Browsing by Author "Miranda, Joana P."
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- The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodiesPublication . Marinho, Aline T.; Batuca, Joana R.; Miranda, Joana P.; Caixas, Umbelina; Dias, Clara G.; Branco, Teresa; Soto, Karina; Pinheiro, Pedro; Bourbon, Mafalda; Marques, M. Matilde; Antunes, Alexandra M.; Monteiro, Emília C.; Pereira, Sofia A.The antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.
- The European Registered Toxicologist (ERT): Current status and prospects for advancementPublication . Wilks, Martin F.; Blaauboer, Bas J.; Schulte-Hermann, Rolf; Wallace, Heather M.; Galli, Corrado L.; Haag-Grönlund, Marie; Matović, Vesna; Teixeira, Joao Paulo; Zilliacus, Johanna; Basaran, Nursen; Bonefeld-Jørgensen, Eva Cecilie; Bourrinet, Philippe; Brueller, Werner; Claude, Nancy; Miranda, Joana P.; Gundert-Remy, Ursula; Håkansson, Helen; Kovatsi, Leda; Liesivuori, Jyrki; Lindeman, Brigitte; Lison, Dominique; Leconte, Isabelle; Martínez-López, Emma; Murias, Marek; Michel, Cécile; Scheepers, Paul T.J.; Stanley, Lesley; Tsatsakis, AristidisFollowing its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members. In order to continue the harmonisation of requirements and processes between national registering bodies as a prerequisite for official recognition of the ERT title as a standard, and to take account of recent developments in toxicology, an update of the ERT Guidelines has been prepared in a series of workshops by the EUROTOX subcommittees for education and registration, in consultation with representatives of national toxicology societies and registers. The update includes details of topics and learning outcomes for theoretical training, and how these can be assessed. The importance of continuing professional development as the cornerstone of re-registration is emphasised. To help with the process of harmonisation, it is necessary to collate and share best practices of registration conditions and procedures across Europe. Importantly, this information can also be used to audit compliance with the EUROTOX standards. As recognition of professionals in toxicology, including specialist qualifications, is becoming more important than ever, we believe that this can best be achieved based on the steps for harmonisation outlined here together with the proposed new Guidelines.