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Geneva, WA, United States

Kiris E.,Geneva Foundation | Kiris E.,U.S. Army | Kiris E.,Frederick National Laboratory for Cancer Research | Burnett J.C.,Leidos Inc. | And 2 more authors.
Current Topics in Medicinal Chemistry | Year: 2014

Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn2+ metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair. © 2014 Bentham Science Publishers Source

Burgert J.M.,U.S. Army | Johnson A.D.,U.S. Army | Garcia-Blanco J.,Geneva Foundation | Froehle J.,U.S. Army | And 4 more authors.
American Journal of Emergency Medicine | Year: 2016

Introduction It is unknown if the anatomical distance of intraosseous (IO) epinephrine injection from the heart affects resuscitative outcome. The purpose of this study was to explore the relationships between the anatomical distance of IO epinephrine injection and measures of resuscitative outcome in an adult swine model of ventricular fibrillation (VF). Methods Thirty-two Yorkshire-cross swine (60-80 kg) were randomly assigned to four groups: humeral IO (HIO), tibial IO (TIO), IV with defibrillation and epinephrine, and IV control: with defibrillation but no epinephrine. Ventricular fibrillation was induced. Swine remained in VF for 4 minutes prior to mechanical chest compressions. After 6 minutes in VF, swine were defibrillated and epinephrine (0.01 mg/kg) administered by group assignment. Defibrillation was repeated every 2 minutes. Epinephrine was repeated every 4 minutes. Interventions continued until return of spontaneous circulation (ROSC) or 26 post-arrest minutes elapsed. Swine achieving ROSC were observed for 30 minutes post-ROSC. Results There were no significant differences between the HIO, TIO, and IV groups relative to the occurrence of ROSC (P >.05 in all cases), 30-minute post-ROSC survival (P >.05 in all cases), and time to ROSC (P =.43). There were significant differences between the HIO, TIO, and IV groups compared to the control group relative to the occurrence of ROSC (P =.02,.01, and.007 respectively), and 30 minute post-ROSC survival (P =.05,.03, and.007, respectively). Conclusion The anatomical distance of IO epinephrine injection from the heart did not affect short-term measures of resuscitative outcome in an adult swine model of VF including the occurrence of ROSC, 30 minute post-ROSC survival, and time to ROSC. Rapidly administered epinephrine, irrespective of route of administration, increased the chance ROSC and survival to 30 minutes post-ROSC would occur in this study. Source

Kiris E.,Geneva Foundation | Kiris E.,U.S. Army | Kiris E.,Frederick National Laboratory for Cancer Research | Kota K.P.,Perkin Elmer Corporation | And 6 more authors.
Expert Review of Molecular Diagnostics | Year: 2014

Botulinum neurotoxins (BoNTs) are exceptionally potent inhibitors of neurotransmission, causing muscle paralysis and respiratory failure associated with the disease botulism. Currently, no drugs are available to counter intracellular BoNT poisoning. To develop effective medical treatments, cell-based assays provide a valuable system to identify novel inhibitors in a time- and cost-efficient manner. Consequently, cell-based systems including immortalized cells, primary neurons and stem cell-derived neurons have been established. Stem cell-derived neurons are highly sensitive to BoNT intoxication and represent an ideal model to study the biological effects of BoNTs. Robust immunoassays are used to quantify BoNT activity and play a central role during inhibitor screening. In this review, we examine recent progress in physiologically relevant cell-based assays and high-throughput screening approaches for the identification of both direct and indirect BoNT inhibitors. © 2014 Informa UK, Ltd. Source

Ceremuga T.E.,U.S. Army | Martinson S.,U.S. Army | Washington J.,U.S. Army | Revels R.,U.S. Army | And 9 more authors.
Scientific World Journal | Year: 2014

Posttraumatic stress disorder (PTSD) is characterized by the occurrence of a traumatic event that is beyond the normal range of human experience. The future of PTSD treatment may specifically target the molecular mechanisms of PTSD. In the US, approximately 20% of adults report taking herbal products to treat medical illnesses. L-theanine is the amino acid in green tea primarily responsible for relaxation effects. No studies have evaluated the potential therapeutic properties of herbal medications on gene expression in PTSD. We evaluated gene expression in PTSD-induced changes in the amygdala and hippocampus of Sprague-Dawley rats. The rats were assigned to PTSD-stressed and nonstressed groups that received either saline, midazolam, L-theanine, or L-theanine + midazolam. Amygdala and hippocampus tissue samples were analyzed for changes in gene expression. One-way ANOVA was used to detect significant difference between groups in the amygdala and hippocampus. Of 88 genes examined, 17 had a large effect size greater than 0.138. Of these, 3 genes in the hippocampus and 5 genes in the amygdala were considered significant (P < 0.05) between the groups. RT-PCR analysis revealed significant changes between groups in several genes implicated in a variety of disorders ranging from PTSD, anxiety, mood disorders, and substance dependence. © 2014 Tomás Eduardo Ceremuga et al. Source

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