RESUMO
Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.
Assuntos
Animais , Masculino , Camundongos , Plasma , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Dasatinibe/análise , FarmacocinéticaRESUMO
Abstract The aim of this work was to perform an extended stability study for the analgesic containing fentanyl, clonidine and ropivacaine in physiological saline solution 0.9% at different infusion sites, such as infusion bags, epidural infusion sets and syringes. The extended stability was assessed by an HPLC system equipped with a photodiode array detector set at 210 nm. The separation was conducted on a C18 column maintained at 40˚C and using an isocratic mobile phase consisted of buffer solution-methanol-acetonitrile (45:45:10, v/v/v). The presence of particulate matter and the pH of each solution were also investigated. Twenty-four hours after the preparation, the formation of one suspected product was observed and for all drugs, in 24 hours it was observed the concentration decrease in different sets (PVC infusion bags, syringes and epidural infusion administration sets). The pH values of each solution varied no more than 5% during the study and no particle was observed. Conclusion: The extended stability study was applied to the analgesic solution and promoted the detection of an unexpected peak in 24 hours. Based on it, further stability studies are necessary to determine the extended stability data.
RESUMO
ABSTRACT Setting: Treatment of tuberculosis (TB) can result in Drug-Induced Liver Injury (DILI) since hepatotoxic metabolites are formed during the biotransformation of isoniazid (INH).DILI can be related to the genetic profile of the patient. Single nucleotide polymorphisms in the CYP2E1 gene and GSTM1 and GSTT1 deletion polymorphisms have been associated with adverse events caused by INH. Objective: To characterize the genetic polymorphisms of CYP2E1, GSTT1 and GSTM1 in TB carriers. Design: This is an observational prospective cohort study of 45 patients undergoing treatment of TB. PCR-RFLP and multiplex-PCR were used. Results: The distribution of genotypic frequency in the promoter region (CYP2E1 gene) was: 98% wild genotype and 2% heterozygous. Intronic region: 78% wild genotype; 20% heterozygous and 2% homozygous variant. GST enzyme genes: 24% Null GSTM1 and 22% Null GSTT1. Patients with any variant allele of the CYP2E1 gene were grouped in the statistical analyses. Conclusion: Patients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI (p = 0.09; OR: 4.57; 95% CI: 0.75-27.6). Individuals with both genotypes had no increased risk compared to individuals with one genotype.