Safety and possible anti-inflammatory effect of paclitaxel associated with LDL-like nanoparticles (LDE) in patients with chronic coronary artery disease: a double-blind, placebo-controlled pilot study

IntroductionStudies in cholesterol-fed rabbits showed that anti-proliferative chemotherapeutic agents such as paclitaxel associated with solid lipid nanoparticles (LDE) have marked anti-atherosclerotic effects. In addition, association with LDE nearly abolishes paclitaxel toxicity. We investigated whether treatment with LDE-paclitaxel changes plaque progression by coronary CT angiography and is safe in patients with chronic coronary artery disease.MethodsWe conducted a prospective, randomized, double-blind, placebo-controlled pilot study in patients with multi-vessel chronic coronary artery disease. Patients were randomized to receive IV infusions of LDE-paclitaxel (paclitaxel dose: 175 mg/m2 body surface) or LDE alone (placebo group), administered every 3 weeks for 18 weeks. All participants received guideline-directed medical therapy. Clinical and laboratory safety evaluations were made at baseline and every 3 weeks until the end of the study. Analysis of inflammatory biomarkers and coronary CTA was also performed at baseline and 4 weeks after treatment.ResultsForty patients aged 65.6 ± 8 years, 20 in LDE-paclitaxel and 20 in placebo group were enrolled. Among those, 58% had diabetes, 50% had myocardial infarction, and 91% were in use of statin and aspirin. Baseline demographics, risk factors, and laboratory results were not different between groups. In all patients, no clinical or laboratory toxicities were observed. From the baseline to the end of follow-up, there was a non-significant trend toward a decrease in IL-6 levels and hsCRP in the LDE-paclitaxel group (−16% and −28%, respectively), not observed in placebo. Regarding plaque progression analysis, variation in plaque parameter values was wide, and no difference between groups was observed.ConclusionIn patients with multivessel chronic coronary artery disease and optimized medical therapy, LDE-paclitaxel was safe and showed clues of potential benefits in reducing inflammatory biomarkers.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT04148833, identifier (NCT04148833)

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Effect of paclitaxel associated with lipid nanoparticles in patients with coronary artery disease: a double-blind, placebo-controlled study

Introdução: As doenças cardiovasculares são as principais causas de óbito global. Atualmente, reconhece-se que sua base fisiopatológica consiste não apenas do acúmulo de lípides na parede arterial, como também de uma resposta inflamatória crônica à lesão vascular. Tendo em vista o importante componente proliferativo-inflamatório no desenvolvimento e progressão da doença aterosclerótica, uma estratégia de tratamento baseada em fármacos antiproliferativos e imunomoduladores, como os usados no tratamento do câncer, pode ser uma nova rota terapêutica promissora. Em modelos animais, foi demonstrado que após injeção endovenosa, as nanopartículas lipídicas (LDE) se ligam aos receptores de LDL, concentrando-se nas placas ateroscleróticas. Quando tratados com paclitaxel associado à LDE, verificamos uma redução de 60% das lesões ateroscleróticas na aorta desses animais, não sendo observado sinais de toxicidade importante. Métodos: Trata-se de estudo prospectivo, randomizado, duplo cego, controlado por placebo que incluiu indivíduos acima de 18 anos com doença arterial coronariana (DAC) multiarterial. Os pacientes, foram randomicamente alocados em dois grupos: um grupo tratado com LDE-paclitaxel e um grupo placebo. Os pacientes receberam por via endovenosa 175 mg/m2 de LDEpaclitaxel ou placebo uma vez a cada 3 semanas por 18 semanas. Os pacientes de ambos os grupos mantiveram terapia medicamentosa otimizada para DAC, conforme as diretrizes atuais. Em ambos os grupos, os pacientes foram submetidos à angiotomografia computadorizada de coronárias e à determinação de marcadores inflamatórios antes da primeira dose da medicação e até 4 semanas após a última dose da medicação. Além disso, foram realizados exames clínicos e laboratoriais a cada 3 semanas em todos os pacientes, a fim de avaliar toxicidade medicamentosa e incidência de eventos adversos. Resultados: Foram randomizados 40 indivíduos com uma média de idade de 65,6 ± 8 anos, em uma proporção de 1:1 entre os grupos. Um total de 58% dos indivíduos apresentava diabetes, 50% história de IAM e 91% dos pacientes estavam em uso de estatina e aspirina. Não houve diferença em relação às características basais clínicas e laboratoriais em ambos os grupos. Em nenhum paciente incluído no estudo foi observada toxicidade clínica ou laboratorial importante. Em relação aos biomarcadores inflamatórios, houve uma tendência não significativa de redução dos níveis de IL-6 e PCRus no grupo LDE-paclitaxel (-16% e -28%, respectivamente), sendo que o mesmo achado não foi observado no grupo placebo. Em relação à progressão angiotomográfica da placa aterosclerótica, os volumes médios de placas apresentaram grande variação, sendo que nenhuma diferença foi observada entre os grupos durante após o seguimento. Conclusão: O uso da formulação LDE-paclitaxel mostrou-se segura em pacientes com DAC multiarterial e com um potencial efeito na modulação da resposta inflamatória através da via da IL-6Introduction: Cardiovascular diseases are the leading cause of global mortality. It is widely acknowledged that their pathophysiological foundation encompasses not only the accumulation of lipids within the arterial wall but also a chronic inflammatory response to vascular injury. Considering the pivotal role of the immune component in the development and progression of atherosclerosis, a strategy based on antiproliferative and immunomodulatory therapy may represent a promising novel therapeutic pathway. In animal models, it has been shown that lipid nanoparticles (LDE) bind to LDL receptors and preferentially accumulate within atherosclerotic plaques. Treatment with paclitaxel associated with LDE reduced aortic atherosclerotic lesions by 60% in these animals without adverse effects. Methods: We conducted a prospective, randomized, double-blinded, placebo-controlled study that included individuals older than 18 with coronary artery disease (CAD), and optimized medical therapy. Patients were randomly assigned to receive LDEpaclitaxel or placebo. Patients received 175 mg/m² of LDE-paclitaxel or placebo intravenously every 21 days for 6 times. All patients underwent coronary CT angiography and had inflammatory biomarker levels assessed at baseline and at the end of follow-up. Furthermore, clinical and laboratory assessments were performed every three weeks to evaluate toxicity and incidence of adverse events. Results: A total of 40 individuals were randomized in a 1:1 ratio. Among those, 58% had diabetes, 50% had myocardial infarction, and 91% were in use of statin and aspirin. Baseline demographics, risk factors, and laboratory results were not different between groups. In all patients, no clinical or laboratory toxicities were observed. From the baseline to the end of follow-up, there was a non-significant trend toward a decrease in IL-6 levels and hsCRP in the LDE-paclitaxel group (-16% and - 28%, respectively), not observed in placebo. Regarding plaque progression analysis, variation in plaque parameter values was wide, and no difference between groups was observed. Conclusion: In SCAD patients with multivessel disease, LDE-paclitaxel was safe and showed clues of potential benefits in reducing inflammatory biomarkers associated with cardiovascular diseas

Genomic evidence of recent hybridization between sea turtles at Abrolhos Archipelago and its association to low reproductive output

Hybridization between sea turtle species occurs with particularly high frequency at two adjacent nesting areas in northeastern Brazil. To understand the outcomes of hybridization and their consequences for sea turtle conservation, we need to evaluate the extent of hybridization occurrence and possible deleterious effects in the hybrid progeny. Thus, we investigated the hypothesis of the existence of a new hybrid spot offshore of Brazil’s northeastern coast. The Abrolhos Archipelago is surrounded by the largest and richest coral reefs in the South Atlantic and is known to be a nesting site for loggerhead turtles (Caretta caretta). In this study, we performed a multidisciplinary investigation into levels of hybridization in sea turtles and their reproductive output in the Abrolhos beaches. Genetic data from mitochondrial DNA (mtDNA) and six autosomal markers showed that there are first-generation hybrid females nesting in Abrolhos, resulting from crossings between hawksbill males (Eretmochelys imbricata) and loggerhead females, and backcrossed hatchlings from both parental species. The type and extent of hybridization were characterized using genomic data obtained with the 3RAD method, which confirmed backcrossing between F1 hybrids and loggerhead turtles. The reproductive output data of Abrolhos nests suggests a disadvantage of hybrids when compared to loggerheads. For the first time, we have shown the association between hybridization and low reproductive success, which may represent a threat to sea turtle conservation

Biomaterials and Adipose-Derived Mesenchymal Stem Cells for Regenerative Medicine: A Systematic Review

The use of biological templates for the suitable growth of adipose-derived mesenchymal stem cells (AD-MSC) and “neo-tissue” construction has exponentially increased over the last years. The bioengineered scaffolds still have a prominent and biocompatible framework playing a role in tissue regeneration. In order to supply AD-MSCs, biomaterials, as the stem cell niche, are more often supplemented by or stimulate molecular signals that allow differentiation events into several strains, besides their secretion of cytokines and effects of immunomodulation. This systematic review aims to highlight the details of the integration of several types of biomaterials used in association with AD-MSCs, collecting notorious and basic data of in vitro and in vivo assays, taking into account the relevance of the interference of the cell lineage origin and handling cell line protocols for both the replacement and repairing of damaged tissues or organs in clinical application. Our group analyzed the quality and results of the 98 articles selected from PubMed, Scopus and Web of Science. A total of 97% of the articles retrieved demonstrated the potential in clinical applications. The synthetic polymers were the most used biomaterials associated with AD-MSCs and almost half of the selected articles were applied on bone regeneration

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation

Objectives To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks

Vitamin K antagonist control in patients with atrial fibrillation in Asia compared with other regions of the world: Real-world data from the GARFIELD-AF registry

Objective: To compare the distribution of international normalized ratios (INRs) in patients receiving vitamin K antagonist (VKA) for newly diagnosed atrial fibrillation in Eastern and Southeastern Asia and in other regions of the world (ORW) represented in the ongoing, global observational study GARFIELD-AF

Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation

Objective We studied evolving antithrombotic therapy patterns in patients with newly diagnosed non-valvular atrial fibrillation (AF) and >= 1 additional stroke risk factor between 2010 and 2015