Toward Global Standards for Comparator Pharmaceutical Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine in the Americas

This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches.

Is income area level associated with blood pressure in adults regardless of individual-level characteristics? A multilevel approach

This population-based health survey was carried out in Florianopolis, Brazil, to assess the association between adult systolic blood pressure (SBP) and contextual income level, after controlling for potential individual-level confounders. A statistically significant negative association between SBP levels and contextual income was identified after adjusting for individual-level characteristics. SBP levels in the highest and in the intermediate tertiles of contextual income were 5.78 and 2.82 mmHg lower, respectively, than that observed in the bottom tertile. The findings suggest an association between income area level and blood pressure, regardless of well-known individual-level hypertension risk factors. (C) 2012 Elsevier Ltd. All rights reserved.

Phenolic compounds from Rosemary (Rosmarinus officinalis L.) attenuate oxidative stress and reduce blood cholesterol concentrations in diet-induced hypercholesterolemic rats

Abstract Background Phenolic compounds combine antioxidant and hypocholesterolemic activities and, consequently, are expected to prevent or minimize cardiometabolic risk. Methods To evaluate the effect of an aqueous extract (AQ) and non-esterified phenolic fraction (NEPF) from rosemary on oxidative stress in diet-induced hypercholesterolemia, 48 male 4-week old Wistar rats were divided into 6 groups: 1 chow diet group (C) and 5 hypercholesterolemic diet groups, with 1 receiving water (HC), 2 receiving AQ at concentrations of 7 and 140 mg/kg body weight (AQ70 and AQ140, respectively), and 2 receiving NEPF at concentrations of 7 and 14 mg/kg body weight (NEPF7 and NEPF14, respectively) by gavage for 4 weeks. Results In vitro, both AQ and NEPF had remarkable antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH●) assay, which was similar to BHT. In vivo, the group that received AQ at 70 mg/kg body weight had lower serum total cholesterol (−39.8%), non-HDL-c (−44.4%) and thiobarbituric acid reactive substance (TBARS) levels (−37.7%) compared with the HC group. NEPF (7 and 14 mg/kg) reduced the tissue TBARS levels and increased the activity of tissular antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). Neither AQ nor NEPF was able to ameliorate the alterations in the hypercholesterolemic diet-induced fatty acid composition in the liver. Conclusions These data suggest that phenolic compounds from rosemary ameliorate the antioxidant defense in different tissues and attenuate oxidative stress in diet-induced hypercholesterolemic rats, whereas the serum lipid profile was improved only in rats that received the aqueous extract.

Immobilization of cholesterol oxidase in LbL films and detection of cholesterol using ac measurements

The preserved activity of immobilized biomolecules in layer-by-layer (LbL) films can be exploited in various applications. including biosensing. In this study, cholesterol oxidase (COX) layers were alternated with layers of poly(allylamine hydrochloride) (PAH) in LbL films whose morphology was investigated with atomic force microscopy (AFM). The adsorption kinetics of COX layers comprised two regimes, a fast, first-order kinetics process followed by a slow process fitted with a Johnson-Mehl-Avrami (JMA) function. with exponent similar to 2 characteristic of aggregates growing as disks. The concept based on the use of sensor arrays to increase sensitivity, widely employed in electronic tongues, was extended to biosensing with impedance spectroscopy measurements. Using three sensing units, made of LbL films of PAH/COX and PAHIPVS (polyvinyl sulfonic acid) and a bare gold interdigitated electrode, we were able to detect cholesterol in aqueous solutions down to the 10(-6) M level. This high sensitivity is attributed to the molecular-recognition interaction between COX and cholesterol, and opens the way for clinical tests to be made with low cost. fast experimental procedures. (C) 2008 Published by Elsevier B.V.

Prevalência e fatores associados à síndrome metabólica em usuários de unidades básicas de saúde em São Paulo - SP

OBJETIVO: Determinar a relação da síndrome metabólica (SM) com o nível socioeconômico, hábitos comportamentais, condições de saúde, antecedentes familiares de morbidades e áreas de residência. MÉTODOS: Trata-se de um estudo de corte transversal. A amostra aleatória foi constituída por usuários de duas Unidades Básicas de Saúde da cidade de São Paulo - Jardim Comercial (UBS1) e Jardim Germânia (UBS2) -, totalizando 452. Para o diagnóstico de SM utilizou-se o critério do Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP-ATP III). Na avaliação antropométrica foram aferidas medidas de peso, estatura, circunferências abdominal e do quadril. Foi utilizado questionário geral para obtenção de dados sociodemográficos, socioeconómicos, antecedentes familiares e pessoais de morbidades, hábitos comportamentais como tabagismo, etilismo e nível de atividade física. Foi estabelecida associação entre as variáveis explicativas de interesse e SM, empregando-se a regressão logística multivariada. RESULTADOS: Na UBS1, o percentual de SM foi de 56,1% e na UBS2, de 34,0%. Houve associação direta e significativa entre SM e idade, sexo feminino, cor, tabagismo, etilismo, nível de atividade física, estresse e antecedentes familiares de doença cardíaca e de diabetes mellitus. A escolaridade apresentou associação inversa: morar no bairro de menor nível socioeconómico aumentou a chance de SM. CONCLUSÃO: Os resultados sugerem que as morbidades que compõem a SM são um grave problema de saúde pública nessa população.

Gene expression profiles displayed by peripheral blood mononuclear cells from patients with type 2 diabetes mellitus focusing on biological processes implicated on the pathogenesis of the disease

Patients with type 2 diabetes mellitus (T2DM) exhibit insulin resistance associated with obesity and inflammatory response, besides an increased level of oxidative DNA damage as a consequence of the hyperglycemic condition and the generation of reactive oxygen species (ROS). In order to provide information on the mechanisms involved in the pathophysiology of T2DM, we analyzed the transcriptional expression patterns exhibited by peripheral blood mononuclear cells (PBMCs) from patients with T2DM compared to non-diabetic subjects, by investigating several biological processes: inflammatory and immune responses, responses to oxidative stress and hypoxia, fatty acid processing, and DNA repair. PBMCs were obtained from 20 T2DM patients and eight non-diabetic subjects. Total RNA was hybridized to Agilent whole human genome 4x44K one-color oligo-microarray. Microarray data were analyzed using the GeneSpring GX 11.0 software (Agilent). We used BRB-ArrayTools software (gene set analysis - GSA) to investigate significant gene sets and the Genomica tool to study a possible influence of clinical features on gene expression profiles. We showed that PBMCs from T2DM patients presented significant changes in gene expression, exhibiting 1320 differentially expressed genes compared to the control group. A great number of genes were involved in biological processes implicated in the pathogenesis of T2DM. Among the genes with high fold-change values, the up-regulated ones were associated with fatty acid metabolism and protection against lipid-induced oxidative stress, while the down-regulated ones were implicated in the suppression of pro-inflammatory cytokines production and DNA repair. Moreover, we identified two significant signaling pathways: adipocytokine, related to insulin resistance; and ceramide, related to oxidative stress and induction of apoptosis. In addition, expression profiles were not influenced by patient features, such as age, gender, obesity, pre/post-menopause age, neuropathy, glycemia, and HbA(1c) percentage. Hence, by studying expression profiles of PBMCs, we provided quantitative and qualitative differences and similarities between T2DM patients and non-diabetic individuals, contributing with new perspectives for a better understanding of the disease. (C) 2012 Elsevier B.V. All rights reserved.

The effects of high-intensity resistance exercise on the blood lipid profile and liver function in hypercholesterolemic hamsters

It is well established that atherogenic dyslipidemia, characterized by high levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol, constitutes important risk factors for cardiovascular disease. Regular exercise has been associated with a reduced risk for metabolic diseases. However, studies supporting the concept that resistance exercise is a modifier of blood lipid parameters are often contradictory. The aim of this study was to investigate the effects of high-intensity resistance exercise on the serum levels of TG, TC, HDL and non-HDL cholesterol, glucose, and the liver function enzymes alanine aminotransferase (ALT, EC 2.6.1.2) and aspartate aminotransferase (AST, EC 2.6.1.1) in golden Syrian hamsters (Mesocricetus auratus (Waterhouse, 1839)) fed a hypercholesterolemic diet. Sedentary groups (S) and exercise groups (E) were fed a standard diet (SS and ES) or a cholesterol-enriched diet (standard plus 1% cholesterol, SC and EC). Resistance exercise was performed by jumps in the water, carrying a load strapped to the chest, representing 10 maximum repetitions (10 RM, 30 s rest, five days per week for five weeks). Mean blood sample comparisons were made by ANOVA + Tukey or ANOVA + Kruskal-Wallis tests (p < 0.05) to compare parametric and nonparametric samples, respectively. There were no differences in blood lipids between the standard diet groups (SS and ES) (p > 0.05). However, the EC group increased the glucose, non-HDL, and TC levels in comparison with the ES group. Moreover, the EC group increased the TG levels versus the SC group (p < 0.05). In addition, the ALT levels were increased only by diet treatment. These findings indicated that high-intensity resistance exercise contributed to dyslipidemia in hamsters fed a hypercholesterolemic diet, whereas liver function enzymes did not differ in regards to the exercise protocol.

High Cholesterol Feeding May Induce Tubular Dysfunction Resulting in Hypomagnesemia

Background/Aims: Hypomagnesemia may induce hypercholesterolemia, but the contrary has not been described yet. Thus, magnesium homeostasis was evaluated in rats fed a cholesterol-enriched diet for 8 days. This study has a relevant clinical application if hypomagnesemia, due to hypercholesterolemia, is confirmed in patients with long-term hypercholesterolemia. Methods: Both hypercholesterolemic (HC) and normocholesterolemic rats (NC) were divided into sets of experiments to measure hemodynamic parameters, physiological data, maximum capacity to dilute urine (C-H2O), variations (Delta) in [Ca2+](i) and the expression of transporter proteins. Results: HC developed hypomagnesemia and showed high magnesuria in the absence of hemodynamic abnormalities. However, the urinary sodium excretion and C-H2O in HC was similar to NC. On the other hand, the responses to angiotensin II by measuring Delta [Ca2+](i) were higher in the thick ascending limb of Henle's loop (TAL) of HC than NC. Moreover, high expression of the cotransporter NKCC2 was found in renal outer medulla fractions of HC. Taken together, the hypothesis of impairment in TAL was excluded. Actually, the expression of the epithelial Mg2+ channel in renal cortical membrane fractions was reduced in HC. Conclusion: Impairment in distal convoluted tubule induced by hypercholesterolemia explains high magnesuria and hypomagnesemia observed in HC. Copyright (C) 2011 S. Karger AG, Basel

Metabolic profile of patients with diabetes in Barbalha, Brazil

Introduction: Modern life has imposed to people sedentary habits and excessive food consumption, what results into an increase of the incidence of metabolic diseases, which promote the development of atherosclerosis. Objectives: We aimed to evaluate the metabolic profile of diabetic patients assisted by the endocrinology service from Ceara Federal University, located in Barbalha, Brazil. Methods: This is a transversal and retrospective study, based on the analysis of patient records. 119 records were reviewed and 35 of them were selected, according to their registers about anthropometric and laboratorial measuring. Results and discussion: Among the selected records, 65.71% were female patients. It was observed a positive relationship between age and the level of triglycerides, between LDL-cholesterol and the use of tobacco and between blood glucose and glycated hemoglobin. Conclusion: The superposition of risk factor in this group shows the necessity of an integrated assistance and a follow-up about their metabolic profile, aiming to mitigate or retard serious circulatory pathologies.

Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion

Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 mu mol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group. LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.

Influence of transportation methods and pre-slaughter rest periods on cortisol level in lambs

This study aimed to verify the influence of the transport in open or closed compartments (0 h), followed by two resting periods (1 and 3 h) for the slaughter process on the levels of cortisol as a indicative of stress level. At the slaughterhouse, blood samples were taken from 86 lambs after the transport and before slaughter for plasma cortisol analysis. The method of transport influenced in the cortisol concentration (0 h; P < 0.01). The animals transported in the closed compartment had a lower level (28.97 ng ml(-1)) than the animals transported in the open compartment (35.49 ng ml(-1)). After the resting period in the slaughterhouse. there was a decline in the plasmatic cortisol concentration, with the animals subjected to 3 h of rest presenting the lower average cortisol value (24.14 ng ml(-1); P < 0.05) than animals subjected to 1 h of rest (29.95 ng ml(-1)). It can be inferred that the lambs that remained 3 h in standby before slaughter had more time to recover from the stress of the transportation than those that waited just 1 h. Visual access to the external environment during the transport of the lambs is a stressful factor changing the level of plasmatic cortisol, and the resting period before slaughter was effective in lowering stress, reducing the plasmatic cortisol in the lambs. (c) 2012 Elsevier B.V. All rights reserved.

Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate

This study describes the hypocholesterolaemic effect of whole lupin and its protein in hamsters. The diets were: casein (control group HC), lupin protein isolate (group HPI) and whole lupin seed (group HWS). Diets from HPI and HWS promoted a significant reduction of total cholesterol and non-HDL cholesterol in the hamsters' plasma as compared with HC. The true digestibility of HPI and HC groups were similar and differed significantly from the HWS one, which in turn showed a significant difference in total sterol excretion as compared to the former groups. Histological analysis of the liver revealed that animals fed on HPI and HWS diets presented a low level of steatosis (level 1) as compared to the ones fed on HC diet (level 4). Our findings demonstrate that protein isolate from Lupinus albus from Brazil has a metabolic effect on endogenous cholesterol metabolism and a protector effect on development of hepatic steatosis. (C) 2011 Elsevier Ltd. All rights reserved.

Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport

Objective: We investigated the effect of advanced glycated albumin (AGE-albumin) on macrophage sensitivity to inflammation elicited by S100B calgranulin and lipopolysaccharide (LPS) and the mechanism by which HDL modulates this response. We also measured the influence of the culture medium, isolated from macrophages treated with AGE-albumin, on reverse cholesterol transport (RCT). Methods and results: Macrophages were incubated with control (C) or AGE-albumin in the presence or absence of HDL, followed by incubations with S100B or LPS. Also, culture medium obtained from cells treated with C- or AGE-albumin, following S100B or LPS stimulation was utilized to treat naive macrophages in order to evaluate cholesterol efflux and the expression of HDL receptors. In comparison with C-albumin, AGE-albumin, promoted a greater secretion of cytokines after stimulation with S100B or LPS. A greater amount of cytokines was also produced by macrophages treated with AGE-albumin even in the presence of HDL Cytokine-enriched medium, drawn from incubations with AGE-albumin and S100B or LPS impaired the cholesterol efflux mediated by apoA-I (23% and 37%, respectively), HDL2 (43% and 47%, respectively) and HDL3 (20% and 8.5%, respectively) and reduced ABCA-1 protein level (16% and 26%, respectively). Conclusions: AGE-albumin primes macrophages for an inflammatory response impairing the RCT. Moreover, AGE-albumin abrogates the anti-inflammatory role of HDL, which may aggravate the development of atherosclerosis in DM. (C) 2012 Elsevier BM. All rights reserved.

The effect of low-level laser irradiation (In-Ga-Al-AsP - 660 nm) on melanoma in vitro and in vivo

Abstract Background It has been speculated that the biostimulatory effect of Low Level Laser Therapy could cause undesirable enhancement of tumor growth in neoplastic diseases. The aim of the present study is to analyze the behavior of melanoma cells (B16F10) in vitro and the in vivo development of melanoma in mice after laser irradiation. Methods We performed a controlled in vitro study on B16F10 melanoma cells to investigate cell viability and cell cycle changes by the Tripan Blue, MTT and cell quest histogram tests at 24, 48 and 72 h post irradiation. The in vivo mouse model (male Balb C, n = 21) of melanoma was used to analyze tumor volume and histological characteristics. Laser irradiation was performed three times (once a day for three consecutive days) with a 660 nm 50 mW CW laser, beam spot size 2 mm2, irradiance 2.5 W/cm2 and irradiation times of 60s (dose 150 J/cm2) and 420s (dose 1050 J/cm2) respectively. Results There were no statistically significant differences between the in vitro groups, except for an increase in the hypodiploid melanoma cells (8.48 ± 1.40% and 4.26 ± 0.60%) at 72 h post-irradiation. This cancer-protective effect was not reproduced in the in vivo experiment where outcome measures for the 150 J/cm2 dose group were not significantly different from controls. For the 1050 J/cm2 dose group, there were significant increases in tumor volume, blood vessels and cell abnormalities compared to the other groups. Conclusion LLLT Irradiation should be avoided over melanomas as the combination of high irradiance (2.5 W/cm2) and high dose (1050 J/cm2) significantly increases melanoma tumor growth in vivo.

Correlation analysis of the long latency auditory evoked potential N2 and cognitive P3 with the level of lead poisoning in children

Introduction: The effects of lead on children’s health have been widely studied. Aim: To analyze the correlation between the long latency auditory evoked potential N2 and cognitive P3 with the level of lead poisoning in Brazilian children. Methods: This retrospective study evaluated 20 children ranging in age from 7 to 14 years at the time of audiological and electrophysiological evaluations. We performed periodic surveys of the lead concentration in the blood and basic audiological evaluations. Furthermore, we studied the auditory evoked potential long latency N2 and cognitive P3 by analyzing the absolute latency of the N2 and P3 potentials and the P3 amplitude recorded at Cz. At the time of audiological and electrophysiological evaluations, the average concentration of lead in the blood was less than 10 ug/dL. Results: In conventional audiologic evaluations, all children had hearing thresholds below 20 dBHL for the frequencies tested and normal tympanometry findings; the auditory evoked potential long latency N2 and cognitive P3 were present in 95% of children. No significant correlations were found between the blood lead concentration and latency (p = 0.821) or amplitude (p = 0.411) of the P3 potential. However, the latency of the N2 potential increased with the concentration of lead in the blood, with a significant correlation (p = 0.030). Conclusion: Among Brazilian children with low lead exposure, a significant correlation was found between blood lead levels and the average latency of the auditory evoked potential long latency N2; however, a significant correlation was not observed for the amplitude and latency of the cognitive potential P3