Magda Susana Perassolo

The Ala54Thr polymorphism of the FABP2 gene influences the postprandial fatty acids in patients with type 2 diabetes.

CONTEXTnThe Ala54Thr polymorphism of FABP2 gene increases affinity of intestinal fatty acid-binding protein 2 for long-chain dietary fatty acids (FA) in subjects without diabetes.nnnOBJECTIVEnOur objective was to evaluate whether the Ala54Thr polymorphism of the FABP2 gene influences the FA composition in chylomicrons after a standard meal in patients with type 2 diabetes.nnnMETHODSnThis clinical trial studied 11 patients with TT and 15 patients with AA genotypes for Ala54Thr polymorphism of FABP2 gene selected from a Brazilian type 2 diabetic cohort. FA in chylomicrons (gas chromatography), plasma glucose, and serum triglycerides were measured after an overnight fast at baseline and, after a standard test meal, at 2-h intervals during 8 h.nnnRESULTSnDuring the test meal, the curves response of unsaturated FA of patients with TT genotype were different from patients with AA genotype: only patients with TT genotype exhibited an increase, with a postprandial peak at 6 h in monounsaturated FA [0.479 (0.248-0.709) to 1.674 (0.698-2.650) g/liter], polyunsaturated FA [0.338 (0.154-0.522) to 1.827 (0.389-3.265) g/liter], and trans-unsaturated FA [0.025 (0.013-0.037) to 0.122 (0.040-0.205) g/liter] (generalized estimating equations for repeated measurements: P<0.05 for all). The increase of saturated FA did not reach statistical significance. Diabetes treatment, previous diet, FA at baseline, and the increase of plasma glucose and triglycerides during the test meal were not different between TT and AA genotypes.nnnCONCLUSIONSnThe TT genotype in Ala54Thr polymorphism of FABP2 gene in patients with type 2 diabetes increased dietary FA absorption, and this might increase the susceptibility to the effects of dietary lipids.

The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system

The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesis-block micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer.

Acompanhamento farmacoterapêutico em pacientes dislipidêmicos de um lar de idosos da cidade de Novo Hamburgo-RS

INTRODUCTION: Since the last century, life expectancy and the incidence of disease in the elderly have increased, especially chronic diseases. OBJECTIVE: This study aims to evaluate the pharmacotherapeutic follow-up(PF) in dyslipidemic patients of a nursing home in Novo Hamburgo city, state of Rio Grande do Sul, Brazil. METHODOLOGY: This is a quantitative, observational study with a longitudinal retrospective design, evaluating 50 elderly patients who live in a nursing home (80.2 ± 7.64 years old, 32 women). We assessed the lipid profile of these patients (total cholesterol, triglycerides, HDL and LDL) before and after one-year PF. The analysis was conducted through descriptive statistics and Student t test or U of Mann Whitney test for paired samples. RESULTS: 56% of the patients presented changes in lipid profile in the beginning of the study and 30% one year later, with significant improvement of the lipid profile after the monitoring. Moreover, total cholesterol levels showed a favorable decrease after a year of monitoring (206 ± 53 vs. 180 ± 43 mg/dL; P = 0.009). Most patients diagnosed with dyslipidemia were using drugs, for at least three months, to treat this pathology (statins and fibrates). The majority of these patients used them correctly. CONCLUSIONS: The patients had significant improvement in their lipid profile after one year of monitoring.

Pharmacogenetic and Pharmacokinetic Dose Individualization of the Taxane Chemotherapeutic Drugs Paclitaxel and Docetaxel.

BACKGROUNDnThe taxane drugs paclitaxel and docetaxel, widely used on cancer chemotherapy, are currently dosed mainly based on body-surface area. This approach is associated with wide interindividual variability in drug exposure, leading to suboptimal dosing for many patients.nnnMETHODSnThe available evidence supporting dose individualization strategies for paclitaxel and docetaxel were reviewed, focusing mainly on the application of therapeutic drug monitoring by a priori pharmacogenetic data or a posteriori drug measurements in biological fluids. The PubMed database was searched, in the period of 1987-2017, using the keywords pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, personalized medicine, taxanes paclitaxel and docetaxel, either alone or in combination.nnnRESULTSnThe current knowledge of pharmacology of the taxane drugs paclitaxel and docetaxel, mainly its pharmacokinetics and the proteins responsible for their biotransformation and transport, along with the genetic polymorphism responsible for variations in the activities of these proteins, opens new opportunities for dose selection for individual patients.nnnCONCLUSIONnConsidering the relation between systemic exposure to these drug and clinical responses, a posteriori TDM, with measurement of drug concentrations in plasma of treated patients, is currently the most straightforward approaches for dose individualization of paclitaxel and docetaxel.

Simultaneous determination of fluoxetine and norfluoxetine in dried blood spots using high-performance liquid chromatography-tandem mass spectrometry

BACKGROUNDnTherapeutic drug monitoring (TDM) of the widely prescribed antidepressant fluoxetine (FLU) is recommended in certain situations, such as occurrence of toxicity, inadequate response or suspect of poor adherence. Dried blood spot (DBS) sampling is an increasingly studied alternative for TDM, particularly for outpatients, due to its ease of collection and inherent stability.nnnOBJECTIVESnThe aim of this study was to develop and validate an LC-MS/MS assay for the simultaneous quantification of FLU and norfluoxetine (NFLU) in DBS.nnnDESIGN AND METHODSnThe assay is based on a liquid extraction of single DBS with 8mm of diameter, using FLU-D6 as the internal standard, followed by reversed phase separation in an Accucore® C18 column (100×2.1mm, 2.6μm). Mobile phase was composed of water and acetonitrile (gradient from 80:20 to 50:50, v/v), both containing formic acid 0.1%. The assay was validated and applied to 30 patients under FLU pharmacotherapy.nnnRESULTSnThe assay was linear in the range 10-750ngmL-1. Precision assays presented CV% of 3.13-9.61 and 3.54-7.99 for FLU and NFLU, respectively, and accuracy in the range of 97.98-110.44% and 100.25-105.8%. FLU and NFLU were stable at 25 and 45°C for 7days. The assay was evaluated in 30 patients under FLU treatment. Concentrations of both compounds were higher in DBS than in plasma, and the use of the multiplying factors 0.71 and 0.68 for FLU and NFLU, respectively, allowed acceptable estimation of plasma concentrations, with median prediction bias of -0.55 to 0.55% and mean differences of 0.4 to 2.2ngmL-1.nnnCONCLUSIONSnThe presented data support the clinical use of DBS for therapeutic drug monitoring of FLU.

Acompanhamento farmacoterapêutico em idosos hipertensos residentes em um lar geriátrico, localizado na Região do Vale dos Sinos, Rio Grande do Sul, Brasil

INTRODUCAO: A hipertensao arterial sistemica (HAS) e um dos problemas de saude de maior prevalencia, afetando cerca de 600 milhoes de pessoas em todo mundo. No Brasil, aproximadamente 65% da populacao idosa e portadora desta doenca. Objetivo: Avaliar a resposta farmacoterapeutica em idosos hipertensos, residentes em um lar geriatrico, apos acompanhamento farmacoterapeutico e intervencoes farmaceuticas. METODOLOGIA: Trata-se de estudo quantitativo, observacional com delineamento longitudinal retrospectivo. Participaram 31 (62%) idosos do total de 50 individuos (acima de 60 anos), de ambos os sexos e com HAS diagnosticada. Avaliaram-se as medias mensais das pressoes sistolica, diastolica e pressao arterial media, no periodo de setembro/2008 a julho/2010. A analise dos resultados ocorreu por meio de estatistica descritiva e teste t de Student para amostras pareadas. RESULTADOS: Quanto ao tratamento medicamentoso para HAS, predominou o uso de Inibidores da ECA (71%) e diureticos tiazidicos (41,9%); 61,3% dos pacientes em estudo fazem tratamento farmacologico em associacao de farmacos anti-hipertensivos. Nao foram observadas interacoes medicamentosas clinicamente relevantes entre os farmacos anti-hipertensivos e as demais classes terapeuticas utilizadas pelos idosos. Houve queda nas medias pressoricas, assim como no numero de pacientes com pressao arterial alterada. CONCLUSAO: O decrescimo das medias pressoricas pode ser atribuido a diversos fatores e, apos o acompanhamento farmacoterapeutico desses pacientes, os niveis de pressao arterial melhoraram.

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity

BACKGROUNDnIrinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patients body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment.nnnMETHODSnThe PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data.nnnCONCLUSIONSnThe findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization.

Oxidative stress in patients with type 2 diabetes mellitus treated with metformin

*** Oxidative stress in patients with type 2 diabetes mellitus treated with metformin *** AIMS: To evaluate oxidative stress parameters in patients with type 2 diabetes mellitus treated with metformin, relating these values to its side effects, plasma levels, glycemic control, diabetic complications, lipid profile, and the influence of pharmacotherapeutic follow-up. METHODS: Patients with type 2 diabetes mellitus , on metformin and in pharmacotherapeutic follow-up for four months, were evaluated. The pharmacotherapeutic follow-up consisted in providing information and answering patients’ questions about medication and disease. In addition, administration times, dosages, and presence or absence of side effects related to the use of metformin were verified. Glycemic and lipid profile, oxidative stress (superoxide dismutase and malondialdehyde) and plasma metformin were evaluated. Pearson’s correlation and Spearman’s correlation were performed to evaluate the relationship between the variables at the beginning of the study. The independent t-test and Mann-Whitney U test were used to assess the difference between the groups with and without diabetic complications. The range of values between the beginning andxa0 end of the study was evaluated using Student’s t-test or Wilcoxon U test. The significance level was set at 5%. RESULTS: The initial sample consisted of 49 patients aged 59±9 years with a body mass index of 29.8±5.1 kg/m 2 , who have had diabetes for a median time of 36 months (interquartile range of 1-240) and have been on metformin for a median time of 36 months (interquartile range of 1-180). Twenty-five patients left the study between the second and fourth meetings. Malondialdehyde levels differed between before and after pharmacotherapeutic follow-up, being positively correlated with blood glucose, glycohemoglobin, and triglyceride level, and negatively correlated with metformin and superoxide dismutase. Blood glucose, glycohemoglobin, and malondialdehyde levels increased, whereas metformin levels decreased in the group with diabetic complications, and there was a correlation between malondialdehyde and the number of diabetic complications per patient. CONCLUSIONS: In this sample of patients with type 2 diabetes mellitus treated with metformin, oxidative stress was more pronounced in those with poor glycemic control and diabetic complications.