Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica

Health related quality of life and patient reported symptoms before and during definitive radio(chemo)therapy using image-guided adaptive brachytherapy for locally advanced cervical cancer and early recovery A mono-institutional prospective study

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II).

Item does not contain fulltextContext: Inactivating mutations within the AR-gene are present in only around 40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR-gene mutation negative group of AIS-individuals with compromised AR-function (AIS type II). Objective: To investigate if AIS type II can be due to epigenetic repression of AR-transcription. Design: Quantification of AR-mRNA and AR proximal promoter CpG-methylation levels in genital skin derived fibroblasts (GF) derived from AIS type II individuals and control individuals. Setting: University Hospital endocrine research laboratory. Patients: GF from control individuals (N=11) and AIS type II individuals (N=14). Intervention(s): None. Main Outcome Measure(s): Measurement of AR-mRNA and AR promoter CpG-methylation as well as activity of AR proximal promoter in vitro. Results: 57% of individuals with AIS type II (N=8) show a reduced AR-mRNA expression in their GF. A significant inverse correlation exists between AR-mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158bp long region containing these CpGs is sufficient to severely reduce reporter gene expression. This region is bound by the Runt Related transcription factor1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells is able to inhibit reporter gene expression through this region. Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR-gene expression and may result in AIS type II. We suggest that transcriptional modifiers, like RUNX1, could play roles therein offering new perspectives for understanding androgen-mediated endocrine diseases

The combined role of wear particles, macrophages and lymphocytes in the loosening of total joint prostheses

This review considers the causes of loosening of prosthetic joint replacement paying attention to the biological mechanisms rather than other effects that are physical, such as component fracture and other failure related to mechanical problems. Infection accounts for approximately 1.5 per cent of joint loosening and when it occurs it is a cause of serious concern to the surgeon. The loosening of prosthetic joints in the absence of infection is by far the most common reason for revision surgery and is known as aseptic loosening. While this may be multifactorial in terms of causation, and non-biological factors may contribute significantly in a particular individual, a significant part is undoubtedly played by the generation of wear debris, mainly from the bearing surfaces of the joint, and the cellular reaction to this in the implant bed. Phagocytic cells (macrophages and multinucleated giant cells) are the ones that remove foreign material from the tissues, and the ways in which these cells function in the interface between implant and bone are described. Mediators produced locally include numerous cytokines, enzymes and integrins. There is evidence for interactions between macrophages and locally recruited lymphocytes, which may or may not give rise to an immunologically mediated process