New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations

The development and spread of drug-resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs in a combination which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapy parasitological data to predict the parasitological endpoints of the combination. This makes it possible to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel-piperaquine and artefenomel-ferroquine drug combinations. In addition, the predictive performance of our novel in vitro model was equivalent to that of the humanized mouse model outcome. Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (Emax) and the concentration producing 50% of the killing maximum effect (EC50) of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas

Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment

The rate at which parasitemia declines in a host after treatment with an antimalarial drug is a major metric for assessment of antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of drug activity for some compounds, potentially confounding its use as a metric for assessing antimalarial activity in vivo. Here, we report a study of the effect of artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the drug effect in mice by estimating the decrease in parasite viability after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after artesunate treatment than does the decline in parasitemia (termed parasite clearance). We also observed that artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the antimalarial activity of artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.)

Symmetry breaking in dynamical systems

Symmetry breaking bifurcations and dynamical systems have obtained a lot of attention over the last years. This has several reasons: real world applications give rise to systems with symmetry, steady state solutions and periodic orbits may have interesting patterns, symmetry changes the notion of structural stability and introduces degeneracies into the systems as well as geometric simplifications. Therefore symmetric systems are attractive to those who study specific applications as well as to those who are interested in a the abstract theory of dynamical systems. Dynamical systems fall into two classes, those with continuous time and those with discrete time. In this paper we study only the continuous case, although the discrete case is as interesting as the continuous one. Many global results were obtained for the discrete case. Our emphasis are heteroclinic cycles and some mechanisms to create them. We do not pursue the question of stability. Of course many studies have been made to give conditions which imply the existence and stability of such cycles. In contrast to systems without symmetry heteroclinic cycles can be structurally stable in the symmetric case. Sometimes the various solutions on the cycle get mapped onto each other by group elements. Then this cycle will reduce to a homoclinic orbit if we project the equation onto the orbit space. Therefore techniques to study homoclinic bifurcations become available. In recent years some efforts have been made to understand the behaviour of dynamical systems near points where the symmetry of the system was perturbed by outside influences. This can lead to very complicated dynamical behaviour, as was pointed out by several authors. We will discuss some of the technical difficulties which arise in these problems. Then we will review some recent results on a geometric approach to this problem near steady state bifurcation points

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Detailed experimental study of high-frequency self-pulsation domains in multi-section DFB-lasers

We establish an extensive experimental registration technique to study the dependence of the pulsation in a three-section DFB-laser. The common feature of continuous pulsation domains is highlighted and the impact of geometrical parameters is investigated. The measurements allow the quantitative determination of pulsation frequency, rf-amplitude, wavelength and optical power at the same time. Based on a reproducible fabrication technology, we found that the phase section plays the main role to control the self-pulsations. The phase section also exhibits a negative reflectivity slope necessary for dispersive Q-switching like the reflector. Phase section lengths in the range between 200 and 500 mu m are very well suited. The length of the reflector section is not very critical Devices with 90 mu m and 200 mu m long reflectors work well. Other parameters that are responsible for the frequency of self-pulsations are determined by the heterostructure and must be optimized separately

4 × 56 Gb/s High Output Power Electroabsorption Modulated Laser Array With up to 7 km Fiber Transmission in L-Band

We present a novel array of electroabsorption modulated lasers as compact and low-cost single-chip solution for future 200 Gb/s transmitters. The array is designed for high optical output power with semiconductor optical amplifiers at the front side of the chip. A common InGaAlAs-MQW active layer structure allows for simple and cost-effective monolithic integration. On chip RF transmission lines are implemented to bring all electrical contacts to the rear side of the array-chip which supports packaging with short wire bonds. The array operates at four different wavelengths spanning over 7.5 nm in the L-band. Uniformity of each wavelength channel is experimentally proven regarding modulation bandwidth >30 GHz, extinction ratio >7 dB, and output power up to 8 dBm. The influence of the semiconducting optical amplifiers on signal quality is investigated by back to back bit error ratio measurements. In transmission experiments over standard single mode fiber links, the array's performance at 4 × 56 GBd NRZ and 4 × 28 GBd PAM4 is demonstrated and the arrays capability for up to 7 km transmission in case of PAM4 signaling is shown

Ultra-low power SiGe driver-IC for high-speed electroabsorption modulated DFB lasers

A small footprint electroabsorption modulated DFB laser TOSA with an ultra-low power SiGe driver with a power efficiency of 3.59 pJ/bit is demonstrated. Good optical eye openings up to 56 GBd NRZ and 64 Gb/s PAM-4 were obtained. The novel SiGe EML driver consumes 84 mW only