Browsing by Author "Pereira, S"
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- Anatomia cirúrgica do osso temporalPublication . Domingues, J; Mendonça, F; Almeida, J; Pereira, S; Sousa, MT, rev.
- Consumo de Psicoestimulantes no Meio Universitário – Aspetos Clínicos e BioéticosPublication . Pereira, S; Costa, AIntrodução: O consumo não-médico de psicoestimulantes tem aumentado de forma significativa nos últimos anos, verificando-se tal fenómeno também no meio académico. Objetivos: Neste artigo pretende-se analisar o padrão de consumo de psicoestimulantes na população universitária, bem como discutir questões clínicas e éticas associadas a esta problemática. Métodos: Para tal foi feito recurso ao que tem sido descrito na literatura sobre o tema. Resultados: Verificou-se que existe uma prevalência significativa de consumo não-médico de psicoestimulantes pelos universitários, sendo a principal fonte de obtenção os colegas, e que este é justificado, na maioria dos casos, pelo desejo de potenciar capacidades cognitivas. Este consumo associa-se a outros consumos recreativos, bem como a maiores níveis de stresse. Apesar da globalização deste fenómeno, não existe evidência conclusiva relativamente aos efeitos cognitivos dos psicoestimulantes, sendo que a maioria dos autores defende que existirá apenas um efeito cognitivo moderado e limitado a capacidades específicas, como a melhoria da memória de trabalho. O efeito motivacional associado ao consumo parece contribuir significativamente para a experiência do utilizador. Conclusões: Este consumo, intimamente relacionado com o fenómeno do neuroenhancement, levanta importantes problemas clínicos e éticos, destacando-se o risco de efeitos adversos, a necessidade de pensar o papel do médico neste fenómeno, e as questões relacionadas com a autonomia individual, o risco de coerção e de injustiça. O consumo não-médico de psicoestimulantes no meio académico é já uma realidade, pelo que se torna essencial estudá-la e compreendê-la, de forma a determinar os pontos mais fraturantes e propor soluções, numa tentativa de uniformizar normas de atuação.
- Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions.Publication . Marinho, A; Rodrigues, P; Caixas, U; Antunes, A; Branco, T; Hargivan, S; Marques, M; Monteiro, E; Pereira, SOBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.
- Efavirenz concentrations in HIV-infected patients with and without viral hepatitisPublication . Pereira, S; Caixas, U; Branco, T; Germano, I; Lampreia, F; Papoila, A; Monteiro, EAIMS: Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included. METHODS: A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period. RESULTS: No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 +/- 1.91 mg l(-1)) vs. co-infected individuals (2.37 +/- 0.37 mg l(-1)). CONCLUSION: It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.
- Effect of efavirenz on high-density lipoprotein antioxidant properties in HIV-infected patientsPublication . Pereira, S; Batuca, J; Caixas, U; Branco, T; Delgado-Alves, J; Germano, I; Lampreia, F; Monteiro, EWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In previous work, we showed a long-term and concentration-dependent beneficial effect of the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) on high-density lipoproteins (HDL) in human immunodeficiency virus (HIV)-infected patients. * Furthermore, it has been suggested that instead of the current practice of only measuring HDL-chelesterol values, the evaluation of HDL function, namely its antioxidant properties, might be an improved tool for identifying subjects at increased risk for cardiovascular events. * Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is responsible for HDL antioxidant function. WHAT THIS STUDY ADDS: * In the present work, we studied the effect of EFV on the activity of PON-1 and showed, for the first time, that EFV-based antiretroviral therapy is associated with a better antioxidant function, i.e. with a higher PON-1 activity. AIMS: A long-term and concentration-dependent beneficial effect of efavirenz (EFV) on cholesterol associated with high-density lipoprotein (HDL-c) in human immunodeficiency virus (HIV)-infected patients has been documented. Furthermore, it has been suggested that, instead of the current practice of only measuring HDL-c values, the evaluation of HDL quality might be an improved tool for identifying subjects at increased risk of cardiovascular events. Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is involved in the onset of cardiovascular disease and responsible for HDL antioxidant function. The aim of the present study was to investigate the effect of EFV on the circulating activity of PON-1 in HIV-infected patients. METHODS: The patients included were adults with a documented HIV-1 infection, nontreated or treated with antiretroviral regimens including EFV 600 mg once daily as first therapeutic regimen for at least 3 months. The influence of treatment with EFV, HDL-c and CD4 cell count on PON-1 activity was analysed. RESULTS: HIV-infected White patients treated with EFV had higher PON-1 activity [77.35 U l(-1) (65.66, 89.04)] (P < 0.05) and higher PON-1 activity : HDL-c ratio [1.88 (1.49, 2.28)] (P < 0.01) than untreated patients. PON-1 activity was higher in Black patients (P < 0.001) and in patients with a CD4 cell count >500 cells ml(-1) (P= 0.0120). CONCLUSIONS: EFV-based antiretroviral regimens are associated with HDL particles with a better antioxidant function, i.e. with a higher PON-1 activity. The PON-1 activity of Black patients is higher than that found in Whites regardless of treatment. Ethnicity should be taken into consideration when studying drug effects on PON-1 activity.
- Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity.Publication . Caixas, U; Antunes, A; Marinho, A; Godinho, A; Grilo, N; Marques, M; Oliveira, M; Branco, T; Monteiro, E; Pereira, SNevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV-1 transmission in developing countries. Despite its clinical efficacy, NVP administration is associated with a variety of toxic responses that include hepatotoxicity and skin rash. Although the reasons for the adverse effects of NVP administration are still unclear, increasing evidence supports the involvement of metabolic activation to reactive electrophiles. In particular, Phase II activation of the NVP metabolite 12-hydroxy-NVP is thought to mediate NVP binding to bionucleophiles, which may be at the onset of toxicity. In the present study, we investigated the nature and specific locations of the covalent adducts produced in human serum albumin and human hemoglobin by reaction in vitro with the synthetic model electrophile 12-mesyloxy-NVP, used as a surrogate for the Phase II metabolite 12-sulfoxy-NVP. Multiple sites of modification were identified by two different mass spectrometry-based methodologies, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-TOF-TOF-MS). These two distinct methodologies, which in some instances afforded complementary information, allowed the identification of multiple adducts involving cysteine, lysine, tryptophan, histidine, serine, and the N-terminal valine of hemoglobin. Tryptophan, which is not a common site of covalent protein modification, was the NVP-modified amino acid residue detected in the two proteins and consistently identified by both LC-ESI-MS/MS and MALDI-TOF-TOF-MS. The propensity of tryptophan to react with the NVP-derived electrophile is further emphasized by the fact that human serum albumin possesses a single tryptophan residue, which suggests a remarkable selectivity that may be useful for biomonitoring purposes. Likewise, the NVP adduct with the terminal valine of hemoglobin, detected by LC-ESI-MS/MS after N-alkyl Edman degradation, appears as an easily assessed marker of NVP binding to proteins. Our results demonstrate the merits and complementarity of the two MS-based methodologies for the characterization of protein binding by NVP and suggest a series of plausible biomarkers of NVP toxicity that should be useful in the monitoring of toxicity effects in patients administered NVP.
- High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches.Publication . Godinho, A; Martins, I; Nunes, J; Charneira, C; Grilo, J; Silva, D; Pereira, S; Soto, K, et al.Drug bioactivation to reactive metabolites capable of covalent adduct formation with bionucleophiles is a major cause of drug-induced adverse reactions. Therefore, elucidation of reactive metabolites is essential to unravel the toxicity mechanisms induced by drugs and thereby identify patient subgroups at higher risk. Etravirine (ETR) was the first second-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) to be approved, as a therapeutic option for HIV-infected patients who developed resistance to the first-generation NNRTIs. Additionally, ETR came into market aiming to overcome some adverse effects associated with the previously used efavirenz (neurotoxicity) and nevirapine (hepatotoxicity) therapies. Nonetheless, post-marketing reports of severe ETR-induced skin rash and hypersensitivity reactions have prompted the U.S. FDA to issue a safety alert on ETR. Taking into consideration that ETR usage may increase in the near future, due to the possible use of the drug for coinfection with malaria and HIV, the development of reliable prognostic tools for early risk/benefit estimations is urgent. In the current study, high resolution mass spectrometry-based methodologies were integrated with MS3 experiments for the identification of reactive ETR metabolites/adducts: 1) in vitro incubation of the drug with human and rat liver S9 fractions in the presence of Phase I and II co-factors, including glutathione, as a trapping bionucleophile; and 2) in vivo, using urine samples from HIV-infected patients on ETR therapy. We obtained evidence for multiple bioactivation pathways leading to the formation of covalent adducts with glutathione and N-acetyl-L-cysteine. These results suggest that similar reactions may occur with cysteine residues of proteins, supporting a role for ETR bioactivation in the onset of the toxic effects elicited by the drug. Additionally, ETR metabolites stemming from amine oxidation, with potential toxicological significance, were identified in vitro and in vivo. Also noteworthy is the fact that new metabolic conjugation pathways of glucuronide metabolites were demonstrated for the first time, raising questions about their potential toxicological implications. In conclusion, these results represent not only a contribution towards the elucidation of new metabolic pathways of drugs in general but also an important step towards the elucidation of potentially toxic ETR pathways, whose understanding may be crucial for reliable risk/benefit estimations of ETR-based regimens.
- HPV type-specific distribution in a group of women attending at Hospital Fernando Fonseca, LisbonPublication . Santos, S; Pista, A; Pedro, A; Álvares, C; Ribeiro, C; Costa, C; Inácio, N; Pereira, S; Verdasca, NIntroduction: Genital HPV infection is very frequent. Nevertheless, type-specific distribution can vary greatly in different populations. Aim: To assess the HPV frequency and type-specific distribution in a highly ethnically diverse region and its association with gynecological cytology. Material and Methods: From March to July 2009, 419 LBC samples (ThinPrep) were collected from women 16-79 years old, attending Hospital Fernando Fonseca and associated Primary Health Care Centers. HPV genotyping was performed using CLINICAL ARRAY HPV 2. Statistical analysis was performed (Chi-Square test). Results: Out of 419 women (median age: 41 years), 74.0% were Caucasian and 21.0% African. Overall, 90.2% of the women had a normal cytology, 4.3% had ASCUS, 3.1% LSIL, 1.7% HSIL, and 0.7% had invasive carcinoma. HPV infection was detected in 25.8% of the cases, whereas in 75.0% of women between 20-45 years. HR-HPV genotypes were identified in 57.8% of the infected women. The most frequent HR-HPV types were HPV16 (11.4%), HPV52 (8.5%), HPV31 and 58 (7.2% each). Multiple infections (2-6 genotypes) were observed in 34.2%. HPV58, 16, 31, and 52 (9.5%, 7.4%, 7.4%, 7.4%, respectively) were the most frequent genotypes. HPV DNA was detected in 19.6% of the women with normal cytology, of which 31.0% had multiple infections. In ASCUS, LSIL, HSIL and invasive carcinoma, HPV was detected in 66.7%, 100%, 100%, and 66.7%, respectively. HPV16, 31, 52, 58 and 42 were most frequent among Caucasian and HPV16, 83, 52, 53 and 54 among African women. HPV16 and 18 were found in 4.5% and 1.0% of the women. Infection by multiple HPV was related to lesion grade (p=0.042). Conclusion: Our results are consistent with the data observed in the literature. Our findings can help achieve a better understanding of the wide spectrum of HPV infection and can contribute to a baseline for future assessment of screening and immunization strategies.
- Recusa escolar em adolescentes: caracterização e situação 27 a 60 meses após a admissão em hospital de diaPublication . Leal, D; Marques, J; Vaz, P; Pereira, S; Matos, AIntrodução: A recusa escolar, definida como ausência escolar por causas emocionais, é o motivo de encaminhamento mais frequente para o Hospital de Dia de Adolescentes da Clí- nica da Juventude. Objectivos: Este estudo pretendeu caracteri- zar os jovens admitidos por recusa escolar e avaliar a sua situação 27 a 60 meses após a sua admissão no Hospital de Dia da Clínica da Juventude. Métodos: Consulta dos processos clínicos de todos os doentes admitidos entre 01 de Janei- ro de 2010 e 31 de Julho de 2012, de modo a avaliar as variáveis: motivo de admissão, sexo, idade, retenções escolares prévias, diag- nóstico, presença de psicopatologia parental, duração do seguimento e número de sessões efectivadas. Foi, ainda, realizado um ques- tionário por via telefónica a todos os doentes que tinham sido admitidos por recusa esco- lar, 27 a 60 meses após a admissão, de modo a apurar a situação escolar/laboral actual, manutenção de seguimento psiquiátrico e sintomatologia emocional e comportamen- tal actual.
- Resultados clínicos de doentes referenciados a Centro OncológicoPublication . Pereira, S; Oliveira, F; Costa, E; Hebe, A; Montalvão, P; Magalhães, MOs tumores da cabeça e pescoço (TCP) associam-se a elevada morbilidade e mortalidade. A referenciação atempada assume particular importância na evolução clínica. No intuito de avaliar a evolução dos doentes observados em consulta de Otorrinolaringologia “Oncológica”, procedeu-se a um estudo dos doentes com TCP referenciados ao Instituto Português de Oncologia (IPO) de Lisboa no ano 2008. Dos 454 doentes observados, a maioria era do sexo masculino (86%) com idade média 60 anos. Os tumores mais comuns foram laríngeos (36%), a maioria (69%) em estadio avançado. A cirurgia foi o tratamento primário em 60%. O intervalo médio de tempo entre primeira consulta e tratamento foi 75 dias, e a sobrevida global aos 2 anos 66%. A maioria dos doentes apresentava tumores avançados aquando da referenciação, o que comprometeu a sobrevida e o controlo locorregional, apesar do início rápido dos tratamentos. Políticas de saúde pública deveriam ser implementadas para melhoria da educação para a saúde, prevenção e referenciação destes doentes.