Les effets pro-arythmiques des médicaments

RésuméLes effets pro-arythmiques des médicaments sont fréquents et graves, et sont associés à une surmortalité non négligeable. La polymédication augmente le nombre d’effets indésirables et d’interactions graves voire mortelles. Certains sont facilement évitables. Cependant, au-delà de l’allongement de l’intervalle QT, d’autres mécanismes peuvent avoir un rôle majeur comme les dysfonctions du RyR2, responsable d’arythmie calcium-dépendantes par surcharge calcique intracellulaire, avec apparition de post-dépolarisations tardives, sans modifications de l’intervalle QT. Les bloqueurs des canaux sodiques sont également un problème sérieux de part le risque de démasquer ou d’aggraver une dysfonction du canal sodique chez des patients atteints de syndrome de Brugada asymptomatique ou non. Leur dépistage à un stade précoce du développement des médicaments peut avoir un intérêt majeur.SummaryThe cardiac safety of new and marketed drugs is a major concern for public authorities, patients, physicians as well as pharmaceutical companies. Letal adverse drug reactions are indeed a leading cause of death worldwide and increase at a greater rate than the increase in total hospital admission. The increasing use of polypharmacy in current clinical practice is also associated to a growing number of side effects and interactions leading to fatal adverse events. Measurement of the QT interval is an established, albeit incomplete, approach to assess the proarrhythmic risk of a drug. Ventricular arrhythmia (VA) can be caused by a QT-prolonging drug inducing abnormal repolarization of the action potential (AP) of ventricular cardiomyocytes. Emerging evidence, derived from recent understanding of these mechanisms and of similar mechanisms reported for heart failure (HF), suggest that diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) related to RyR2 dysfunction can induce Ca2+ dependent arrhythmia. In this report, we review mechanisms underlying drug-induced arrhythmogenic effects and Ca2+ dependent arrhythmia, and, for the latter, we discuss some of the issues associated to worsening of cardiac arrhythmias

On the validity of the reduced Salpeter equation

We adapt a general method to solve both the full and reduced Salpeter equations and systematically explore the conditions under which these two equations give equivalent results in meson dynamics. The effects of constituent mass, angular momentum state, type of interaction, and the nature of confinement are all considered in an effort to clearly delineate the range of validity of the reduced Salpeter approximations. We find that for $J\not{\hspace*{-1.0mm}=}0$ the solutions are strikingly similar for all constituent masses. For zero angular momentum states the full and reduced Salpeter equations give different results for small quark mass especially with a large additive constant coordinate space potential. We also show that $\frac{1}{m}$ corrections to heavy-light energy levels can be accurately computed with the reduced equation.Comment: Latex (uses epsf macro), 24 pages of text, 12 postscript figures included. Slightly revised version, to appear in Phys. Rev.

Neutrinos as Source of Ultra High Energy Cosmic Rays in Extra Dimensions

If the neutrinos are to be identified with the primary source of ultra-high energy cosmic rays(UHECR), their interaction on relic neutrinos is of great importance in understanding their long intergalactic journey. In theories with large compact dimensions, the exchange of a tower of massive spin-2 gravitons (Kaluza-Klein excitations) gives extra contribution to $\nu\bar{\nu} \longrightarrow f\bar{f}$ and $\gamma\gamma$ processes along with the opening of a new channel for the neutrinos to annihilate with the relic cosmic neutrino background $\nu\bar{\nu} \longrightarrow G_{kk}$ to produce bulk gravitons in the extra dimensions. This will affect their attenuation. We compute the contribution of these Kaluza-Klein excitations to the above processes and find that for parameters of the theory constrained by supernova cooling, the contribution does indeed become the dominant contribution above $\sqrt{s} \simeq 300$ GeV.Comment: 16 pages Latex2e file including 4 postscript figures. Effect of brane fluctuation taken into accoun

gamma nu -> gamma gamma nu and crossed processes at energies below m_W

The cross sections for the processes $\gamma \nu\to \gamma \gamma \nu$, $\gamma\gamma\to\gamma\nu\bar{\nu}$ and $\nu\bar{\nu}\to\gamma\gamma\gamma$ are calculated for a range of center of mass energies from below $m_e$ to considerably above $m_e$, but much less than $m_W$. This enables us to treat the neutrino--electron coupling as a four--Fermi interaction and results in amplitudes which are electron box diagrams with three real photons and one virtual photon at their vertices. These calculations extend our previous low--energy effective interaction results to higher energies and enable us to determine where the effective theory is reliable.Comment: 12 pages, RevTex, 10 postscript figures include

High energy photon-neutrino elastic scattering

The one-loop helicity amplitudes for the elastic scattering process $\gamma\nu\to\gamma\nu$ in the Standard Model are computed at high center of mass energies. A general decomposition of the amplitudes is utilized to investigate the validity of some of the key features of our results. In the center of mass, where $\sqrt{s} = 2\omega$, the cross section grows roughly as $\omega^6$ to near the threshold for $W$-boson production, $\sqrt{s} = m_W$. Although suppressed at low energies, we find that the elastic cross section exceeds the cross section for $\gamma\nu\to\gamma\gamma\nu$ when $\sqrt{s}>13$ GeV. We demonstrate that the scattered photons are circularly polarized and the net value of the polarization is non-zero. Astrophysical implications of high energy photon-neutrino scattering are discussed.Comment: 9 pages, 7 figures, RevTeX

Reduction of the two-body dynamics to a one-body description in classical electrodynamics

We discuss the mapping of the conservative part of two-body electrodynamics onto that of a test charged particle moving in some external electromagnetic field, taking into account recoil effects and relativistic corrections up to second post-Coulombian order. Unlike the results recently obtained in general relativity, we find that in classical electrodynamics it is not possible to implement the matching without introducing external parameters in the effective electromagnetic field. Relaxing the assumption that the effective test particle moves in a flat spacetime provides a feasible way out.Comment: 20 pages, revtex; minor change

High-energy neutrino conversion and the lepton asymmetry in the universe

We study matter effects on oscillations of high-energy neutrinos in the Universe. Substantial effect can be produced by scattering of the neutrinos from cosmological sources (z\gta 1) on the relic neutrino background, provided that the latter has large CP-asymmetry: \eta\equiv (n_\nu-n_{\bar{\nu}})/n_\gamma\gta 1, where $n_\nu$, $n_{\bar{\nu}}$ and $n_\gamma$ are the concentrations of neutrinos, antineutrinos and photons. We consider in details the dynamics of conversion in the expanding neutrino background. Applications are given to the diffuse fluxes of neutrinos from GRBs, AGN, and the decay of super-heavy relics. We find that the vacuum oscillation probability can be modified by $\sim (10-20)$ and in extreme cases allowed by present bounds on $\eta$ the effect can reach $\sim 100$. Signatures of matter effects would consist (i) for both active-active and active-sterile conversion, in a deviation of the numbers of events produced in a detector by neutrinos of different flavours, $N_{\alpha}~(\alpha=e,\mu,\tau)$, and of their ratios from the values given by vacuum oscillations; such deviations can reach $\sim 5-15$, (ii) for active-sterile conversion, in a characteristic energy dependence of the ratios $N_{e}/N_{\mu},N_{e}/N_{\tau},N_{\mu}/N_{\tau}$. Searches for these matter effects will probe large CP and lepton asymmetries in the universe.Comment: 32 pages, RevTeX, 16 figures. Substantial changes in the treatment of conversion effects in the relic neutrino background and of active-active oscillations of high-energy neutrinos. Figures and references added; conclusions partially modifie

Functional cyclophilin D moderates platelet adhesion, but enhances the lytic resistance of fibrin

In the course of thrombosis, platelets are exposed to a variety of activating stimuli classified as ‘strong’ (e.g. thrombin and collagen) or ‘mild’ (e.g. ADP). In response, activated platelets adhere to injured vasculature, aggregate, and stabilise the three-dimensional fibrin scaffold of the expanding thrombus. Since ‘strong’ stimuli also induce opening of the mitochondrial permeability transition pore (MPTP) in platelets, the MPTP-enhancer Cyclophilin D (CypD) has been suggested as a critical pharmacological target to influence thrombosis. However, it is poorly understood what role CypD plays in the platelet response to ‘mild’ stimuli which act independently of MPTP. Furthermore, it is unknown how CypD influences platelet-driven clot stabilisation against enzymatic breakdown (fibrinolysis). Here we show that treatment of human platelets with Cyclosporine A (a cyclophilin-inhibitor) boosts ADP-induced adhesion and aggregation, while genetic ablation of CypD in murine platelets enhances adhesion but not aggregation. We also report that platelets lacking CypD preserve their integrity in a fibrin environment, and lose their ability to render clots resistant against fibrinolysis. Our results indicate that CypD has opposing haemostatic roles depending on the stimulus and stage of platelet activation, warranting a careful design of any antithrombotic strategy targeting CypD