A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine. This manuscript is a position paper, where the Brazilian Society of Clinical Oncology (SBOC) aims to describe pertinent issues regarding the approval and use of biosimilars in oncology. As a working group on behalf of SBOC, we discuss aspects related to definition, labeling/nomenclature, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, and the potential impact on financial burden in healthcare. We take a stand in favor of the introduction of biosimilars, as they offer a viable, safe, and cost-effective alternative to the biopharmaceutical products currently used in cancer. We hope this document can provide valuable information to support therapeutic decisions that maximize the clinical benefit for the thousands of cancer patients in Brazil and can contribute to expedite the introduction of this new drug class in clinical practice. We expect the conveyed information to serve as a basis for further discussion in Latin America, this being the first position paper issued by a Latin American Oncology Society.

Abstract Respiratory diseases have received increasing attention in recent decades. Airway bifurcations are difficult regions to study, and computational fluid dynamics (CFD) offers an alternative way of evaluating the behavior of pharmaceutical aerosols used in the treatment of respiratory disorders. In this work, particle deposition was analyzed using a three-dimensional model with four ramifications (three bifurcations), under different respiratory conditions: inhalation, exhalation, and breath holding. The main aim of the work was to verify the medical recommendation to hold one's breath during a few seconds after inhaling pharmaceutical aerosols, rather than exhaling immediately after the inhalation. The deposition of particles with 5 µm diameter was considered. The results showed that the number of aerosols collected on the airway walls was higher for the situation of breath holding, which supported the medical recommendation.

Background: Neonatal infection is a serious public health problem. The aim of this study was to assess the influence of the antenatal care on the risk of early-onset neonatal healthcare associated infection in two Brazilian maternities.Methods: Cohort study - Newborns admitted at two public neonatal intensive care units from 2008 to 2009 were included in the study. Data on antenatal and perinatal variables were collected from maternal prenatal cards and medical charts. Newborns were actively surveyed for early-onset neonatal healthcare associated infection, defined as a neonatal infection diagnosed within 48 h after birth. Multiple logistic regression was used to assess variables independently associated with early-onset neonatal healthcare associated infection.Results: 561 neonate-mother pairs were included in the study. Early-onset neonatal health-care associated infection was diagnosed in 283 neonates (51%), an incidence rate of 43.5/1000 live births. Neonates whose mothers had less then six antenatal visits were under risk significantly higher for early-onset neonatal healthcare associated infection (OR = 1.69, 95% CI = 1.11-2.57), after adjusting for birth weight, membranes ruptured for >18 h, maternal complications during delivery, maternal infection at admission, and hospital where patients received care.Conclusions: The risk of neonatal early-onset neonatal healthcare associated infection was significantly associated with insufficient number of antenatal care visits. Further studies assessing the quality of antenatal care and targeting its improvement are warranted.

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73%), 55 (11%), and 76 (16%) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25%) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.

O comportamento reológico de dispersões com alto teor de sólidos, de misturas de amido de milho ceroso hidrolisado (HWS), em presença do concentrado de proteínas do soro do leite (WPC) e uréia, foi estudado por medidas oscilatórias de pequena amplitude no regime linear, sob aquecimento a 80 ºC e resfriamento a 25 ºC, a pH 7,5. A amostra de HWS não-gelificante foi obtida por sonicação de amido de milho ceroso previamente gelatinizado. O fluxo sob cisalhamento contínuo e a microestrutura foram investigados após o resfriamento a 25 ºC. As dispersões foram preparadas na razão 1:1 (m/m) WPC/uréia, com concentrações crescentes de HWS. Comportamentos reológicos típicos de sólidos e de líquidos foram observados após resfriar as misturas a baixa temperatura, em função da razão HWS/WPC. Na menor razão HWS/WPC, uma estrutura tixotrópica foi caracterizada sob fluxo contínuo, e visualizada por microscopia óptica sob baixa ampliação como uma rede contínua. Com o aumento da razão HWS/WPC dentro de uma certa faixa, misturas gelificantes e não-gelificantes resultaram em estruturas com separação de fases, as quais não fluíram. Com a razão HWS/WPC mais alta, uma dispersão pseudoplástica foi formada, consistente com o comportamento reológico típico de líquidos sob regime linear, e homogênea, quando visualizada sob microscopia óptica.

The rheological behaviour of some high-solid mixed dispersions of partially hydrolysed waxy maize starch (HWS), in the presence of whey protein concentrate (WPC) and urea, was followed by small-amplitude oscillatory measurements in the linear domain, under heating to 80 °C and cooling to 25 °C, at pH 7.5. The non-gelling HWS sample was obtained by sonication of previously gelatinised waxy maize starch. Steady-shear flow and microstructure were investigated after cooling to 25 °C. Dispersions were prepared at 1:1 (m/m) WPC/urea ratio, with increasing HWS concentrations. Typical solid- and liquid-like rheological behaviours were observed after quenching the mixtures to low temperature, depending on HWS/WPC ratio. At the lowest HWS/WPC ratio, a thixotropic structure was characterised under steady-shear flow, and visualised by light microscopy at low magnification as a continuous network. With increasing HWS/WPC ratio within a certain range, gelling and non-gelling mixtures resulted in phase-separated structures, which hindered viscous flow. At the highest HWS/WPC ratio, a shear-thinning dispersion was formed, consistent with the liquid-like small deformation properties and the homogeneous image obtained by light microscopy.

Partial hydrolysis of whey proteins by enzymes immobilized on an inert support can either change or evidence functional properties of the produced peptides, thereby increasing their applications. The hydrolysis of sweet cheese whey proteins by alcalase, which is multipoint-immobilized on agarose gel, is studied here. A Michaelis-Menten model that takes into account competitive inhibition by the product was fitted to experimental data. The influence of pH on the kinetic parameters in the range 6.0 to 11.0 was assessed, at 50ºC. Initial reaction-rate assays in a pHstat at different concentrations of substrate were used to estimate kinetic and Michaelis-Menten parameters, k and K M. Experimental data from long-term batch assays were used to quantify the inhibition parameter, K I. The fitting of the model to the experimental data was accurate in the entire pH range.

Carnitine, a structurally choline-like metabolite, has been used to increase athletic performance, although its effects on neuromuscular transmission have not been investigated. It is present in skeletal muscle and its plasma levels are about 30 to 90 µM. Using rat phrenic nerve diaphragm preparations indirectly and directly stimulated with high rate pulses, D-carnitine (30 and 60 µM), L-carnitine (60 µM) and DL-carnitine (60 µM) were shown to induce tetanic fade (D-carnitine = 19.7 ± 3.1%, N = 6; L-carnitine = 16.6 ± 2.4%, N = 6; DL-carnitine = 14.9 ± 2.1%, N = 6) without any reduction of maximal tetanic tension. D-carnitine induced tetanic fade in neuromuscular preparations previously paralyzed with d-tubocurarine and directly stimulated. The effect was greater than that obtained by indirect muscle stimulation. Furthermore, previous addition of atropine (20 to 80 µM) to the bath did not reduce carnitine isomer-induced tetanic fade. In contrast to D-carnitine, the tetanic fade induced by L- and DL-carnitine was antagonized by choline (60 µM). The combined effect of carnitine isomers and hemicholinium-3 (0.01 nM) was similar to the effect of hemicholinium-3 alone. The data suggest that L- and DL-carnitine-induced tetanic fade seems to depend on their transport into the motor nerve terminal.

Os efluentes lançados nos principais tributários da represa da Pampulha (Sarandi e Ressaca) estão em grande parte representados por metais pesados. Embora não haja enquadramento para a qualidade da água destes tributários, por apresentarem trechos canalizados, os limites recomendados para o reservatório o classificam como classe 2. Dentre os aspectos ecotoxicológicos considerados no monitoramento da Bacia da Pampulha, foram investigados teores de metais pesados (Zn, Pb, Cd, Ni, Cu, Cr, Fe e Mn) na água, em locais com potencial de toxicidade e contaminação, durante agosto (estação seca) e novembro/98 (estação chuvosa). Os primeiros resultados mostraram concentrações relativamente elevadas de zinco (0,22 mg.L<FONT FACE=Symbol>-</FONT>1) na porção inicial do reservatório. No início do Córrego Sarandi, foram encontrados os maiores teores de níquel e cromo (0,19 e 0,89 mg.L<FONT FACE=Symbol>-</FONT>1, respectivamente), enquanto as maiores concentrações de chumbo (0,05 mg.L<FONT FACE=Symbol>-</FONT>1), cádmio (0,014 mg. L<FONT FACE=Symbol>-</FONT>1), manganês (0,43 mg.L<FONT FACE=Symbol>-</FONT>1) e ferro (15,25 mg.L<FONT FACE=Symbol>-</FONT>1) foram encontradas no Córrego Ressaca, onde está situado o aterro sanitário de Belo Horizonte. Uma concentração relativamente elevada de cádmio também foi verificada na junção dos córregos Sarandi e Ressaca. No segundo período de análises, verificou-se um aumento nas concentrações de zinco em todos os pontos de amostragem, exceto no controle, com valores entre 0,71 (Córrego Sarandi) e 2,50 mg.L<FONT FACE=Symbol>-</FONT>1 (Córrego Ressaca). Chumbo, cádmio, níquel e cromo apresentaram-se em maiores concentrações no Córrego Ressaca, não tendo sido detectados nos demais pontos de amostragem. Os valores de cobre foram mais elevados que os obtidos em agosto/98, entre 0,10 (controle) e 0,38 mg.L<FONT FACE=Symbol>-</FONT>1 (junção). O mesmo foi verificado em relação ao manganês e ao ferro, cujos valores chegaram a 19,3 e 125,0 mg.L<FONT FACE=Symbol>-</FONT>1, respectivamente. Além disso, todos os valores de metais detectados no segundo período de amostragem estiveram muito acima dos valores recomendados para águas classe 2. Os resultados mostram a necessidade de continuidade do monitoramento desses metais, devido ao interesse na melhoria da qualidade da água do reservatório.

A great amount of heavy metals enter Pampulha Reservoir via it's main tributaries (Sarandi and Ressaca). Although no water quality classification has been carried out for these tributaries, the reservoir is expected to be in class 2 of the CONAMA-86 system. As part of a monitoring scheme of the Pampulha Watershed, heavy metals (Zn, Pb, Cd, Ni, Cu, Cr, Mn and Fe) were investigated in the water at a control site (considered free from direct human influence) and at potential sites of toxicity and contamination during August (dry season) and November (wet season) of 1998. The results for the first sampling period showed relatively high concentrations of zinc (0.22 mg.L<FONT FACE=Symbol>-</FONT>1) in the upper portion of the reservoir. The highest values of nickel and chromium (0.19 and 0.89 mg.L<FONT FACE=Symbol>-</FONT>1, respectively) were found in the initial portion of the Sarandi Stream, while the highest concentrations of lead (0.05 mg.L<FONT FACE=Symbol>-</FONT>1), cadmium (0.014 mg.L<FONT FACE=Symbol>-</FONT>1), manganese (0.43 mg.L<FONT FACE=Symbol>-</FONT>1) and iron (15.25 mg.L<FONT FACE=Symbol>-</FONT>1) were detected in the Ressaca Stream by the landfill dump of Belo Horizonte. A relatively high concentration of cadmium was also detected at the confluence of the two streams. During the second sampling period, there was an increase in the concentrations of zinc at all sampling sites except the control, with values varying from 0.71 mg.L<FONT FACE=Symbol>-</FONT>1 (the Sarandi Stream) to 2.50 mg.L<FONT FACE=Symbol>-</FONT>1 (the Ressaca Stream). Lead, cadmium, nickel and chromium concentrations were also higher in the Ressaca Stream, but not detected at the other sampling sites. Copper values were higher than in the first period: 0.10 mg.L<FONT FACE=Symbol>-</FONT>1 at the control up to 0.38 mg.L<FONT FACE=Symbol>-</FONT>1 at the confluence of the streams. Similar results were found for manganese and iron, with values reaching up to 19.30 and 125 mg.L<FONT FACE=Symbol>-</FONT>1, respectively. Moreover, all values recorded in the second sampling period were much higher than recommended for class 2 waters. These results emphasize the need for such monitoring in relation to better water quality management of this reservoir.

The time-course changes of the responsiveness of glycogen breakdown to a- and ß-adrenergic agonists during insulin-induced hypoglycemia (IIH) were investigated. Blood glucose levels were decreased prior to the alteration in the hepatic responsiveness to adrenergic agonists. The activation of hepatic glucose production and glycogenolysis by phenylephrine (2 µM) and isoproterenol (20 µM) was decreased in IIH. The changes in the responsiveness of glycogen catabolism were first observed for isoproterenol and later for phenylephrine. Hepatic ß-adrenergic receptors showed a higher degree of adrenergic desensitization than did a-receptors. Liver glycogen synthase activity, glycogen content and the catabolic effect of dibutyryl cyclic AMP (the ß-receptor second messenger) were not affected by IIH.