Lipophilicity profiling of anthracycline antibiotics by microemulsion electrokinetic chromatography-effects on cardiotoxicity and endotheliotoxicity.

Accurate profiling of the lipophilicity of amphoteric compounds might be complex and laborious. In the present work the lipophilicity of 12 anthracycline antibiotics-four parent drugs: doxorubicin, daunorubicin, epidoxorubicin, and epidaunorubicin and eight novel formamidyne derivatives with attached morpholine, hexamethylenoimine or piperidine rings-was determined based on novel approach using MEEKC. In the second stage, lipophilicity was correlated with anthracycline toxicity towards two cell lines. In rat cardiomyoblast cell line (h9c2) a significant correlation between the logP and toxicity was found. The anthracycline lipophilicity was not correlated with toxicity towards the endothelial hybrid cell line (EAhy.926). In conclusion, the lipophilicity of anthracyclines seems to determine their toxicity towards cardiomyoblasts but not on endothelial cells, suggesting a different mechanism of anthracyclines intercellular transport or extrusion in cardiomyoblast and endothelial cells.

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration-QTc Relationships.

"Thorough QT/corrected QT (QTc)" (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a diverse sample of human subjects can serve as a "TQT study in a dish." For 10 positive and 3 negative control drugs, in vitro concentration-QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration-QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10 ms QTc prolongation would be breached were also consistent with in vivo evidence. This "TQT study in a dish," consisting of a population-based iPSC-derived cardiomyocyte model and Bayesian concentration-QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern.

Association of occupational exposures with cardiovascular disease among US Hispanics/Latinos.

OBJECTIVE: Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the USA. The role of occupational exposures to chemicals in the development of CVD has rarely been studied even though many agents possess cardiotoxic properties. We therefore evaluated associations of self-reported exposures to organic solvents, metals and pesticides in relation to CVD prevalence among diverse Hispanic/Latino workers. METHODS: Cross-sectional data from 7404 employed individuals, aged 18-74 years, enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analysed. Participants from four US cities provided questionnaire data and underwent clinical examinations, including ECGs. CVD was defined as the presence of at least one of the following: coronary heart disease, atrial fibrillation, heart failure or cerebrovascular disease. Prevalence ratios reflecting the relationship between each occupational exposure and CVD as well as CVD subtypes were calculated using Poisson regression models. RESULTS: Hispanic/Latino workers reported exposures to organic solvents (6.5%), metals (8.5%) and pesticides (4.7%) at their current jobs. Overall, 6.1% of participants had some form of CVD, with coronary heart disease as the most common (4.3%) followed by cerebrovascular disease (1.0%), heart failure (0.8%) and atrial fibrillation (0.7%). For individuals who reported working with pesticides, the prevalence ratios for any CVD were 2.18 (95% CI 1.34 to 3.55), coronary heart disease 2.20 (95% CI 1.31 to 3.71), cerebrovascular disease 1.38 (95% CI 0.62 3.03), heart failure 0.91 (95% CI 0.23 to 3.54) and atrial fibrillation 5.92 (95% CI 1.89 to 18.61) after adjustment for sociodemographic, acculturation, lifestyle and occupational characteristics. Metal exposures were associated with an almost fourfold (3.78, 95% CI 1.24 to 11.46) greater prevalence of atrial fibrillation. Null associations were observed for organic solvent exposures. CONCLUSIONS: Our results suggest that working with metals and pesticides could be risk factors for CVD among Hispanic/Latino workers. Further work is needed to evaluate these relationships prospectively.

Diagnóstico y prevención de la cardiotoxicidad inducida por fármacos antineoplásicos: de la imagen a las tecnologías «ómicas» / Early diagnosis and prediction of anticancer drug-induced cardiotoxicity: from cardiac imaging to ‘omics’ technologies

La insuficiencia cardiaca secundaria al tratamiento del cáncer continúa siendo una causa significativa de morbilidad y mortalidad en el paciente oncológico. A menudo estos pacientes no tienen manifestaciones de la enfermedad hasta que la insuficiencia cardiaca se presenta. Sería necesario identificar de manera precisa qué individuos están en riesgo de cardiotoxicidad, incluso antes de las manifestaciones clínicas. El objetivo de este trabajo es ofrecer una revisión sobre el papel prometedor de las técnicas de imagen y las tecnologías «ómicas», especialmente la proteómica y la genómica, en la prevención y el diagnóstico precoz de la cardiotoxicidad, así como en la respuesta individual de cada paciente al tratamiento antineoplásico (AU)

Heart failure due to antineoplastic therapy remains a major cause of morbidity and mortality in oncological patients. These patients often have no prior manifestation of disease. There is therefore a need for accurate identification of individuals at risk of such events before the appearance of clinical manifestations. The present article aims to provide an overview of cardiac imaging as well as new ‘-omics’ technologies, especially with regard to genomics and proteomics as promising tools for the early detection and prediction of cardiotoxicity and individual responses to antineoplastic drugs (AU)

Top-down venomics of the East African green mamba, Dendroaspis angusticeps, and the black mamba, Dendroaspis polylepis, highlight the complexity of their toxin arsenals.

We report the characterization, by combination of high-resolution on-line molecular mass and disulfide bond profiling and top-down MS/MS analysis, of the venom proteomes of two congeneric African snake species of medical importance, Dendroaspis angusticeps (green mamba) and D. polylepis (black mamba). Each of these mamba venoms comprised more than two-hundred polypeptides belonging to just a few toxin families. Both venom proteomes are overwhelmingly composed of post-synaptically-acting short- and long-chain neurotoxins that potently inhibit muscle- and neuronal-type nicotinic acetylcholine receptors; muscarinic cardiotoxins; and dendrotoxins, that block some of the Kv1, n-class of K+ channels. However, the identity of the major proteins and their relative abundances exhibit marked interspecific variation. In addition, the greater resolution of the top-down venomic analytical approach revealed previously undetected protein species, isoforms and proteoforms, including the identification and precise location of modified lysine residues in a number of proteins in both venoms, but particularly in green mamba toxins. This comparative top-down venomic analysis unveiled the untapped complexity of Dendroaspis venoms and lays the foundations for rationalizing the notably different potency of green and black mamba lethal arsenals at locus resolution. SIGNIFICANCE PARAGRAPH: We report the characterization, by combination of high-resolution on-line molecular mass and disulfide bond profiling and top-down MS/MS analysis, of the venom proteomes of two congeneric African snake species of medical importance, Dendroaspis angusticeps (green mamba) and D. polylepis (black mamba). Each of these mamba venoms comprised more than two-hundred polypeptides belonging to just a few toxin families. Both venom proteomes are overwhelmingly composed of post-synaptically-acting short- and long-chain neurotoxins that potently inhibit muscle- and neuronal-type nicotinic acetylcholine receptors; muscarinic cardiotoxins; and dendrotoxins, that block some of the Kv1, n-class of K+ channels. However, the identity of the major proteins and their relative abundances exhibit marked interspecific variation. In addition, the greater resolution of the top-down venomic analytical approach revealed previously undetected protein species, isoforms and proteoforms, including the identification and precise location of modified lysine residues in a number of proteins in both venoms, but particularly in green mamba toxins. This comparative top-down venomic analysis unveiled the untapped complexity of Dendroaspis venoms and lays the foundations for rationalizing the notably different potency of green and black mamba lethal arsenals at locus resolution.

Confirmation of Stormwater Bioretention Treatment Effectiveness Using Molecular Indicators of Cardiovascular Toxicity in Developing Fish.

Urban stormwater runoff is a globally significant threat to the ecological integrity of aquatic habitats. Green stormwater infrastructure methods such as bioretention are increasingly used to improve water quality by filtering chemical contaminants that may be harmful to fish and other species. Ubiquitous examples of toxics in runoff from highways and other impervious surfaces include polycyclic aromatic hydrocarbons (PAHs). Certain PAHs are known to cause functional and structural defects in developing fish hearts. Therefore, abnormal heart development in fish can be a sensitive measure of clean water technology effectiveness. Here we use the zebrafish experimental model to assess the effects of untreated runoff on the expression of genes that are classically responsive to contaminant exposures, as well as heart-related genes that may underpin the familiar cardiotoxicity phenotype. Further, we assess the effectiveness of soil bioretention for treating runoff, as measured by prevention of both visible cardiac toxicity and corresponding gene regulation. We find that contaminants in the dissolved phase of runoff (e.g., PAHs) are cardiotoxic and that soil bioretention protects against these harmful effects. Molecular markers were more sensitive than visible toxicity indicators, and several cardiac-related genes show promise as novel tools for evaluating the effectiveness of evolving stormwater mitigation strategies.

Death of a South American fur seal (Arctocephalus australis) after the ingestion of toads--evaluation of toad poisoning by toxicological analysis.

Animals in zoological gardens are at risk of severe and even lethal poisoning when they accidentally ingest toads. Here we report the case of an eleven month old male South American fur seal (Arctocephalus australis) which was found dead in its outdoor enclosure in the zoo of Dortmund, Germany. Autopsy revealed the presence of two adult, partly digested common toads (Bufo bufo) in the stomach. Toxicological analysis of the stomach content using high performance liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF MS) proved the presence of bufadienolides, the major cardiotoxic components of toad poisons. Using electrochemical luminescens immunoassay (ECLIA) compounds equivalent to digitoxin were detected in the blood sample confirming the absorption of toad poison components from the intestines into the circulation potentially leading to cardiac failure. In zoological gardens special precautions are necessary to protect non-native animals from encountering toads and the risk of poisoning, particularly in early spring, the spawning period of the toads.

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

PURPOSE: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. METHODS: Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. RESULTS: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. CONCLUSIONS: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Unexpectedly high mortality in Pacific herring embryos exposed to the 2007 Cosco Busan oil spill in San Francisco Bay.

In November 2007, the container ship Cosco Busan released 54,000 gallons of bunker fuel oil into San Francisco Bay. The accident oiled shoreline near spawning habitats for the largest population of Pacific herring on the west coast of the continental United States. We assessed the health and viability of herring embryos from oiled and unoiled locations that were either deposited by natural spawning or incubated in subtidal cages. Three months after the spill, caged embryos at oiled sites showed sublethal cardiac toxicity, as expected from exposure to oil-derived polycyclic aromatic compounds (PACs). By contrast, embryos from the adjacent and shallower intertidal zone showed unexpectedly high rates of tissue necrosis and lethality unrelated to cardiotoxicity. No toxicity was observed in embryos from unoiled sites. Patterns of PACs at oiled sites were consistent with oil exposure against a background of urban sources, although tissue concentrations were lower than expected to cause lethality. Embryos sampled 2 y later from oiled sites showed modest sublethal cardiotoxicity but no elevated necrosis or mortality. Bunker oil contains the chemically uncharacterized remains of crude oil refinement, and one or more of these unidentified chemicals likely interacted with natural sunlight in the intertidal zone to kill herring embryos. This reveals an important discrepancy between the resolving power of current forensic analytical chemistry and biological responses of keystone ecological species in oiled habitats. Nevertheless, we successfully delineated the biological impacts of an oil spill in an urbanized coastal estuary with an overlapping backdrop of atmospheric, vessel, and land-based sources of PAC pollution.

Cardiotoxicidad asociada a trastuzumab en la práctica clínica asistencial / Cardiotoxicity associated with trastuzumab in normal clinical practice

Objetivo: Evaluar la incidencia de cardiotoxicidad asociada al tratamiento con trastuzumab en la práctica clínica asistencial, describiendo sus características, su manejo y los factores de riesgo asociados.Método: Estudio observacional retrospectivo que incluyó a pacientes con cáncer de mama HER-2 positivo en tratamiento con trastuzumab durante el primer trimestre de 2007 en un hospital de tercer nivel. Se realizó un seguimiento desde el inicio del tratamiento hasta fi nales de marzo de 2008. Las fuentes de datos utilizadas fueron el programa informático de oncología del servicio de farmacia, Oncowin®, y la historia clínica del paciente. Se recogieron variables relacionadas con las características basales del paciente, con el tratamiento y con la seguridad.Resultados: Se incluyó a 61 pacientes en el estudio; 19 (32,8 %) mujeres presentaron cardiotoxicidad, que supuso el segundo efecto adverso atribuido el tratamiento en frecuencia. La mediana de tiempo de aparición de la toxicidad fue de 7 meses, con un descenso medio de fracción de eyección del ventrículo izquierdo (FEVI) de 15,6 ± 9,1 puntos. En el 63,2 % fue sintomática, la manifestación más frecuente fue la disnea de esfuerzo y hubo un único caso de fallo cardíaco congestivo. La cardiotoxicidad supuso la suspensión del tratamiento en el 22,9 % del total de pacientes, y fue de forma defi nitiva en 7 de las 14 pacientes que interrumpieron el tratamiento. No se hallaron diferencias estadísticamente signifi cativas en cuanto a los posibles factores de riesgo.Conclusiones: La incidencia de cardiotoxicidad en la práctica clínica asistencial se muestra mucho más elevada que la esperada. Su importante implicación clínica y el uso creciente de trastuzumab hacen que suponga un nuevo reto para el tratamiento óptimo del cáncer de mama HER-2 positivo (AU)

Objective: To evaluate the incidence of cardiotoxicity associated with treatment with trastuzumab in clinical practice by describing its characteristics, progress and associated risk factors.Methods: Retrospective observational study of patients with HER2-positive breast cancer treated with trastuzumab in the fi rst quarter of 2007 in a tertiary hospital. Follow-up was performed from start of treatment until the end of March 2008. The data sources used were the oncological computer program Oncowin® from the pharmacy department and the patient clinical history. We gathered variables related to patient baseline characteristics, treatment and safety.Results: The study included 61 patients. 19 women (32.8 %) presented cardiotoxicity, which was the second most common adverse affect of those frequently attributed to the treatment. The average time for toxicity to appear was 7 months, with an average FEVI decrease of 15.6 ± 9.1 points. In 63.2 % of the patients it was symptomatic, and its most frequent manifestation was stress-induced dyspnoea, with a single case of congestive heart failure. Cardiotoxicity led to suspension of treatment in 22.9 % of the total patients, which was defi nitive for 7 out of the 14 patients who interrupted the treatment. No statistically signifi cant differences were found for the possible risk factors.Conclusions: The incidence of cardiotoxicity in clinical practice is much higher than expected. The important clinical implication of this information and the increasing use of trastuzumab mean that there is a new challenge for the optimal treatment of HER2-positive breast cance (AU)