Cardiac effect induced by Crotalus durissus cascavella venom: Morphofunctional evidence and mechanism of action.

Envenoming, resulting from snake bites, is a global public health problem. The present study was undertaken to investigate the influence of Crotalus durissus cascavella (Cdcas) venom on cardiac activity and the mechanisms of action underlying its effect. To investigate the inotropic and chronotropic effects induced by Cdcas, studies were performed on the left and right atria. A series of tests were conducted to investigate whether the negative inotropic effect, induced by Cdcas, was related to cardiac damage. Cdcas venom (0.1-30 µg/mL) elicited a significant negative inotropic effect. The addition of Cdcas crude venom (7.5, 15 and 30 µg/mL) did not induce significant alterations in cell proliferation, nor in the enzymatic activity of total-CK and CKMB. Ultrastructural evaluation demonstrated that cardiac cells from isoproterenol and Cdcas groups revealed discreet swelling and displaced intermyofibrillar mitochondria with disorganization of the cristae. No change was observed in cardiac electrical activity in perfused isolated rat hearts with Cdcas. In addition, Cdcas reduced contractility in isolated cardiomyocytes from the rat left ventricle. The negative inotropic effect of Cdcas was reduced by l-NAME (100 µM), PTIO (100 µM), ODQ (10 µM) and KT5823 (1 µM), suggesting the participation of NO/cGMP/PKG pathway due to Cdcas. In non-anesthetized rats, Cdcas induced hypotension followed by bradycardia, the latter was also observed by ECG (anesthetized animals). Our results suggest that the negative inotropic effect induced by Cdcas venom is unrelated to cardiac toxicity, at least, at the concentrations tested; and occurs through of NO/cGMP/PKG pathway, likely leading to hypotension and bradycardia when administered in vivo.

Should the Vancomycin Minimal Inhibitory Concentration be used as an Infant Critical Care Regular Criteria?

BACKGROUND: Vancomycin is the first-line antibiotic used for the treatment of staphylococcal infections. Because of its narrow therapeutic window and the pharmacokinetics variability, vancomycin trough serum concentration should be monitored. However, due to the increased cases of staphylococcus' commensal species infections and the case of vancomycin resistance, the minimal inhibitory concentration should be considered on antimicrobial therapy. OBJECTIVE: This article aimed to show the importance of the minimal inhibitory concentration to infants on vancomycin therapy as regular criteria. MATERIALS AND METHODS: Three infants in the use of vancomycin, hospitalized in the same maternity hospital, and that had at least one blood culture performed during the intensive-care-unit hospitalization were included in the study. Vancomycin serum concentrations were determined by particleenhanced- turbidimetric inhibition-immunoassay. The vancomycin minimal inhibitory concentration data were interpreted by following the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The trough serum concentration range of 10 to 20 mg.L-1 was considered therapeutic. RESULTS: All three patients had at least one infection by S. epidermidis, being one patient exhibit vancomycin- resistant S. epidermidis infection. All patients had stoppages in the vancomycin treatment, and the minimal inhibitory concentration was performed for only one patient. CONCLUSION: The data obtained from these patients also showed the need to perform therapeutic monitoring by using minimal inhibitory concentration values, because, although the serum concentrations were within the reference range, they are insufficient to guarantee patient therapeutic success.

Vancomycin Therapeutic Regime Adjustment in Newborns and Infants with Bacterial Infection: Case Series.

BACKGROUND: Vancomycin is used mostly to overcome infections caused by methicillinresistant microorganisms. There are no well-established administration protocols for neonates and infants, so the leak of a specific administration regime in that population may lead to serum concentrations beyond the specified range. OBJECTIVE: This case series evaluated the pharmacokinetics adjustment from a vancomycin therapeutic regimen prescribed to neonates and infants with bacterial infection at a neonatal public hospital intensive- care-unit, with the primary purpose to verify cases of nephrotoxicity. METHODS: Three neonates and four infants taking vancomycin therapy, hospitalized in a public hospital from November 2014 to March 2015, were included in the study. Vancomycin serum concentrations were determined by particle-enhanced-turbidimetric inhibition-immunoassay. The vancomycin concentrations were used for dose adjustment by USC*Pack-PC-Collection®, a non-parametric maximization program. The trough serum concentration range of 10 to 20mg.L-1 was considered therapeutic. RESULTS: Three patients had serum concentration outside the reference-range, one with subtherapeutic, and two with supratherapeutic concentrations. All patients had concomitant use of drugs which interfered with vancomycin distribution and excretion pharmacokinetics parameters, including drugs that may enhance nephrotoxicity. One patient showed signs of acute renal damage, by low vancomycin and creatinine estimated clearances. CONCLUSION: The pharmacokinetic adjustment has been proven to be a useful and necessary tool to increase therapeutic efficacy and treatment benefits. The standard dose of vancomycin can be used to initiate therapy in neonates and infants admitted to the ICU, but after reaching the drug steady state, the dosing regimen should be individualized and guided by pharmacokinetic parameters.

Differences in the Prevalence of Non-Communicable Disease between Slum Dwellers and the General Population in a Large Urban Area in Brazil.

Residents of urban slums are at greater risk for disease than their non-slum dwelling urban counterparts. We sought to contrast the prevalences of selected non-communicable diseases (NCDs) between Brazilian adults living in a slum and the general population of the same city, by comparing the age and sex-standardized prevalences of selected NCDs from a 2010 survey in Pau da Lima, Salvador Brazil, with a 2010 national population-based telephone survey. NCD prevalences in both populations were similar for hypertension (23.6% (95% CI 20.9⁻26.4) and 22.9% (21.2⁻24.6), respectively) and for dyslipidemia (22.7% (19.8⁻25.5) and 21.5% (19.7⁻23.4)). Slum residents had higher prevalences of diabetes mellitus (10.1% (7.9⁻12.3)) and of overweight/obesity (46.5% (43.1⁻49.9)), compared to 5.2% (4.2⁻6.1) and 40.6% (38.5⁻42.8) of the general population in Salvador. Fourteen percent (14.5% (12.1⁻17.0)) of slum residents smoked cigarettes compared to 8.3% (7.1⁻9.5) of the general population in Salvador. The national telephone survey underestimated the prevalence of diabetes mellitus, overweight/obesity, and smoking in the slum population, likely in part due to differential sampling inside and outside of slums. Further research and targeted policies are needed to mitigate these inequalities, which could have significant economic and social impacts on slum residents and their communities.

Serum levels of cytokines and chemokines associated with cardiovascular disease in Brazilian patients treated with statins for dyslipidemia.

The anti-inflammatory effect of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) has been investigated in dyslipidemic patients treated with these pharmacologic agents. The aim of this study was to investigate the serum levels of cytokines and chemokines that have been associated with atherosclerosis and cardiovascular disease in Brazilian patients treated for hypercholesterolemia with statin. The serum levels of the cytokines IL-1ß, IL-6, IL-10, TNF-α and TGF-ß, and the levels of the chemokines IL-8 (CXCL8) and MCP-1 were determined by enzyme-linked immunosorbent assay and tested for their association with cardiovascular disease. The suppression of circulating levels of TNF-α, MCP-1 and IL-8 and their enhancing effect on IL-10 and TGF-ß production were more pronounced in male patients. Female patients treated with statins who had a previous myocardial infarction presented higher median levels of both TNF-α and IL-8 (P<0.05) and a lower median level of IL-10 than female patients without MI (P<0.05). Except in women with a previous myocardial infarction, the treatment of dyslipidemic Brazilian patients with statins down-modulates the production of atherogenic cytokines and chemokines and increases the circulating levels of anti-atherogenic cytokines.

Hypertriglyceridemic waist phenotype: association with metabolic abnormalities in adolescents.

OBJECTIVE: This study aimed to identify the prevalence of hypertriglyceridemic waist (HTW) phenotype, and to evaluate its association with metabolic abnormalities in adolescents of low socioeconomic status. METHOD: This was a cross-sectional study with a random sample of 1,076 adolescents between 11 and 17 years, of both genders, from public schools. The participants underwent anthropometric measurements (weight, height, and waist circumference), and levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), non-HDL cholesterol, triglyceride (TG), and fasting glucose were measured. Information regarding the socioeconomic status of the participants' families was obtained. The HTW phenotype was defined by the simultaneous presence of increased waist circumference (≥ 90(th) percentile for age and gender) and serum triglyceride levels (≥ 100mg/dL). A logistic regression analysis was used to evaluate the associations of interest. RESULTS: The prevalence of HTW phenotype was 7.2% among the adolescents, being higher in the presence of obesity (63.4%) and high levels of non-HDL cholesterol (16.6%) and LDL-C (13.7%). The bivariate analysis indicated that, of the metabolic variables, only blood glucose was not associated with the HTW phenotype. Multivariate analysis adjusted for age and gender indicated that the HTW phenotype was positively associated with high non-HDL cholesterol (odds ratio: 7.0; 95% CI: 3.9-12.6) and low HDL-C levels (odds ratio: 2.7; 95% CI: 1.5-4.8). CONCLUSIONS: This study demonstrated that the HTW phenotype was associated with an atherogenic lipid profile, and this phenotype is suggested as a screening tool to identify adolescents with metabolic alterations.

Fenótipo cintura hipertrigliceridêmica: associação com alterações metabólicas em adolescentes / Hypertriglyceridemic waist phenotype: association with metabolic abnormalities in adolescents

OBJETIVO: O presente estudo objetivou identificar a prevalência do fenótipo cintura hipertrigliceridêmica (CHT) e avaliar sua associação com alterações metabólicas em adolescentes de baixa condição econômica. MÉTODO: Estudo transversal com amostra probabilística de 1.076 adolescentes entre 11 e 17 anos, de ambos os sexos, estudantes de escolas públicas. Os participantes foram submetidos à avaliação antropométrica (peso, altura e circunferência da cintura) e à dosagem dos níveis de colesterol total, LDL-C, HDL-C, colesterol não HDL, triglicérides (TG) e glicemia de jejum. Foram obtidas informações referentes às condições econômicas das famílias dos participantes.O fenótipo CHT foi definido pela presença simultânea da circunferência da cintura aumentada (> percentil 90 por idade e sexo) e dos níveis séricos de triglicérides elevados (> 100 mg/dL). A análise de regressão logística foi utilizada para avaliação das associações de interesse. RESULTADOS: A prevalência do fenótipo CHT foi de 7,2% entre os adolescentes, sendo mais elevada na presença de obesidade (63,4%), do colesterol não HDL (16,6%) e do LDL-C (13,7%) altos. A análise bivariada indicou que, das variáveis metabólicas, apenas a glicemia não se associou ao fenótipo CHT. A análise multivariada, ajustada por sexo e idade, indicou que o fenótipo CHT se associou positivamente com o colesterol não HDL alto (odds ratio, 7,0; IC 95% 3,9-12,6) e com o HDL-C baixo (odds ratio, 2,7; IC 95%, 1,5-4,8). CONCLUSÕES: Este estudo mostrou que o fenótipo CHT se associou com um perfil lipídico aterogênico e sugere esse fenótipo como uma ferramenta de screening que pode ser utilizada para identificar adolescentes com alterações metabólicas.

OBJECTIVE: This study aimed to identify the prevalence of hypertriglyceridemic waist (HTW) phenotype, and to evaluate its association with metabolic abnormalities in adolescents of low socioeconomic status. METHOD: This was a cross-sectional study with a random sample of 1,076 adolescents between 11 and 17 years, of both genders, from public schools. The participants underwent anthropometric measurements (weight, height, and waist circumference), and levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), non-HDL cholesterol triglyceride (TG), and fasting glucose were measured. Information regarding the socioeconomic status of the participants' families was obtained. The HTW phenotype was defined by the simultaneous presence of increased waist circumference (> 90th percentile for age and gender) and serum triglyceride levels (> 100 mg/dL). A logistic regression analysis was used to evaluate the associations of interest. RESULTS: The prevalence of HTW phenotype was 7.2% among the adolescents, being higher in the presence of obesity (63.4%) and high levels of non-HDL cholesterol (16.6%) and LDL-C (13.7%). The bivariate analysis indicated that, of the metabolic variables, only blood glucose was not associated with the HTW phenotype. Multivariate analysis adjusted for age and gender indicated that the HTW phenotype was positively associated with high non-HDL cholesterol (odds ratio: 7.0; 95% CI: 3.9-12.6) and low HDL-C levels (odds ratio: 2.7; 95% CI: 1.5-4.8). CONCLUSIONS: This study demonstrated that the HTW phenotype was associated with an atherogenic lipid profile, and this phenotype is suggested as a screening tool to identify adolescents with metabolic alterations.

Levels of high-density lipoprotein cholesterol (HDL-C) among children with steady-state sickle cell disease.

BACKGROUND: The search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis. METHODS: We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. RESULTS: Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis. CONCLUSIONS: We hypothesize that some SCD patients can have a specific dyslipidemic subphenotype characterized by low HDL-C with hypertriglyceridemia and high VLDL-C in association with other biomarkers, including those related to inflammation. This represents an important step toward a more reliable clinical prognosis. Additional studies are warranted to test this hypothesis and the probably mechanisms involved in this complex network of markers and their role in SCD pathogenesis.

Deposition of free cholesterol in the blood vessels of patients with coronary artery disease: a possible novel mechanism for atherogenesis.

A cholesterol-rich nanoemulsion (LDE) that mimics the composition of low-density lipoprotein (LDL) acquires apoE in the plasma and is taken-up by the cells by LDL receptors. In this study, to verify whether free cholesterol (FC) and the cholesteryl ester (CE) components of LDL are taken-up differently by the vessels. LDE labeled with (3)H-cholesterol and (14)C-cholesteryl oleate was injected into 20 coronary artery disease patients 24 h before a scheduled myocardial coronary artery bypass grafting. The plasma kinetics of both radiolabels was determined from plasma samples collected over 24 h, and fragments of vessels discarded during surgery were collected and analyzed for radioactivity. LDE FC was removed faster than CE. The radioactive counting of LDE CE was greater than that of LDE FC in the blood, but the uptake of FC was markedly greater than that of CE in all fragments: fivefold greater in the aorta (p = 0.04), fourfold greater in the internal thoracic artery (p = 0.03), tenfold greater in the saphenous vein (p = 0.01) and threefold in the radial artery (p = 0.05). In conclusion, the greater removal from plasma of FC compared with CE and the remarkably greater vessel tissue uptake of FC compared with CE suggests that, in the plasma, FC dissociates from the nanoemulsion particles and precipitates in the vessels. Considering LDE as an artificial nanoemulsion model for LDL, our results suggest that dissociation of FC from lipoprotein particles and deposition in the vessel wall may play a role as an independent mechanism in atherogenesis.

Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies.

A cholesterol-rich microemulsion or nanoparticle termed LDE concentrates in cancer tissues after injection into the bloodstream. Here the cytotoxicity, pharmacokinetics, toxicity to animals and therapeutic action of a paclitaxel lipophilic derivative associated to LDE is compared with those of the commercial paclitaxel. Results show that LDE-paclitaxel oleate is stable. The cytostatic activity of the drug in the complex is diminished compared with the commercial paclitaxel due to the cytotoxicity of the vehicle Cremophor EL used in the commercial formulation. Competition experiments in neoplastic cultured cells show that paclitaxel oleate and LDE are internalized together by the LDL receptor pathway. LDE-paclitaxel oleate arrests the G(2)/M phase of cell cycle, similarly to commercial paclitaxel. Tolerability to mice is remarkable, such that the lethal dose (LD(50)) was ninefold greater than that of the commercial formulation (LD(50) = 326 microM and 37 microM, respectively). LDE concentrates paclitaxel oleate in the tumor roughly fourfold relative to the normal adjacent tissues. At equimolar doses, the association of paclitaxel oleate with LDE results in remarkable changes in the drug pharmacokinetic parameters when compared to commercial paclitaxel (t(1/2)=218 min and 184 min, AUC=1,334 microg h/ml and 707 microg h/ml and CL=0.125 ml/min and 0.236 ml/min, respectively). Finally, the therapeutic efficacy of the complex is pronouncedly greater than that of the commercial paclitaxel, as indicated by the reduction in tumor growth, increase in survival rates and % cure of treated mice. In conclusion, LDE-paclitaxel oleate is a stable complex and compared with paclitaxel toxicity is considerably reduced and activity is enhanced, which may lead to improved therapeutic index in clinical use.

Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients.

PURPOSE: We had previously shown in acute leukemia and in breast and ovary carcinoma patients that a cholesterol-rich emulsion (LDE) that binds to receptors for low-density lipoprotein (LDL) may concentrate in neoplastic tissues. In this study, the potential of LDE as a carrier for anticancer drugs was investigated. METHODS: LDE was associated with carmustine, and the cytotoxicity of the LDE-carmustine complex was studied in a neoplastic cell line and its biodistribution was studied in mice. The plasma kinetics of the complex and its uptake by tumor and normal tissue were determined in cancer patients. Finally, an exploratory clinical study to determine the toxicity profile of LDE-carmustine at escalating dose levels was conducted in 42 advanced cancer patients refractory to conventional chemotherapy. RESULTS: Carmustine formed a stable association with LDE. The pharmacological action of carmustine, as tested in cancer cells, was not diminished by association with LDE compared with the free drug and was indeed mediated by the LDL receptor. The biodistribution in mice and plasma kinetics in patients of the emulsion were not changed by association of the drug. The uptake of LDE-carmustine by tumor was severalfold greater than the uptake by the corresponding normal tissue. Finally, patients treated with LDE-carmustine showed negligible side effects even at very high dose levels. CONCLUSIONS: Association with LDE preserves the cytotoxicity of carmustine and markedly diminishes its side effects.