Advanced Boolean modeling of biological networks applied to systems pharmacology.

Motivation: Literature on complex diseases is abundant but not always quantitative. Many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. Tools for analysis of discrete networks are useful to capture the available information in the literature but have not been efficiently integrated by the pharmaceutical industry. We propose an expansion of the usual analysis of discrete networks that facilitates the identification/validation of therapeutic targets. Results: In this article, we propose a methodology to perform Boolean modeling of Systems Biology/Pharmacology networks by using SPIDDOR (Systems Pharmacology for effIcient Drug Development On R) R package. The resulting models can be used to analyze the dynamics of signaling networks associated to diseases to predict the pathogenesis mechanisms and identify potential therapeutic targets. Availability and Implementation: The source code is available at https://github.com/SPIDDOR/SPIDDOR . Contact: itzirurzun@alumni.unav.es , itroconiz@unav.es. Supplementary information: Supplementary data are available at Bioinformatics online.

Population pharmacokinetic/pharmacodynamic modelling of the effects of axomadol and its O-demethyl metabolite on pupil diameter and nociception in healthy subjects.

AIM: The aim of the present study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of the active components of axomadol and to quantify their contribution to observed the pupillometric and analgesic (measured through the cold pressor test) effects linking the PD engagement biomarker with clinical response. METHODS: Healthy subjects (n = 74) received either placebo or axomadol orally at doses ranging from 66 mg to 225 mg following multiple dosing regimens in two separate clinical trials. Plasma concentrations of the two enantiomers of axomadol and their metabolites, and PD responses were measured at specific times. The population analysis was performed using NONMEM 7.2. RESULTS: The kinetics of the parent drug and its metabolite could be described simultaneously using an extra compartment mimicking the liver, where the metabolite is formed. The SS parent compound elicited a plasma concentration-dependent increase in pupil diameter, with estimates (percentage relative standard errors) of maximal effect (Emax ) and plasma concentration exerting a half-maximal effect (C50 ) of 0.79 (17.4) mm, and 90.7 (27) ng ml(-1) , respectively. The predicted effect site concentrations of the RR O-demethyl metabolite decreased the pupil diameter linearly, with an estimate of the slope of 0.00967 (18.7) mm·ml ng(-1) . An additive model, integrating the net effect on pupil diameter, described adequately the reduction in pain with a linear function. The PK/PD model revealed that each 0.5 mm change in pupil diameter is associated with a 10% decrease in cold pressor area under the concentration-time curve effects. CONCLUSIONS: The PK/PD analysis performed enabled the individual contributions of the active compounds to the observed effects to be identified and quantified. These effects were in accordance with the known mechanisms of action - namely, opioid agonism and noradrenaline reuptake inhibition.

Vibrot, a simple device for the conversion of vibration into rotation mediated by friction: preliminary evaluation.

While "vibrational noise" induced by rotating components of machinery is a common problem constantly faced by engineers, the controlled conversion of translational into rotational motion or vice-versa is a desirable goal in many scenarios ranging from internal combustion engines to ultrasonic motors. In this work, we describe the underlying physics after isolating a single degree of freedom, focusing on devices that convert a vibration along the vertical axis into a rotation around this axis. A typical Vibrot (as we label these devices) consists of a rigid body with three or more cantilevered elastic legs attached to its bottom at an angle. We show that these legs are capable of transforming vibration into rotation by a "ratchet effect", which is caused by the anisotropic stick-slip-flight motion of the leg tips against the ground. Drawing an analogy with the Froude number used to classify the locomotion dynamics of legged animals, we discuss the walking regime of these robots. We are able to control the rotation frequency of the Vibrot by manipulating the shaking amplitude, frequency or waveform. Furthermore, we have been able to excite Vibrots with acoustic waves, which allows speculating about the possibility of reducing the size of the devices so they can perform tasks into the human body, excited by ultrasound waves from the outside.