Cyanides are highly toxic compounds that have been used as weapons of terrorism throughout history. Cyanide (CN) is acutely toxic by all routes of administration; however, inhalation is the main exposure route. To adequately test effective countermeasures against inhalational CN threats, robust and well-characterized animal models are needed.
View Article and Find Full Text PDFObjective: Cyanide is a highly toxic chemical, and acute exposure depletes cells and tissue of oxygen, depressing the respiratory, cardiovascular and neurological systems and potentially leading to death. Cyanide has been used as a weapon since ancient Rome and continues to pose a potential threat today. A well-characterized animal model is necessary for the development of novel methods of rapid detection and treatment.
View Article and Find Full Text PDFOrganophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED), and therapeutic index (TI = oxime 24-h LD/oxime ED) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO).
View Article and Find Full Text PDFUnlabelled: Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the acute toxicity of phorate is acetylcholinesterase (AChE) inhibition mediated by its bioactivated oxon metabolite. AChE reactivation is a critical aspect in the treatment of acute OP intoxication.
View Article and Find Full Text PDFStudy Objective: The 2 antidotes for acute cyanide poisoning in the United States must be administered by intravenous injection. In the out-of-hospital setting, intravenous injection is not practical, particularly for mass casualties, and intramuscular injection would be preferred. The purpose of this study is to determine whether sodium nitrite and sodium thiosulfate are effective cyanide antidotes when administered by intramuscular injection.
View Article and Find Full Text PDFAnticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study.
View Article and Find Full Text PDFPurpose: Aldicarb and methomyl are carbamate pesticides commonly implicated in human poisonings. The primary toxic mechanism of action for carbamate poisoning is cholinesterase (ChE) inhibition. As such, it is logical to assume that the currently accepted therapies for organophosphate poisoning (muscarinic antagonist atropine and the oxime acetylcholinesterase reactivator pralidoxime chloride [2-PAM Cl]) could afford therapeutic protection.
View Article and Find Full Text PDFThe oral toxicity of phorate oxon (PHO), with emphasis on gender- and age-related effects, was characterized in the Sprague-Dawley rat. The oral LD (95% fiducial limits) for PHO in corn oil was 0.88 (0.
View Article and Find Full Text PDFContext: Phosgene's primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6-24 h post-exposure.
Objective: To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures.
Methods: A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8 ppm) or air (sham).
Given the rapid onset of symptoms from intoxication by organophosphate (OP) compounds, a quick-acting, efficacious therapeutic regimen is needed. A primary component of anti-OP therapy is an oxime reactivator to rescue OP-inhibited acetylcholinesterases. Male guinea pigs, clipped of hair, received neat applications of either VR, VX, parathion, or phorate oxon (PHO) at the 85(th) percentile lethal dose, and, beginning with presentation of toxicosis, received the human equivalent dose therapy by intramuscular injection with two additional follow-on treatments at 3-hr intervals.
View Article and Find Full Text PDFThe currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE).
View Article and Find Full Text PDFIntroduction: A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube.
Methods: Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by an in-line pneumotach, pressure transducer, and Buxco pulmonary analysis computer/software.
Sulfur mustard (SM) is a bifunctional alkylating agent causing skin inflammation, edema and blistering. A hallmark of SM-induced toxicity is follicular and interfollicular epithelial damage. In the present studies we determined if SM-induced structural alterations in hair follicles and sebaceous glands were correlated with cell damage, inflammation and wound healing.
View Article and Find Full Text PDFSulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control.
View Article and Find Full Text PDFPurpose: The goals of this study were (1) to compare the injury at the basement membrane zone (BMZ) of rabbit corneal organ cultures exposed to half mustard (2 chloroethyl ethyl sulfide, CEES) and nitrogen mustard with that of in vivo rabbit eyes exposed to sulfur mustard (SM); (2) to test the efficacy of 4 tetracycline derivatives in attenuating vesicant-induced BMZ disruption in the 24-h period postexposure; and (3) to use the most effective tetracycline derivative to compare the improvement of injury when the drug is delivered as drops or hydrogels to eyes exposed in vivo to SM.
Methods: Histological analysis of hematoxylin and eosin–stained sections was performed; the ultrastructure of the corneal BMZ was evaluated by transmission electron microscopy; matrix metalloproteinase-9 was assessed by immunofluorescence; doxycycline as drops or a hydrogel was applied daily for 28 days to eyes exposed in vivo to SM. Corneal edema was assessed by pachymetry and the extent of neovascularization was graded by length of longest vessel in each quadrant.
The chemical warfare agent sulfur mustard (SM) produces blister formation with a severe inflammatory reaction in skin of exposed individuals. The development of efficacious countermeasures against SM vesication requires an understanding of the cellular and molecular mechanism of SM-induced tissue injury. This study examined SM-induced alterations in gene expression using Atlas Mouse 5K DNA microarrays (5002 genes) to identify transcriptional events associated with SM skin injury.
View Article and Find Full Text PDFThe chemical warfare agent sulfur mustard [bis-(2-chloroethyl)-sulfide; SM] produces a delayed inflammatory response followed by blister formation in skin of exposed individuals. Studies are underway evaluating the efficacy of pharmacological compounds to protect against SM skin injury. Microarray analysis provides the opportunity to identify multiple transcriptional biomarkers associated with SM exposure.
View Article and Find Full Text PDFWe have developed a therapeutic for the treatment of anthrax using an affinity-enhanced monoclonal antibody (ETI-204) to protective antigen (PA), which is the central cell-binding component of the anthrax exotoxins. ETI-204 administered preexposure by a single intravenous injection of a dose of between 2.5 and 10 mg per animal significantly protected rabbits from a lethal aerosolized anthrax spore challenge ( approximately 60 to 450 times the 50% lethal dose of Bacillus anthracis Ames).
View Article and Find Full Text PDFSulfur mustard [bis(2-chloroethyl)sulfide; SM] is a chemical warfare agent that produces edema and blister formation with a severe inflammatory reaction. The mouse ear vesicant model for SM injury has been used to evaluate pharmacological agents for countering SM dermal injury. The vanilloid olvanil reduces SM-induced edema and mRNA expression of cytokines and chemokines, suggesting that blocking the inflammatory effects of neuropeptides, such as substance P (SP), may provide protection against SM-induced dermal injury.
View Article and Find Full Text PDFAnthrax is considered a serious biowarfare and bioterrorism threat because of its high lethality, especially by the inhalation route. Rhesus macaques (Macaca mulatta) are the most commonly used nonhuman primate model of human inhalation anthrax exposure. The nonavailability of rhesus macaques necessitated development of an alternate model for vaccine testing and immunologic studies.
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