Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.

Tobacco dependence reaches one-third of the world population, and is the second leading cause of death around the world. Cotinine, a major metabolite of nicotine, is the most appropriate parameter to evaluate tobacco exposure and smoking status due to its higher stability and half-life when compared to nicotine. The procedure involves liquid-liquid extraction, separation on a RP column (Zorbax XDB C(8)), isocratic pump (0.5 mL/min of water-methanol-sodium acetate (0.1 M)-ACN (50:15:25:10, v/v/v/v), 1.0 mL of citric acid (0.034 M) and 5.0 mL of triethylamine for each liter) and HPLC-UV detection (261 nm). The analytical procedure proved to be sensitive, selective, precise, accurate and linear (r>0.99) in the range of 5-500.0 ng/mL for cotinine. 2-Phenylimidazole was used as the internal standard. The LOD was 0.18 ng/mL and the LOQ was 5.0 ng/mL. All samples from smoking volunteers were collected simultaneously to establish a comparison between serum, plasma, and urine. The urinary cotinine levels were normalized by the creatinine and urine density. A significant correlation was found (p<0.01) between all matrices. Results indicate that the urine normalization by creatinine or density is unnecessary. This method is considered reliable for determining cotinine in serum and plasma of smokers and in environmental tobacco smoke exposure.

BackgroundDespite the existence of various published studies regarding the effects of tobacco smoking on pregnancy, and especially in regards to placental blood flow and vascular resistance, some points still require clarification. In addition, the amount of damage due to tobacco smoking exposure that occurs has not been quantified by objective means. In this study, we looked for a possible association between flow resistance indices of several arteries and the levels of urinary cotinine and the concentration of carbon monoxide in the exhaled air (COex) of both smoking and non-smoking pregnant women. We also looked for a relationship between those findings and fetal growth and birth weight.MethodsIn a prospective design, thirty pregnant smokers and thirty-four pregnant non-smokers were studied. The volunteers signed consent forms, completed a self-applied questionnaire and were subjected to Doppler velocimetry. Tobacco smoking exposure was quantified by subject provided information and confirmed by the measurement of urinary cotinine levels and by the concentration of carbon monoxide in the exhaled air (COex). The weight of newborns was evaluated immediately after birth.ResultsComparing smoking to non-smoking pregnant women, a significant increase in the resistance index was observed in the uterine arteries (P = 0.001) and umbilical artery (P = 0.001), and a decrease in the middle cerebral artery (P = 0.450). These findings were associated with progressively higher concentrations of COex and urinary cotinine. A decrease in the birth weight was also detected (P < 0.001) in association with a progressive increase in the tobacco exposure of the pregnant woman.ConclusionsIn pregnant women who smoke, higher arterial resistance indices and lower birth weights were observed, and these findings were associated with increasing levels of tobacco smoking exposure. The values were significantly different when compared to those found in non-smoking pregnant women. This study contributes to the findings that smoking damage during pregnancy is dose-dependent, as demonstrated by the objective methods for measuring tobacco smoking exposure.

Tuberculosis (TB) is a major global health threat. There is a need for the development of more efficient drugs for the sterilization of the disease's causative agent, Mycobacterium tuberculosis (MTB). A more comprehensive understanding of the bacilli's nucleotide metabolic pathways could aid in the development of new anti-mycobacterial drugs. Here we describe expression and purification of recombinant iunH-encoded nucleoside hydrolase from MTB (MtIAGU-NH). Glutaraldehyde cross-linking results indicate that MtIAGU-NH predominates as a monomer, presenting varied oligomeric states depending upon binding of ligands. Steady-state kinetics results show that MtIAGU-NH has broad substrate specificity, accepting inosine, adenosine, guanosine, and uridine as substrates. Inosine and adenosine displayed positive homotropic cooperativity kinetics, whereas guanosine and uridine displayed hyperbolic saturation curves. Measurements of kinetics of ribose binding to MtIAGU-NH by fluorescence spectroscopy suggest two pre-existing forms of enzyme prior to ligand association. The intracellular concentrations of inosine, uridine, hypoxanthine, and uracil were determined and thermodynamic parameters estimated. Thermodynamic activation parameters (Ea, ΔG(#), ΔS(#), ΔH(#)) for MtIAGU-NH-catalyzed chemical reaction are presented. Results from mass spectrometry, isothermal titration calorimetry (ITC), pH-rate profile experiment, multiple sequence alignment, and molecular docking experiments are also presented. These data should contribute to our understanding of the biological role played by MtIAGU-NH.

This difference may be decisive for the therapy. In some cases, this may affect the individual dosage adjustment and subsequent treatment.

OBJETIVO: Medir os níveis de monóxido de carbono no ar exalado (COex) em tabagistas com e sem DPOC. MÉTODOS: Tabagistas frequentadores dos ambulatórios do Hospital São Lucas em Porto Alegre (RS) entre setembro de 2007 e março de 2009 foram convidados a participar do estudo. Os participantes responderam a um questionário com características demográficas e epidemiológicas e realizaram espirometria, medição de cotinina urinária e de COex. Os participantes foram agrupados conforme a presença de DPOC. RESULTADOS: Foram incluídos 294 tabagistas, 174 (59,18%) diagnosticados com DPOC. Todos os participantes apresentavam níveis de cotinina urinária > 50 ng/mL. Os fumantes com DPOC apresentaram medianas significativamente superiores as do grupo sem DPOC para as variáveis idade e maços-ano (p < 0,001 e p = 0,026, respectivamente). Não houve diferença significativa nas demais variáveis. Quando ajustados para sexo, início do tabagismo, cigarros/dia e cotinina urinária, os valores médios de COex foram mais altos no grupo DPOC que no grupo sem DPOC, mas sem significância estatística (17,8 ± 0,6 ppm e 16,6 ± 0,7 ppm, respectivamente; p = 0,200). As diferenças permaneceram não significativas quando o método de base logarítmica foi usado. Uma ampla dispersão dos valores de COex foi encontrada quando os participantes foram classificados conforme os valores de VEF1 (r = -0,06; p = 0,53) ou o sistema de classificação de Global Initiative for Chronic Obstructive Lung Disease (r = 0,08; p = 0,34). As proporções de resultados falso-negativos para tabagismo foram de 18,4% e 6,7%, respectivamente, nos grupos com e sem DPOC (p = 0,007). CONCLUÕES: Esse estudo mostrou que os valores de COex não apresentaram diferenças significativas em fumantes com ou sem DPOC. Desse modo, parece não haver nenhuma restrição relevante para a sua aplicabilidade em fumantes com DPOC.

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Our results bring support to the hUP1 inhibitor strategy as a novel possibility of prevention and treatment of mucositis during the 5-FU chemotherapy, based on the approach of uridine accumulation in plasma and tissues.