2224 research outputs found
Sort by
High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches.
No full textDrug 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.info:eu-repo/semantics/publishedVersio
The Burden of Iron Deficiency in Heart Failure: Therapeutic Approach
No full textHeart failure (HF) is highlighted by its burdening symptom-limited exercise capacity and recurrent hospitalizations. Despite substantial advances regarding disease-modifying drugs in HF with reduced ejection fraction, additional therapeutic strategies to improve quality of life are invaluable. Currently, iron deficiency (ID) is overwhelmingly recognized in over 30% to 50% of patients with stable chronic HF, which worsens prognosis. The established pathophysiological mechanisms of progressive HF may be intertwined with increasing myocardial iron scarcity, wherein one begets the other. Most importantly, ID constitutes a novel target for symptom relief in carefully selected patients. In this regard, intravenous iron may be a safe and efficacious intervention, potentially reducing HF hospitalizations. We discuss the evidence and gaps in knowledge concerning iron therapy in HF and propose a practical, comprehensive, clinically oriented algorithm for timely adequate iron replenishment in different clinical scenarios. Finally, we further debate imperative decision-making before intervention and the drawbacks of such a strategy.info:eu-repo/semantics/publishedVersio
Neonatal Alloimmune Thrombocytopaenia: A Diagnosis to Keep in Mind
Get PDFA trombocitopenia aloimune neonatal é das principais causas de trombocitopenia grave no recém-nascido, estimando-se que
afete um em 1000-10000 nados vivos, estando provavelmente subdiagnosticada. Deve-se à transferência placentar de anticorpos maternos contra antigénios presentes nas plaquetas do feto mas ausentes nas plaquetas da mãe. A trombocitopenia é
de início precoce, podendo ser grave com complicações como a hemorragia intracraniana, que pode ocorrer antes ou após o
nascimento. Descreve-se o caso de um recém-nascido filho de pais naturais da China com uma trombocitopenia grave de início
precoce de causa aloimune por incompatibilidade do antigénio HPA-3b. Esta é uma causa rara de trombocitopenia aloimune
(os antigénios mais frequentes são o HPA-1a e HPA-5b), com poucos casos descritos na literatura. O diagnóstico colocou dificuldades acrescidas, uma vez que os anticorpos maternos são lábeis, tendo a genotipagem plaquetária sido importante para o
esclarecimento da incompatibilidade.info:eu-repo/semantics/publishedVersio
What Should the Role of a Clinical Pharmacist in the Emergency Department be? The Physicians’ Perception
Get PDFIntrodução: O objetivo deste estudo foi encontrar um consenso relativamente às funções do Farmacêutico
Clínico mais valorizadas pelos médicos de uma unidade de internamento de curta duração de um Serviço
de Urgência.
Métodos: O estudo foi realizado no Hospital Prof. Dr. Fernando Fonseca, EPE que serve 700 000 habitantes
do concelho Amadora e Sintra. A uma equipa fixa de 13 clínicos aplicou-se, usando a técnica de Delphi, um
questionário que avaliava as intervenções do Farmacêutico em dois momentos: intervenções detalhadas durante a admissão, internamento e alta do doente e apreciação geral do seu trabalho no Serviço de Urgência.
O questionário foi aplicado três vezes e cada perito valorizou a intervenção do Farmacêutico de acordo com
uma escala qualitativa de Likert. O consenso foi atingido em abril/maio de 2017.
Resultados: Da aplicação do questionário obtiveram-se 21 indicadores com consenso, 12 relacionados com
o momento da admissão e internamento e os restantes com a apreciação geral do trabalho do Farmacêutico.
Os peritos valorizaram indicadores relativos à identificação de reações adversas, de problemas com medicamentos de alto risco, de padrões incorretos de prescrição, de problemas na distribuição do medicamento
correto e à necessidade de discussão de todos os problemas encontrados com o clínico. Algumas intervenções consideradas muito importantes do ponto de vista farmacêutico não foram valorizadas pelos clínicos
como a reconciliação da terapêutica, a monitorização de parâmetros clínicos, a validação farmacêutica de
antibióticos e a promoção da adesão à terapêutica. Os clínicos consensualmente referem que o Farmacêutico
tem um impacto positivo nos resultados clínicos do doente e aumenta a eficiência, segurança e efetividade
do medicamento, antecipando problemas.
Conclusão: O Farmacêutico Clínico do Serviço de Urgência tem um papel importante e é reconhecido dentro da sua equipa como um elemento que acrescenta valor à prática clínica.info:eu-repo/semantics/publishedVersio
DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.
No full textDOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow-channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS.info:eu-repo/semantics/publishedVersio
A challenged case of Vogt-Koyanagi-Harada syndrome: when dermatological manifestations came first.
No full textNTRODUCTION:
Vogt-Koyanagi-Harada syndrome (VKHS) is an inflammatory systemic autoimmune disease principally affecting pigmented tissues in the ocular, auditory, integumentary and central nervous systems. Patients are generally women in the fourth decade of life. The prognosis is correlated mainly with the time between diagnosis and the start of treatment and number of recurrent episodes of inflammation. Most complications are mainly ocular. The purpose of this paper is to describe a clinical case of VKHS.
MATERIAL AND METHODS:
A child with a challenging clinical presentation in which the dermatological symptoms occurred before ocular manifestations.
DISCUSSION AND CONCLUSION:
VKHS is rare in children and can be a diagnostic challenge. It seemed interesting to share this case as an opportunity to expand our knowledge of the clinical spectrum of diseases and reflect about current diagnostic criteria.info:eu-repo/semantics/publishedVersio
Epididymal metastasis from prostate adenocarcinoma: An unusual and challenging diagnosis suspected in gallium-68 prostate-specific membrane antigen-positron emission tomography/computed tomography and histologically confirmed
Get PDFA few cases of prostate adenocarcinoma (PCa) metastases to the epididymis have been documented in literature. We report a case of a 69-year-old man with a left epididymal metastasis, 6 years after radical prostatectomy and adjuvant radiation therapy for PCa. Although he developed biochemical recurrence, only gallium-68 prostate-specific membrane antigen-positron emission tomography/computed tomography revealed high uptake in the left testis and retrovesical space. An unrecognized painless firm nodule was palpable on the left epididymis. Radical orchiectomy was performed, and histopathological examination confirmed PCa metastasis located in the epididymis. To the best of our knowledge, this is the 27th reported case of epididymal metastasis from PCa.info:eu-repo/semantics/publishedVersio