is complex to use and features low throughput. Recent studies have demonstrated that 3D-nanostructured electrodes enable to obtain intracellular signals from many cardiomyocytes in parallel; however, the tedious electrode fabrication and limited measurement duration still remain major issues for cardiotoxicity testing. Here, we demonstrate how porous Pt-black electrodes, arranged in high-density micro-electrode arrays, can be used to record intracellular-like signals of cardiomyocytes at large scale repeatedly over an extended period of time. The developed technique, which yields highly parallelized electroporations using stimulation voltages around 1 V peak-to-peak amplitude, enabled intracellular-like recordings at high success rates without causing significant alteration in key electrophysiological features. In a proof-of-concept study, we investigated electrophysiological modulations induced by two clinically applied drugs, nifedipine and quinidine. As the obtained results were in good agreement with previously published data, we are confident that the developed technique has the potential to be routinely used in in vitro platforms for cardiotoxicity screening.

Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo.

Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.

Circulating Microbiota in Cardiometabolic Disease.

The rapid expansion of microbiota research has significantly advanced our understanding of the complex interactions between gut microbiota and cardiovascular, metabolic, and renal system regulation. Low-grade chronic inflammation has long been implicated as one of the key mechanisms underlying cardiometabolic disease risk and progression, even before the insights provided by gut microbiota research in the past decade. Microbial translocation into the bloodstream can occur via different routes, including through the oral and/or intestinal mucosa, and may contribute to chronic inflammation in cardiometabolic disease. Among several gut-derived products identifiable in the systemic circulation, bacterial endotoxins and metabolites have been extensively studied, however recent advances in microbial DNA sequencing have further allowed us to identify highly diverse communities of microorganisms in the bloodstream from an -omics standpoint, which is termed “circulating microbiota.” While detecting microorganisms in the bloodstream was historically considered as an indication of infection, evidence on the circulating microbiota is continually accumulating in various patient populations without clinical signs of infection and even in otherwise healthy individuals. Moreover, both quantitative and compositional alterations of the circulating microbiota have recently been implicated in the pathogenesis of chronic inflammatory conditions, potentially through their immunostimulatory, atherogenic, and cardiotoxic properties. In this mini review, we aim to provide recent evidence on the characteristics and roles of circulating microbiota in several cardiometabolic diseases, such as type 2 diabetes, cardiovascular disease, and chronic kidney disease, with highlights of our emerging findings on circulating microbiota in patients with end-stage kidney disease undergoing hemodialysis.

DDX3X alleviates doxorubicin-induced cardiotoxicity by regulating Wnt/β-catenin signaling pathway in an in vitro model.

The life‐threatening adverse effects of doxorubicin (Dox) caused by its cardiotoxic properties limit its clinical application. DDX3X has been shown to participate in a variety of physiological processes, and it acts as a regulator of Wnt/β‐catenin signaling. However, the role of DDX3X in Dox‐induced cardiotoxicity (DIC) remains unclear. In this study, we found that DDX3X expression was significantly decreased in H9c2 cardiomyocytes treated with Dox. Ddx3x knockdown and RK‐33 (DDX3X ATPase activity inhibitor) pretreatment exacerbated cardiomyocyte apoptosis and mitochondrial dysfunction induced by Dox treatment. In contrast, Ddx3x overexpression ameliorated the DIC response. Moreover, Wnt/β‐catenin signaling in cardiomyocytes treated with Dox was suppressed, but this suppression was reversed by Ddx3x overexpression. Overall, this study demonstrated that DDX3X plays a protective role in DIC by activating Wnt/β‐catenin signaling.

Proteomic analysis reveals rattlesnake venom modulation of proteins associated with cardiac tissue damage in mouse hearts

Snake envenomation is a common but neglected disease that affects millions of people around the world annually. Among venomous snake species in Brazil, the tropical rattlesnake (Crotalus durissus terrificus) accounts for the highest number of fatal envenomations and is responsible for the second highest number of bites. Snake venoms are complex secretions which, upon injection, trigger diverse physiological effects that can cause significant injury or death. The components of C. d. terrificus venom exhibit neurotoxic, myotoxic, hemotoxic, nephrotoxic, and cardiotoxic properties which present clinically as alteration of central nervous system function, motor paralysis, seizures, eyelid ptosis, ophthalmoplesia, blurred vision, coagulation disorders, rhabdomyolysis, myoglobinuria, and cardiorespiratory arrest. In this study, we focused on proteomic characterization of the cardiotoxic effects of C. d. terrificus venom in mouse models. We injected venom at half the lethal dose (LD50) into the gastrocnemius muscle. Mouse hearts were removed at set time points after venom injection (1 h, 6 h, 12 h, or 24 h) and subjected to trypsin digestion prior to high-resolution mass spectrometry. We analyzed the proteomic profiles of >1300 proteins and observed that several proteins showed noteworthy changes in their quantitative profiles, likely reflecting the toxic activity of venom components. Among the affected proteins were several associated with cellular deregulation and tissue damage. Changes in heart protein abundance offer insights into how they may work synergistically upon envenomation. SignificanceVenom of the tropical rattlesnake (Crotalus durissus terririficus) is known to be neurotoxic, myotoxic, nephrotoxic and cardiotoxic. Although there are several studies describing the biochemical effects of this venom, no work has yet described its proteomic effects in the cardiac tissue of mice. In this work, we describe the changes in several mouse cardiac proteins upon venom treatment. Our data shed new light on the clinical outcome of the envenomation by C. d. terrificus, as well as candidate proteins that could be investigated in efforts to improve current treatment approaches or in the development of novel therapeutic interventions in order to reduce mortality and morbidity resulting from envenomation.

Citronellal alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and apoptosis via Na+ /H+ exchanger-1 inhibition.

The medical usage of Doxorubicin (DOX) as a chemotherapeutic agent is restricted owing to its cardiotoxic properties. This study was designed to explore the effect and underlying mechanisms of Citronellal (CT) on DOX-related cardiotoxicity in rats. Rats were divided into six groups: control, DOX, CT, Lithium chloride (LiCl) (a Na+/H+exchanger-1 [NHE1] activator), DOX + CT, and DOX + CT + LiCl. To induce cardiotoxicity, a cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats. CT (150 mg/kg) and LiCl (1 mg/kg) were given daily by oral gavage for 6 weeks. CT improved cardiac functional parameters and attenuated the cardiac pathological changes induced by DOX. Further study indicated that CT administration regulated the levels of oxidative stress and apoptosis-related factors and in myocardial tissues, reducing cell per-oxidative damage and apoptosis. Besides this, CT attenuated DOX-induced NHE1 upregulation, and the preventive effects of CT against DOX-induced cardiotoxicity were abrogated by the concurrent administration of LiCl. These results demonstrate that CT could ameliorate DOX-induced cardiotoxicity by inhibiting the NHE1-mediated oxidative stress, apoptosis in rats.

A COMPARATIVE STUDY OF 0.5 % BUPIVACAINE WITH FENTANYL VERSUS 0.75% ROPIVACAINE WITH FENTANYL IN EPIDURALANESTHESIA FOR ABDOMINAL HYSTERECTOMY

INTRODUCTION Abdominal hysterectomy (AH) is a quite common gynaecological surgical procedure and electively done under central neuraxial blockade. AH is performed for malignant as well as benign indications such as uterine leiomyoma, persistent vaginal bleeding, or pelvic organ prolapse. AIMS AND OBJECTIVES Compare the onset of motor and sensory block. Find out the duration of the sensory and motor blockade. Observe intraoperative hemodynamic changes and assess post-operative analgesia requirements in 24 hour. Duration of analgesia assessed by requirement of rst rescue analgesic. Observe any untoward incident during intraoperative and post-operative period and managed accordingly MATERIALS AND METHODS Study Area: Department of Anesthesiology & critical care, DARBHANGAMEDICALCOLLEGE AND HOSPITAL. Study Population: Adult patients (30- 65 years) undergoing elective abdominal hysterectomy with regional anaesthesia were included for this study. Study Period:January 2019 to March 2020 Sample Design: Subjects were divided into two groups (n=35) equal in numbers and they sampled as per computerized randomization chart. These patients were divided into two groups, group B (with epidural 0.5% bupivacaine and 100g fentanyl) and group R (with epidural 0.75% ropivavaine and 100g fentanyl). Study Design: Prospective, open, randomized, controlled study. RESULTS: In Our study showed that 3.38kg/m2 and 24.86 3.60 kg/m2in group B and R respectively. The duration of surgery was 100.86 9.35minutes and 98.86 8.32 minutes and the duration of stay, was4.86 0.81days and 4.60 0.914 days in group B and group R respectively. Now with comparison of both groups, time to onset of sensory block (uptoT6) has signicant variation. But the other parameters namely, time to onset of motor block, two segment regression or duration of sensory block, rescue analgesia timing and complete motor recovery time were comparable and not signicant statistically in both groups. SUMMARY & CONCLUSIONS To conclude that in the present study using 0.5% bupivacaine with fentanyl and 0.75% ropivacaine with fentanyl epidurally, ropivacaine produced an earlier onset but similar duration of sensory block. The onset, quality and duration of motor block werecomparable in both the groups. It is important that new local anaesthetics with lower cardiotoxic property are adopted to ensure that regional techniques using large amounts of local anaesthetics remain safe with minimal complications. The recovery prole of ropivacaine may be useful where prompt mobilization is require

A TRADITIONAL MEDICINE PRACTICE IN SNAKEBITE

Snakebite is one of the main causes of morbidity and mortality in Turkey, especially in rural areas. There are 41 snake species living in Turkey, 28 of which are non-poisonous and 13 are venomous. Of these 13 venomous snakes, 10 species are from the Viperidae family, 2 species from the Colubridae and 1 species from the Elapidae (Cobras) family and can be lethal with the venom they inject when they bite. The venom has mostly hematotoxic rarely neurotoxic effects. In addition to these effects, it also has cardiotoxic, myotoxic and nephrotoxic properties. A 50-year-old female patient was admitted to the emergency department 30-40 minutes after her left hand was bitten by a snake bite from the second finger. The patient, who was conscious, agitated and restless, had ecchymosis, widespread edema, pain and tenderness at the wound site. The wound area was cleaned with an antiseptic solution, 80 mg Prednisolone, 20 snake antiserum, 100 mg ulcer and tetanus prophylaxis were administered in the emergency room. The patient was absorbed 80-90 cc of fluid and blood absorption from three different areas on the left hand using the cupping vacuum method, then a splint was taken and elevation was performed. In the examination of the patient 20 hours after the application, edema in the hand decreased, swelling decreased, limitation of movement disappeared and the patient had minimal pain. The blood parameters of the patient were checked and evaluated as normal. The patient was discharged in a healthy way after 40 hours of admission to the hospital, following control and follow-up. As in our case, it should not be forgotten that besides all modern medical practices, cupping absorption therapy, which is a traditional medical treatment, is also very important in terms of supportive treatment and local tissue.

Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19–31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82–1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes.