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Homicide
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
Burkhard Madea, Musshoff Frank, Schmidt Peter
Ballard et al. [12] have described a rather complex analytical strategy for quaternary ammonium neuromuscular blocking agents including SUX and SMC using LC/MS, but without any validation data or results from authentic cases (only four SMC positive samples were described). Due to its analytically challenging character, determination of SUX content is not part of routine toxicological analyses. For further clinical studies, as well as applications in the forensic sciences, we developed a simple solid-phase extraction procedure for the simultaneous extraction of SUX and SMC with deuterated analogues as internal standards [91]. Paraoxon was found to be a useful stabilizing agent to prevent further enzymatic in vitro degradation. Degradation due to bacterial activity was not observed and is not described in the literature.
Neuronal Networks in Convulsant Drug-Induced Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Subconvulsive doses of pilocarpine produce seizures with concurrent injections of NMDA or kainate into the EP.159 Thus, these data suggest that the entopeduncular nucleus is an important component of the neuronal network subserving forebrain/limbic seizures, but further work is needed with additional convulsant drugs before any potential role of this structure in seizures of brainstem origin can be ascertained. Increased 2-DG labeling was observed in the EP following administration of paraoxon, an acetylcholinesterase inhibitor that is also a convulsant.85
Brain-Penetrating Reactivators of Organophosphate-InhibitedAcetylcholinesterase
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Janice. E. Chambers, Edward. C. Meek
Our group uses highly relevant nerve agent surrogates, which substitute only the leaving group and therefore phosphylate AChE with the same chemical group as the actual nerve agent (Meek et al., 2012): a sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP) and a VX surrogate nitrophenyl ethyl methylphosphonate (NEMP). While less toxic than sarin and VX, they are nonetheless potent anticholinesterases. Our group has also extensively studied paraoxon (PXN), the active anticholinesterase metabolite of the prototypical and highly toxic OP insecticide parathion. PXN is also a potent anticholinesterase inhibiting AChE in the nanomolar range. These oximes were less effective in our standard in vitro screening tests than 2-PAM and TMB-4, but many of the novel oximes did show appreciable reactivation ability (Chambers et al., 2013).
Apoptosis is involved in paraoxon-induced histological changes in rat cerebellum
Published in Drug and Chemical Toxicology, 2022
Zohreh Zare, Sam Zarbakhsh, Shamim Mashhadban, Afshin Moradgholi, Moslem Mohammadi
Organophosphate (OP) compounds are cholinesterase inhibitors commonly used as nerve agents on the battlefield and as insecticides in agriculture (Collombet 2011). Parathion is an OP insecticide that requires metabolic activation by the cytochrome P450 (CYP) system to become biologically active. Paraoxon is the active neurotoxic metabolite of parathion (Carr et al. 2002, Rocha et al. 1996). The OP compounds exert their primary toxic effects through binding, phosphorylation, and inhibition of the acetylcholinesterase (AChE), followed by accumulation of acetylcholine (ACh) in the synaptic clefts and development of cholinergic crisis (Chowdhary et al. 2014, Howard et al. 2007). The onset of seizure activity by OP-induced repetitive stimulation of central muscarinic receptors and its maintenance and progression by recruitment of other neurotransmitter systems contribute to neuronal damage and brain histopathology (McDonough and Shih 1997, Mohammadi et al. 2016).
Nigella sativa oil and thymoquinone reduce oxidative stress in the brain tissue of rats exposed to total head irradiation
Published in International Journal of Radiation Biology, 2020
Elif Demir, Seyithan Taysi, Hasan Ulusal, Davut Sinan Kaplan, Kadir Cinar, Mehmet Tarakcioglu
The total sulfhydryl (-SH) of the brain tissue was assayed according to Ellman's method (Ellman 1959). The results are expressed as mmol/gr protein. Paraoxonase (PON) activity was measured in the basal activity. The rate of paraoxon hydrolysis was measured by monitoring the increase in absorbance at 412 nm at 37 °C. The amount of generated p-nitrophenol was calculated from the molar absorptivity coefficient at pH 8, which was 17,000 M−1 cm−1 (Eckerson et al. 1983). PON activity was expressed as U/gr protein. Phenylacetate was used as a substrate to measure arylesterase (ARYL) activity by monitoring the increase in absorbance at 270 nm at 37 °C. The activity was calculated from the molar absorptivity coefficient of the produced phenol, 1310 M−1 cm−1 (Haagen and Brock 1992). One unit of ARYL activity was defined as 1 μmol phenol generated/min under the above conditions and expressed as U/gr protein. Lipid hydroperoxide (LOOH) levels were measured by the ferrous ion oxidation-xylenol orange method as previously described (Nourooz-Zadeh 1999). The results are expressed as µmol/gr protein. The protein content was determined as described (Bradford 1976). Biochemical measurements were carried out using a spectrophotometer (Shimadu U 1601, Japan).
Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects
Published in Xenobiotica, 2022
Peter Gorycki, Mindy Magee, Peter Ackerman, Xiusheng Miao, Katy Moore
The incubation mixtures consisted of human liver microsomes (2 mg protein/mL), [14C]-TMR (10 µM), tris-HCl buffer (50 mM, pH 8), and NaCl (10 mM) with a final volume of 0.5 mL. Either CaCl2 (1 mM) or EDTA (2 mM) were added to aliquots of this mixture, allowed to react for 60 minutes, and then quenched with cold acetonitrile (0.5 mL). The samples were mixed by vortexing and centrifuged for 10 minutes at 14,000 rpm (∼13,000 g). A portion of the supernatant (50–80 µL) was injected into LC/MS for biotransformation profiling and mass-spectral analysis. A positive control incubation was conducted with paraoxon at 10 µM in the same manner.