A short overview on mycophenolic acid pharmacology and pharmacokinetics.

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non-competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric-coated mycophenolate sodium salt (EC-MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post-transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects.

Biomarkers of occupational exposure to pesticides: Systematic review of insecticides.

INTRODUCTION: Pesticides are widely used around the world, and rural workers have greater risk of poisoning. The use of biomarkers for insecticides can contribute to the diagnosis and prevention of poisoning. OBJECTIVE: To identify, in the scientific literature, the biomarkers of occupational exposure to insecticides of different insecticide classes. METHODS: The PubMed, Lilacs and Embase databases were analyzed using a systematic search strategy and in accordance with the criteria established by the PRISMA methodology. Articles with information related to the use of biomarkers to identify active ingredients, or insecticide metabolites, or effects on the human biological matrices were analyzed. RESULTS: A total of 840 studies was found, and 30 met the selection criteria. The search identified 118 results for insecticide biomarkers, of which 45% were of exposure, 42% of effect, and 14% of susceptibility. Additionally, 78 were possible biomarkers, and only 67 confirmed to be different biomarkers for insecticides. Acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 3,5,6-trichloro-2-pyridinol (TCP-y), specific for Chlorpyrifos, were among the most common biomarkers identified; however, most metabolites found were non-specific. CONCLUSION: Various insecticide biomarkers were mentioned; nonetheless, only a few are specific and used to identify the wide range of insecticides to which farm workers are exposed.

Comparison of plasma and oral fluid concentrations of mycophenolic acid and its glucuronide metabolite by LC-MS in kidney transplant patients.

PURPOSE: Mycophenolic acid is one of the most used immunosuppressive drugs in solid organ transplant treatments in the world. Developing a highly sensitive analytical method to analyse the drug and its metabolites in oral fluid and plasma is important to evaluate the possibility of using oral fluid as a biological matrix in therapeutic drug monitoring, instead of plasma. METHOD: The liquid chromatography coupled to mass spectrometry (LC-MS) method was developed and validated for determining mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in oral fluid and plasma, with both matrices presenting a detection limit of 1 ng/mL for MPA and 5 ng/mL for MPAG. Both analytes were analysed after a simple protein precipitation procedure. Transplanted-kidney samples of oral fluid and blood were collected from 13 patients that were hospitalised and kept at - 80 °C until analyses. RESULTS: The proposed method was linear in the concentration range of 5-500 ng/mL for MPA and 10-500 ng/mL for MPAG, with correlation coefficients (r) between 0.9925 and 0.9973. It was then applied to samples collected from kidney-transplanted patients and used for calculation of pharmacokinetics parameters. CONCLUSION: After comparing plasma and oral fluid concentrations as well as performing a non-compartmental pharmacokinetic analysis of the average curves, it is possible to suggest that oral fluid concentration may be used as an alternative for MPA and MPAG monitoring in kidney transplant patients.

Monitoring an outdoor smoking area by means of PM2.5 measurement and vegetal biomonitoring.

The extension of pollutant accumulation in plant leaves associated with its genotoxicity is a common approach to predict the quality of outdoor environments. However, this approach has not been used to evaluate the environmental quality of outdoor smoking areas. This study aims to evaluate the effects of environmental tobacco smoke (ETS) by assessing particulate matter 2.5 µm (PM2.5) levels, the pollen abortion assay, and trace elements accumulated in plant leaves in an outdoor smoking area of a hospital. For this, PM2.5 was measured by active monitoring with a real time aerosol monitor for 10 days. Eugenia uniflora trees were used for pollen abortion and accumulated element assays. Accumulated elements were also assessed in Tradescantia pallida leaves. The median concentration of PM2.5 in the smoking area in all days of monitoring was 66 versus 34 µg/m3 in the control area (P < 0.001). In addition, the elements Al, Cd, Cu, Ni, Pb, Rb, Sb, Se, and V in Tradescantia pallida and Al, Ba, Cr, Cu, Fe, Mg, Pb, and Zn in Eugenia uniflora were in higher concentration in the smoking area when compared to control area. Smoking area also showed higher rate of aborted grains (26.1 ± 10.7 %) compared with control (17.6 ± 4.5 %) (P = 0.003). Under the study conditions, vegetal biomonitoring proved to be an effective tool for assessing ETS exposure in outdoor areas. Therefore, vegetal biomonitoring of ETS could be a complement to conventional analyses and also proved to be a cheap and easy-handling tool to assess the risk of ETS exposure in outdoor areas.

Cotinine and polycyclic aromatic hydrocarbons levels in the amniotic fluid and fetal cord at birth and in the urine from pregnant smokers.

Cigarette smoking during pregnancy has several impacts on fetal development, including teratogenic effects. The objective of this study was to assess whether the toxic substances (cotinine and polycyclic aromatic hydrocarbons) found in pregnant smokers are transmitted to their fetuses. The outcomes were analyzed measuring cotinine and 1-hydroxypyrene in the amniotic fluid and maternal urine, benzopyrene and cotinine in the umbilical cord blood. Through a controlled cross-sectional design, 125 pregnant women were selected and classified according to their smoking status: 37 current smokers, 25 passive smokers and 63 non-smokers (controls). We performed high-performance liquid chromatography to measure substances' concentrations. A post-hoc Tukey's test was used to analyze the differences between the groups. All variables were significantly different between controls and smokers. The mean ratios between the concentration of cotinine in smokers compared to controls were as follows: 5.9 [2.5-13.5], p<0.001 in the urine; 25 [11.9-52.9], p<0.001 in the amniotic fluid; and 2.6 [1.0-6.8], p = 0.044 in the umbilical cord blood. The mean ratios of 1-hydroxypyrene concentration between smokers and controls were 7.3 [1.6-29.6], p = 0.003 in the urine and 1.3 [1.0-1.7], p = 0.012 in the amniotic fluid, and of benzopyrene in umbilical cord blood was 2.9 [1.7-4.7], p<0.001. There were no significant differences between controls and passive smokers. When comparing the three groups together, there were statistical differences between all variables. Thus, the fetuses of pregnant smokers are exposed to toxic and carcinogens substances. To our knowledge, this is the first study to measure 1-hydroxypyrene in the amniotic fluid and benzopyrene in umbilical cord blood by high-performance liquid chromatography when considering pregnant women in relation to smoking exposure only.

Evaluation of genotoxic effects of benzene and its derivatives in workers of gas stations.

The search for reliable biomarkers of human exposure to benzene and its derivatives is still subject of research. Many of the proposed biomarkers have limitations ranging from the low sensitivity to the wide variability of results. Thus, the aim of our study was to assess the frequencies of chromosomal abnormalities (CA) and sister chromatid exchanges (SCE) in workers of gas stations, with (cases, n = 19) and without (local controls, n = 6) risk of exposure to benzene and its derivatives, comparing them with the results from the general population (external controls, n = 38). The blood dosages of benzene, toluene, and xylenes were measured in all participants. Blood solvent levels were compared with the findings obtained in cytogenetic evaluation and a research protocol which included data of the workplace, lifestyle, and health of the individuals. We did not detect the presence of benzene and its derivatives and did not find chromosomal damage that may be associated with the gas station activity in cases. Moreover, although we found an association of increased SCE and the working time in the local controls, the values found for SCE are within normal limits. Thus, our evaluation of SCE and CA reflected the levels of benzene and its derivatives observed in the blood. We believe, therefore, that SCE and CA may actually constitute possible tests for the evaluation of these exposures. However, we believe that further studies, including individuals at risk, are important to confirm this assertion.

Application of the buccal micronucleus cytome assay and analysis of PON1Gln192Arg and CYP2A6*9(-48T>G) polymorphisms in tobacco farmers.

Tobacco is a major Brazilian cash crop. Tobacco farmers apply large amounts of pesticides to control insect growth. Workers come into contact with green tobacco leaves during the tobacco harvest and absorb nicotine through the skin. In the present study, micronucleus frequency, cell death, and the frequency of basal cells were measured in tobacco farmers using the buccal micronucleus cytome assay (BMCyt), in parallel with measurement of blood butyrylcholinesterase (BChE) and nicotine levels. Polymorphisms in PONIGln192Arg and CYP2A6*9(-48T>G) were evaluated to verify the relationship between genetic susceptibility and the measured biomarkers. Peripheral blood and buccal cell samples were collected from 106 agricultural workers, at two different crop times (during pesticide application and leaf harvest), as well as 53 unexposed controls. BMCyt showed statistically significant increases in micronuclei, nuclear buds, and binucleated cells among exposed subjects in differentiated cells, and in micronuclei in basal cells. In addition, the exposed group showed higher values for condensed chromatin, karyorrhectic, pyknotic, and karyolitic cells, indicative of cell death, and an increase in the frequency of basal cells compared to the unexposed control group. A slight difference in mutagenicity using the BMCyt assay was found between the two different sampling times (pesticide application and leaf harvest), with higher micronucleus frequencies during pesticide application. Elevated cotinine levels were observed during the leaf harvest compared to the unexposed controls, while BChE level was similar among the farmers and controls. PONIGln192Arg and CYP2A6*9(-48T>G) polymorphisms were associated with DNA damage induced by pesticides and cell death.

Nicotine alters the ectonucleotidases activities in lymphocytes: In vitro and in vivo studies.

The aim of the present study was to investigate the effects in vivo and in vitro of nicotine, an important immunosuppressive agent, on NTPDase and ADA activities in lymphocytes of adult rats. The following nicotine doses in vivo study were evaluated: 0.0, 0.25 and 1.0mg/kg/day injected subcutaneously in rats for 10days. The activity of the enzymes were significantly decreased with nicotine 0.25 and 1mg/kg which inhibited ATP (22%, 54%), ADP (44%, 30%) hydrolysis and adenosine (43%, 34%) deamination, respectively. The expression of the protein NTPDase in rat lymphocytes was decreased to nicotine 1mg/kg and the lymphocytes count was decreased in both nicotine doses studied. The purine levels measured in serum of the rats treated with nicotine 0.25mg/kg significantly increased to ATP (39%), ADP (39%) and adenosine (303%). The nicotine exposure marker was determinate by level of cotinine level which significantly increased in rats treated with nicotine 0.25 (39%) and 1mg/kg (131%) when compared to rats that received only saline. The second set of study was in vitro assay which the ATP-ADP-adenosine hydrolysis were decreased by nicotine concentrations 1mM (0% - 0% - 16%, respectively), 5mM (42% - 32% - 74%, respectively), 10mM (80% - 27% - 80%, respectively) and 50mM (96% - 49% - 98%, respectively) when compared with the control group. We suggest that alterations in the activities of these enzymes may contribute to the understanding of the mechanisms involved in the suppression of immune response caused by nicotine.

A integração ensino-serviço como estratégia na formação profissional para o SUS / Integration between learning and health services as a strategy for professional training in the Unified Health System

Trata-se de um relato de experiência relativo às estratégias e ações adotadas para a integração ensino-serviço, com a finalidade de contribuir no processo de formação profissional na área da saúde, em consonância com as diretrizes e princípios do Sistema Único de Saúde (SUS). O trabalho aborda as descobertas, os avanços, as potencialidades, as dificuldades e os pontos críticos encontrados, assim como as experiências bem-sucedidas e a sustentabilidade vivenciada no contexto da Atenção Primária à Saúde com os programas Pró-Saúde e PET-Saúde.

This is a case report on an experience with strategies and actions for the integration of learning and health services, with the aim of contributing to professional training in health, in keeping with the guidelines and principles of the Unified National Health System (SUS). The study addresses the discoveries, advances, potentialities, difficulties, and critical points, as well as successful experiences and sustainability in the context of Primary Healthcare with the Pró-Saúde and PET-Saúde programs.

Influence of physical exercise and gender on acetylcholinesterase and butyrylcholinesterase activity in human blood samples.

The determination of cholinesterase activity in plasma and erythrocytes serves as a useful and sensitive biomarker of exposure to organophosphorus and carbamate pesticides. However, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity may be influenced by factors such as age, gender, drugs, and physical exercise. The aim of this study was to evaluate the effects of gender and physical exercise on the activity of AChE and BuChE in healthy individuals. The values for both enzymes were lower for women. Physical exercise increased the levels of BuChE, and had no significant effect on AChE. To our knowledge, this is the first clinical study evaluating the influence of physical exercise in levels of these enzymes. Considering that cholinesterase activity is a useful parameter in assessing the exposure of individuals to pesticides, it is important to understand factors that influence the determination of the enzymes in order to avoid the erroneous interpretation of results.

[A retrospective study analysis of urinary hippuric acid levels in occupational toxicology exams]. / Estudo retrospectivo dos níveis de ácido hipúrico urinário em exames de toxicologia ocupacional.

Hippuric acid is the primary metabolite of toluene, a solvent widely used in industrial processes with considerable toxic effects, a fact which justifies regularly monitoring individuals with occupational exposure to this solvent. This work aims at evaluating urinary hippuric acid levels found in workers subject to biological monitoring. A retrospective study was carried out with data referring from 2002 to 2005, in which exams results and employment status were analyzed (periodic, post-employment, and pre-employment exams). Results indicate a significant reduction in hippuric acid levels for 2005. Periodic exams presented higher results than pre-employment and post-employment exams. No significant difference was found in individuals grouped according to their status in each of the established intervals, their reference numbers, and maximum biological levels allowed. Hippuric acid levels detected indicate low risk of toluene exposure for the population under evaluation, probably due to a growing concern with the deployment of measures regarding occupational hygiene.

Evaluation of the exhaled carbon monoxide levels in smokers with COPD.

OBJECTIVE: To measure exhaled carbon monoxide (COex) levels in smokers with and without COPD. METHODS: Smokers treated at outpatient clinics of São Lucas Hospital in the city of Porto Alegre, Brazil, between September of 2007 and March of 2009 were invited to participate in this study. The participants completed a questionnaire regarding demographic and epidemiologic characteristics and were submitted to spirometry, as well as to determination of COex and urinary cotinine levels. The participants were divided into two groups: those with COPD and those without COPD. RESULTS: The study involved 294 smokers, of whom 174 (59.18%) had been diagnosed with COPD. All of the participants presented with urinary cotinine levels > 50 ng/mL. Smokers with COPD presented significantly higher median values for age and pack-years than did those without COPD (p < 0.001 and p = 0.026, respectively). No other statistically significant differences were found. When adjusted for gender, age at smoking onset, number of cigarettes/day and urinary cotinine level, the mean values of COex were higher, but not statistically so, in the COPD group than in the non-COPD group (17.8 +/- 0.6 ppm and 16.6 +/- 0.7 ppm, respectively; p = 0.200). The differences remained nonsignificant when plotted logarithmically. A wide dispersion of COex values was found when the participants were classified by FEV1 level (r = -0.06; p = 0.53) or by Global Initiative for Chronic Obstructive Lung Disease classification (r = 0.08; p = 0.34). The proportions of false-negative results for smoking were 18.4% and 6.7%, respectively, in the COPD and non-COPD groups (p = 0.007). CONCLUSIONS: Since COex values did not differ significantly between smokers with COPD and those without, there seem to be no major contraindications to their use in smokers with COPD.

Avaliação da concentração de monóxido de carbono no ar exalado em tabagistas com DPOC / Evaluation of the exhaled carbon monoxide levels in smokers with COPD

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 por cento) 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 por cento e 6,7 por cento, 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.

OBJECTIVE: To measure exhaled carbon monoxide (COex) levels in smokers with and without COPD. METHODS: Smokers treated at outpatient clinics of São Lucas Hospital in the city of Porto Alegre, Brazil, between September of 2007 and March of 2009 were invited to participate in this study. The participants completed a questionnaire regarding demographic and epidemiologic characteristics and were submitted to spirometry, as well as to determination of COex and urinary cotinine levels. The participants were divided into two groups: those with COPD and those without COPD. RESULTS: The study involved 294 smokers, of whom 174 (59.18 percent) had been diagnosed with COPD. All of the participants presented with urinary cotinine levels > 50 ng/mL. Smokers with COPD presented significantly higher median values for age and pack-years than did those without COPD (p < 0.001 and p = 0.026, respectively). No other statistically significant differences were found. When adjusted for gender, age at smoking onset, number of cigarettes/day and urinary cotinine level, the mean values of COex were higher, but not statistically so, in the COPD group than in the non-COPD group (17.8 ± 0.6 ppm and 16.6 ± 0.7 ppm, respectively; p = 0.200). The differences remained nonsignificant when plotted logarithmically. A wide dispersion of COex values was found when the participants were classified by FEV1 level (r = -0.06; p = 0.53) or by Global Initiative for Chronic Obstructive Lung Disease classification (r = 0.08; p = 0.34). The proportions of false-negative results for smoking were 18.4 percent and 6.7 percent, respectively, in the COPD and non-COPD groups (p = 0.007). CONCLUSIONS: Since COex values did not differ significantly between smokers with COPD and those without, there seem to be no major contraindications to their use in smokers with COPD.

Estudo retrospectivo dos níveis de ácido hipúrico urinário em exames de toxicologia ocupacional / A retrospective study analysis of urinary hippuric acid levels in occupational toxicology exams

O ácido hipúrico é o principal metabólito do tolueno, solvente amplamente utilizado em processos industriais e com importantes efeitos tóxicos, fato que justifica a preocupação em monitorar regularmente sujeitos com risco de exposição ocupacional a este solvente. O objetivo deste trabalho foi avaliar os níveis de ácido hipúrico encontrados em trabalhadores submetidos à monitorização biológica. Foi realizado um estudo retrospectivo com dados dos anos de 2002 a 2005, no qual foram analisados os resultados e a situação do empregado na oportunidade do exame (periódico, demissional e admissional). Os resultados indicam uma redução significativa nos níveis de ácido hipúrico em 2005. Exames periódicos obtiveram resultados superiores aos exames admissionais e demissionais, e não foi verificada diferença significativa nas proporções dos sujeitos agrupados de acordo com a situação funcional em cada um dos intervalos estabelecidos segundo o valor de referência e o índice biológico máximo permitido. Os níveis de ácido hipúrico detectados indicam um baixo de risco de exposição ao tolueno na população avaliada, provavelmente em decorrência da preocupação crescente com a implantação de medidas de higiene ocupacional.

Hippuric acid is the primary metabolite of toluene, a solvent widely used in industrial processes with considerable toxic effects, a fact which justifies regularly monitoring individuals with occupational exposure to this solvent. This work aims at evaluating urinary hippuric acid levels found in workers subject to biological monitoring. A retrospective study was carried out with data referring from 2002 to 2005, in which exams results and employment status were analyzed (periodic, post-employment, and pre-employment exams). Results indicate a significant reduction in hippuric acid levels for 2005. Periodic exams presented higher results than pre-employment and post-employment exams. No significant difference was found in individuals grouped according to their status in each of the established intervals, their reference numbers, and maximum biological levels allowed. Hippuric acid levels detected indicate low risk of toluene exposure for the population under evaluation, probably due to a growing concern with the deployment of measures regarding occupational hygiene.

Cotinine as a biomarker of tobacco exposure: development of a HPLC method and comparison of matrices.

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.

A high-performance liquid chromatography method for the determination of carbamazepine and carbamazepine-10,11-epoxide and its comparison with chemiluminescent immunoassay.

BACKGROUND: Carbamazepine is a first-choice antiepileptic drug for the treatment of simple and complex partial seizures. The use of an established therapeutic range for carbamazepine concentration is limited by the presence of carbamazepine-10,11-epoxide, its active metabolite that significantly contributes to the efficacy and toxicity and is not routinely measured and accounted for. This article describes the development of a HPLC method for determination of carbamazepine and carbamazepine-10,11-epoxide in serum, and compares it with chemiluminescence immunoassay to evaluate the importance of considering the active metabolite in therapeutic strategies. METHODS: The procedure involves protein precipitation, separation on a reverse-phase column and ultraviolet detection. The analytical procedure proved to be sensitive, selective, precise, accurate and linear (regression coefficients >0.999) in the range of 0.5-25.0 microg/mL and 0.1-10.0 microg/mL for quantification of carbamazepine and carbamazepine-10,11-epoxide, respectively. For the comparison between methods, serum samples of 75 patients using the medication were evaluated. RESULTS: The Pearson correlation coefficient showed that the carbamazepine concentrations measured by HPLC are significantly higher than those obtained by immunoassay (mean difference of 1.07 microg/mL, 95% limits of agreement from -0.65 to 2.80 microg/mL). CONCLUSIONS: This difference may be decisive for the therapy. In some cases, this may affect the individual dosage adjustment and subsequent treatment.

Therapeutic drug monitoring of tacrolimus in pancreas transplantation at São Lucas Hospital

Tacrolimus (FK 506), a potent immunosuppressive drug used in prevention and treatment of rejection of transplanted organs, exhibits efficacy related to its blood levels and has a narrow therapeutic index. These factors require frequent monitoring of patients blood levels, in attempt to adjust the dose to reach the best drug concentration with minimum side effects. In this historic study, the authors evaluated tacrolimus blood profile in patients submitted to pancreas transplantation between June 2002 and March 2004. The results show that blood levels were, mostly, within subtherapeutic (39.1 percent) and toxic (43.4 percent) ranges. Considering post-transplantation period, subtherapeutic levels were more frequent until three months after the graft receiving (51.1 percent) and between three and six months (41.9 percent), whereas toxic levels were more common six months after the transplantation (63 percent). Patients who received pancreas/kidney transplantation showed a tendency to present toxic levels. The same did not happen with the patients who received isolated pancreas and pancreas after kidney; these patients presented subtherapeutic blood levels in all post-transplantation periods. The results found in this study reassure the importance of therapeutic monitoring to achieve the adequate blood levels of tacrolimus following pancreas transplantation.

O tacrolimus (FK506), um potente imunossupressor utilizado na profilaxia e no tratamento de rejeições pós-transplante, exibe eficácia relacionada com sua concentração sangüínea e possui estreita janela terapêutica. Esses fatores requerem o freqüente monitoramento dos níveis sangüíneos em pacientes que fazem uso do fármaco, tendo como objetivo o ajuste de dose para uma concentração terapêutica ótima com efeitos colaterais mínimos. Este estudo retrospectivo foi realizado através do acesso à base de dados do Laboratório de Patologia Clínica do Hospital São Lucas, da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), e teve por objetivo analisar o perfil das concentrações sanguíneas de tacrolimus em pacientes transplantados de pâncreas, no período de junho de 2002 a março de 2004. Os resultados mostram que as concentrações se encontravam, em sua maioria, em níveis subterapêuticos (39,1 por cento) e tóxicos (43,4 por cento). Considerando-se o período pós-transplante, níveis subterapêuticos foram mais freqüentes nos períodos de zero a três meses (51,1 por cento) e de três a seis meses (41,9 por cento) após o transplante, enquanto níveis tóxicos (63 por cento) foram mais freqüentes após seis meses. Pacientes que receberam pâncreas/rim simultâneo apresentaram, de maneira geral, mais concentrações em níveis tóxicos; o mesmo não aconteceu em pacientes que receberam pâncreas isolado e pâncreas pós-rim. Os pacientes que receberam pâncreas isolado e pâncreas pós-rim tenderam a apresentar níveis subterapêuticos em todos os períodos pós-transplante considerados. Os resultados obtidos neste trabalho demonstram a importância do monitoramento terapêutico, uma vez que seus resultados orientam o ajuste das doses.

Laboratory diagnosis of toluene-based inhalants abuse.

UNLABELLED: Toluene is the main substance contained in products used as inhalants. The frequent abuse of toluene-based inhalants requires the definition of a simple laboratory parameter that allows acute exposure assessment. This study aimed at defining urinary hippuric acid (UHA) levels related to intentional exposure to toluene, and to correlate them to blood toluene concentration (BT). METHODS: BT and UHA levels were measured in 65 homeless adolescents of Porto Alegre, Brazil. RESULTS: Toluene was detected in 91.9% of the investigated population, who presented BT levels from 0.5 to 83.7 microg/mL. There was good correlation between UHA and BT concentrations (r = 0.78), and in homeless adolescents, UHA levels higher than 3.0 g/g creatinine indicate intentional exposure to toluene. CONCLUSIONS: The determination of UHA concentrations can be used as a screening method for the detection of intentional exposure to toluene, but its diagnosis must include BT toluene dosage, as well as circumstantial and clinical evidence.

Interferência do consumo de Chimarrão nos níveis de ácido hipúrico urinário / Chimarrão consumption interference and hippuric acid urine levels

O ácido hipúrico (AH) é empregado como indicador de exposição ocupacional ao tolueno, uma vez que é seu principal metabólito na urina. Contudo, o AH pode ser originado também do ácido benzóico, presente em algumas frutas e alimentos. Considerando que a erva-mate apresenta entre seus constituintes precursores do ácido benzóico, este estudo foi realizado com o objetivo de verificar a provável interferência do consumo de chimarrão nos níveis de AH urinário. Foram analisadas 70 amostras de urina de indivíduos não expostos ao tolueno ou qualquer alimento rico em seus precursores. O AH foi determinado por cromatografia gasosa e os resultados corrigidos pela creatinina urinária. A média dos resultados foi significativamente maior entre os consumidores de chimarrão (média=1,40+- erro padrão= 0,2953), demonstrando que o consumo recente desta bebida pode interferir nos resultados de AH urinário. São necessãrios estudos adicionais para avaliar a interferência do tipo de erva-mate e do padrão de consumo.