Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.

RESUMO:A espécie Calceolaria chelidonioides (Scrophulariaceae), até então inédita nas citações científi cas, foi estudada sob o ponto de vista farmacológico buscando-se identifi car possíveis atividades antimicrobiana e antioxidante em metodologia in vitro. As partes aéreas dessa espécie demonstraram atividade antioxidante em modelo usando o radical livre DPPH. As fl ores de C. chelidonioides mostraram grande potencial antibacteriano frente à bactéria Staphylococcus aureus resistente a meticilina MRSA, um dos principais responsáveis em casos de infecção hospitalar.Unitermos: Calceolaria chelidonioides, Scrophulariaceae, MRSA, DPPH.ABSTRACT: "Antioxidant and anti-microbial activity from Calceolaria chelidonioides Humb. Bonpl. & Kunth." The species Calceolaria chelidonioides (Scrophulariaceae), not scientifi c described so for, was studied in pharmacological aspects aiming to identify some anti-microbial and antioxidant activity. The aerial parts showed antioxidant activity using in vitro DPPH model. The fl owers from C. chelidonioides showed strong antibacterial potential against meticiline resistant Staphylococcus aureus (MRSA) strains the main responsible for hospital infection complications.

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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 r 2 >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.

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