Drug interaction | EPFL Graph Search

Drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. The cause is often inhibition of, or less effective action, of the specific receptors available to the drug. This influences drug molecules to bind to secondary targets, which may result in an array of unwanted side-effects. The term selectivity describes a drug’s ability to target a single receptor, rendering a predictable physiological response. For example, the binding of acetylcholine to muscarinic tracheal smooth-muscle receptors (M3) results in smooth muscle contractions. When freely binding receptors interact with agonist- chemicals that activate receptors - and antagonists- that inhibit/ block activation - the opportunity for selective drugs to bind with the intended receptor cells decreases as most receptors are already accounted for. Therefore, the drugs are more likely to bind to other receptors relative to the in

Comprendre la société-Monde par ses enjeux et ses acteurs

Olivier Vilaça

The aim of this thesis is to understand the World as a full-fledged object, namely as the space of a society. This objective is at the same time necessary and problematic. It is necessary because the sudden end of the Cold War entailed the need of new conceptual frameworks to understand the World without the confrontation of two ideological blocs. In parallel, the acceleration of globalization based on transnational and reticular processes profoundly questioned the apportionment of the World in territories and the classical distinction between the national and international spheres. This phenomenon also brought about the emergence of social issues (such as AIDS and climate change) and of non-state actors (such as globalized companies and Non-Governmental Organizations) which cannot be understood without taking into account their global dimension. Faced with these profound changes, it is important to be able to apprehend the World in its global dimension, going beyond its economic aspects. The so-called Global society model, which considers the existence of a global society as a possible option, allows this. However, the methodological nationalism – on which social sciences were based and according to which each society is necessarily linked with a territory, a State and a nation – makes it difficult to use this model to understand the World. Social sciences concepts, theories and methods were developed to conceive the World as a sum of objects (i.e. states, civilizations) and not as a full-fledged object. To go beyond this limit, the approach of this thesis is to apprehend the World through its issues and actors. In particular, I tried to understand if, and how, the involvement of the Lafarge company in the fight against the HIV/AIDS epidemic between 2002 and 2005 contributed to the development of a global society. Through the results of participant observation and an analysis of non-directive interviews with managers from Lafarge who were involved in the development of the company's AIDS program, I identified three main contributions to the emergence of a global society. First, the company contributed to the social construction of the AIDS epidemic as a global issue : in particular, the global approach the company adopted to deal with the AIDS epidemic was notably different from its traditional modus operandi in the field of social responsibility based on a local and decentralized approach. In addition, through its decision to provide its employees, their families and sometimes local communities with antiretroviral treatments in certain circumstances, the company participated in global controversies on cost-effectiveness of triple therapy, use of generic drugs and health as a global public good. Second, Lafarge's AIDS program contributed to reinforce the global dimension of the group, mainly by providing the power of the corporate with legitimacy, but also by contributing to the development of a global identity and by promoting interactions among subsidiaries. Third, the company contributed to building a global political arena, in particular through its interactions with a series of other global actors belonging to the same responsibility community. These interactions created legitimacy, transparency, institutions and norms at the global level, contributing to the emergence of a transnational deliberative arena. This thesis thus shows that it is possible to view the world as a full-fledged object and to overcome methodological nationalism by studying transnational objects, such as a globalized company and a global issue. It shows that Lafarge's involvement in the fight against AIDS contributes to the emergence of a global societal reference with a strong political dimension.

EPFL2009

More Medicines for Tuberculosis: Fuelling Drug Discovery against Mycobacterium tuberculosis

Shi-Yan Caroline Foo

Tuberculosis (TB), whose etiological agent is Mycobacterium tuberculosis (M. tuberculosis), has plagued humanity since antiquity. Even with chemotherapy available today, TB is the leading cause of death due to an infectious disease. Modern day factors, such as the HIV epidemic and the emergence of drug-resistant TB strains, have redefined the complexities and challenges of tackling the TB pandemic. Current treatments for TB are lengthy, and poor adherence to such prolonged treatment further exacerbates the issue of drug resistance. Moreover, therapies for drug-resistant TB have low cure rates. There is therefore a pressing need for improved therapies that are short and efficacious against all TB strains, which can be achieved through new antimicrobials that are more potent and have novel mechanisms of action, in addition to being affordable, orally bioavailable, and without drug-drug interactions. Such new anti-TB drugs need to be discovered and developed through a long, risky, and costly process, in which attrition rates are high. While there are promising compounds currently being developed, including the benzothiazinones (BTZs), it is necessary to further populate and enhance the Global TB drug pipeline to ensure the availability of new drugs. This thesis aims to address this need through the discovery work of two new, highly promising families, the AX and PB compounds, and of BTZs. The piperazine-based AX analogs are easily synthesised and demonstrate potent activity against M. tuberculosis in vitro and in vivo. Their target, identified in this work, is the QcrB subunit of the cytochrome bc1-aa3 complex, a terminal oxidase of the mycobacterial respiratory chain. Notably, AX compounds are bactericidal in the absence of the alternate terminal oxidase, cytochrome bd. As this family interacts differently in the same binding site of QcrB as Q203, a drug candidate in clinical trials, AX compounds could potentially serve as a backup series for QcrB inhibitors. The PB family, derived from the natural product lapachol, is also easily synthesised and shows substantially improved activity against M. tuberculosis in vitro compared to the parent compound. PB analogs also demonstrated activity against the non-replicating bacillus and in infected macrophages. The mechanism of action of PB compounds relies on the F420 cofactor, although not on the F420-dependent nitroreductase Ddn, therefore this family has a novel mechanism of action which is highly specific to M. tuberculosis. To support the clinical development of PBTZ169, the mechanism of resistance to BTZs was further elucidated in this thesis. Five mutations at cysteine 387 of the target enzyme, DprE1, were identified as mediating resistance to BTZs, which would serve as resistance markers for clinical screening. The impact of these mutations on M. tuberculosis and on DprE1 was further characterised, revealing a fitness cost imposed on the bacillus intracellularly and reduced catalytic efficiency of the enzyme. This thesis additionally contributed to the characterisation of a PBTZ169 backup series and the design of an optimal regimen with other TB drugs. The compounds presented herein merit further optimisation so their full antibiotic potential may be realised for TB, and possibly for other mycobacterial diseases as well. Altogether, this thesis has contributed to the fuelling of drug discovery against M. tuberculosis, and a step towards more medicines for TB.

EPFL2018

Ultra-thin dielectric layers on metal substrates studied by scanning tunneling microscopy and scanning tunneling spectroscopy

In this thesis, ultra-thin dielectric layers on metal substrates are studied mainly by scanning tunneling microscopy and scanning tunneling spectroscopy. In chapter 2, field emission resonances, i.e. bound states in the potential well between sample and tip with an applied voltage, are used to determine the local work function on a sample with patches of different structural composition. To do so, a simple theoretical model is developed and used to simulate the peak positions of the measured dI/dV spectra. In the present case the sample is a Ag(100) surface covered by up to three monolayers of NaCl. The presented method is also applicable to other systems suitable for STM measurements. Additionally, the surface potential is locally probed in the dipole layer region between domains of different work function. In chapter 3, new molecular structures on silver surfaces are presented, that are formed by a mixture of gases. This mixture contains the small molecules H2, H2O, CO, CO2, and N2. No final conclusion can be drawn on the chemical nature of these structures due to the impossibility of the scanning tunneling microscope to determine chemical species. But already the presence of these structures indicates that there is a multitude of unknown interactions, that are possible between a transition metal surface and even smallest molecules. In chapter 4, the moiré pattern is described that a BC3 film creates on a NbB2(0001) surface. As the growth of the BC3 sheet is incommensurate, a moiré pattern is formed that modulates the apparent height of the atoms on the STM images, i.e. the local density of states. The BC3 layer exhibits a completely different behavior than the closely related graphite layer, because it is transparent for the tunnel current. In the present case, the BC3 layer is visible on the STM images only by its moiré effect.