Citalopram Enhances the Activity of Chloroquine in Resistant Plasmodium in Vitro and in Vivo 1

ABSTRACT Citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. Citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC 50 ϭ 1.51 Ϯ .6 M) but only limited activity against the chloroquine-sensitive strain (IC 50 ϭ 33.27 Ϯ 5.87 M) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquineresistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain-a pattern found with other reversal agents. Citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo. Malaria is a significant source of global morbidity and mortality. Despite the development of new antimalarial agents such as mefloquine, halofantrine and the artemisins, chloroquine remains the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria infections, due to its low cost, rapid onset of action and its low toxicity. However, the efficacy of chloroquine has diminished due to the emergence and prevalence of chloroquine-resistant strains of P. falciparum (Wensdorfer and Payne, 1991). The rapid development and spread of resistance to chloroquine and other antimalarials, and the tremendous cost of drug development has emphasized the necessity to optimize the use of existing antimalarial agents A number of adjunct drugs have been identified from a wide variety of chemical classes including calcium-channel blockers Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3dihydroisobenzofuran-5-carbonite), is an extremely potent inhibitor of neuronal serotonin reuptake The low toxicity coupled with the chemical similarity to chemosensitizers (resistance reversal agents) prompted us to investigate the chemosensitizing effect of citalopram in Plasmodium. In this study, we screened citalopram for chloroquine potentiating activity in chloroquine-resistant and chloroquine sensitive-parasites; both in vitro against P. falciparum and in a rodent malaria model (Plasmodium chabaudi). Methods Effect of Citalopram in Vitro Parasites. Two well-characterized isolates of P. falciparum were used for the drug assays. The chloroquine-resistant FCR-3 strain (IC 50 ϳ 150 nM) (donated by J. Freese, Research in diseases of the Tropical Environment, Durban, South Africa) and the chloroquine

Imaginary-time quantum many-body theory out of equilibrium I: Formal equivalence to Keldysh real-time theory and calculation of static properties

We discuss the formal relationship between the real-time Keldysh and imaginary-time theory for nonequilibrium in quantum dot systems. The latter can be reformulated using the recently proposed Matsubara voltage approach. We establish general conditions for correct analytic continuation procedure on physical observables, and apply the technique to the calculation of static quantities in steady-state non-equilibrium for a quantum dot subject to a finite bias voltage and external magnetic field. Limitations of the Matsubara voltage approach are also pointed out.Comment: 24 pages, 10 figure

Direct characterization of photo-induced lattice dynamics in BaFe₂As₂

Ultrafast light pulses can modify electronic properties of quantum materials by perturbing the underlying, intertwined degrees of freedom. In particular, iron-based superconductors exhibit a strong coupling among electronic nematic fluctuations, spins and the lattice, serving as a playground for ultrafast manipulation. Here we use time-resolved X-ray scattering to measure the lattice dynamics of photoexcited BaFe$_{2}$As$_{2}$. On optical excitation, no signature of an ultrafast change of the crystal symmetry is observed, but the lattice oscillates rapidly in time due to the coherent excitation of an A$_{1g}$ mode that modulates the Fe–As–Fe bond angle. We directly quantify the coherent lattice dynamics and show that even a small photoinduced lattice distortion can induce notable changes in the electronic and magnetic properties. Our analysis implies that transient structural modification can be an effective tool for manipulating the electronic properties of multi-orbital systems, where electronic instabilities are sensitive to the orbital character of bands

Time- and angle-resolved photoemission spectroscopy of solids in the extreme ultraviolet at 500 kHz repetition rate

Time- and angle-resolved photoemission spectroscopy (trARPES) employing a 500 kHz extreme-ultraviolet light source operating at 21.7 eV probe photon energy is reported. Based on a high-power ytterbium laser, optical parametric chirped pulse amplification, and ultraviolet-driven high-harmonic generation, the light source produces an isolated high-harmonic with 110 meV bandwidth and a flux of more than 1011 photons/s on the sample. Combined with a state-of-the-art ARPES chamber, this table-top experiment allows high-repetition rate pump-probe experiments of electron dynamics in occupied and normally unoccupied (excited) states in the entire Brillouin zone and with a temporal system response function below 40 f

A comparision of GHG emissions from UK field crop production under selected arable systems with reference to disease control

Crop disease not only threatens global food security by reducing crop production at a time of growing demand, but also contributes to greenhouse gas (GHG) emissions by reducing efficiency of N fertiliser use and farm operations and by driving land use change. GHG emissions associated with adoption of reduced tillage, organic and integrated systems of field crop production across the UK and selected regions are compared with emissions from conventional arable farming to assess their potential for climate change mitigation. The reduced tillage system demonstrated a modest (<20%) reduction in emissions in all cases, although in practice it may not be suitable for all soils and it is likely to cause problems with control of diseases spread on crop debris. There were substantial increases in GHG emissions associated with the organic and integrated systems at national level, principally due to soil organic carbon losses from land use change. At a regional level the integrated system shows the potential to deliver significant emission reductions. These results indicate that the conventional crop production system, coupled to reduced tillage cultivation where appropriate, is generally the best for producing high yields to minimise greenhouse gas emissions and contribute to global food security, although there may be scope for use of the integrated system on a regional basis. The control of crop disease will continue to have an essential role in both maintaining productivity and decreasing GHG emissions.Peer reviewe