A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis.

Sepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways.

In vivo distribution of organophosphate antidotes: autoradiography of [14C]HI-6 in the rat.

In order to visualize the distribution of HI-6 in the rat after iv administration, autoradiographic experiments were carried out with [14C]HI-6, labeled at the carbon of the carboxamide moiety. Autoradiography clearly confirms penetration of HI-6 into the central nervous system. Considerable radioactivity was found in the cerebrum, the cerebellum, and the choroid plexus.

Identification of two metabolites of the cholinesterase reactivator HI-6 isolated from rat urine.

Two metabolites, isolated from the urine of rats given the cholinesterase reactivator HI-6 intravenously, still contained quaternary nitrogen atoms and therefore could not be extracted from aqueous solutions by organic solvents. Both metabolites were isolated by preparative high performance liquid chromatography and were identified using mass spectrometry, gas chromatography, infrared spectrometry, ultraviolet spectrometry and proton nuclear magnetic resonance spectrometry. The structures were confirmed by in-vitro preparation of the compounds.

Stereospecific reactivation of human brain and erythrocyte acetylcholinesterase inhibited by 1,2,2-trimethylpropyl methylphosphonofluoridate (soman).

Human erythrocyte and brain acetylcholinesterase are preferentially inhibited by the P(-)-isomers of C(+/-)P(+/-)-soman. The enzymes inhibited by the P(-)-isomers behave similarly with respect to oxime-induced reactivation and aging. HI-6 is the best reactivator for C(+)P(-)-soman-inhibited acetylcholinesterases.

Kinetic profile in blood and brain of the cholinesterase reactivating oxime HI-6 after intravenous administration to the rat.

The kinetic profile of the oxime HI-6, a potent cholinesterase reactivator, after iv administration of 0.1325 mmol/kg (50 mg/kg) to rats is described. The blood concentrations measured over a period of 300 min can be described by a two-compartment open model.

Determination of some pyridinium aldoxime compounds by means of ion-pair reversed-phase high-performance liquid chromatography: application in biological material.

Two reversed-phase high-performance liquid chromatographic systems are presented for the separation and assay of the pyridinium aldoximes benzyl-P2A, HI-6 and obidoxime in aqueous solutions and biological samples. The systems involve a 5-micrometer C18 silica gel stationary phase. The eluent consists of methanol, acetic acid buffer (pH 4.