Repurposing FDA-approved drugs to treat chemical weapon toxicities: Interactive case studies for trainees.

The risk of a terrorist attack in the United States has created challenges on how to effectively treat toxicities that result from exposure to chemical weapons. To address this concern, the United States has organized a trans-agency initiative across academia, government, and industry to identify drugs to treat tissue injury resulting from exposure to chemical threat agents. We sought to develop and evaluate an interactive educational session that provides hands-on instruction on how to repurpose FDA-approved drugs as therapeutics to treat toxicity from exposure to chemical weapons. As part of the Rutgers Summer Undergraduate Research Fellowship program, 23 undergraduate students participated in a 2-h session that included: (1) an overview of chemical weapon toxicities, (2) a primer on pharmacology principles, and (3) an interactive session where groups of students were provided lists of FDA-approved drugs to evaluate potential mechanisms of action and suitability as countermeasures for four chemical weapon case scenarios. The interactive session culminated in a competition for the best grant "sales pitch." From this interactive training, students improved their understanding of (1) the ability of chemical weapons to cause long-term toxicities, (2) impact of route of administration and exposure scenario on drug efficacy, and (3) re-purposing FDA-approved drugs to treat disease from chemical weapon exposure. These findings demonstrated that an interactive training exercise can provide students with new insights into drug development for chemical threat agent toxicities.

Chloropicrin induced ocular injury: Biomarkers, potential mechanisms, and treatments.

Ocular tissue, especially the cornea, is overly sensitive to chemical exposures. The availability and adoption of chemical threat agent chloropicrin (CP) is growing in the United States as a pesticide and fumigant; thereby increasing the risk of its use in warfare, terrorist attacks and non-intentional exposure. Exposure to CP results in immediate ocular, respiratory, and dermal injury; however, we lack knowledge on its mechanism of toxicity as well as of its breakdown products like chlorine and phosgene, and effective therapies are elusive. Herein, we have reviewed the recent findings on exposure route, toxicity and likely mechanisms of CP induced ocular toxicity based on other vesicating chemical warfare agents that cause ocular injury. We have focused on the implication of their toxicity and mechanistic outcomes in the ocular tissue, especially the cornea, which could be useful in the development of broad-spectrum effective therapeutic options. We have discussed on the potential countermeasures, overall hallmarks and challenges involved in studying ocular injuries from chemical threat agent exposures. Finally, we reviewed useful available technologies and methods that can assist in the identification of effective medical countermeasures for chemical threat agents related ocular injuries.

Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.

Translational research on chemical nerve agents.

This special issue will describe cutting-edge translational research on the development of safe and effective therapeutics for treating exposure to toxic chemical threat agents that target the nervous system. These studies are supported by the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program. Chemical threats include chemical warfare agents, pesticides and other toxic chemicals whose primary mode of action is targeted within the nervous system. Depending on the dose, the effects of these toxic chemicals can be lethal or cause serious morbidity including neuropathology and neurological deficits. Current topics in research on organophosphorus pesticides and chemical warfare agents include developing alternatives to currently approve acetylcholinesterase reactivators, control of seizures that are refractory to benzodiazepine drugs, and treatments for serious morbidity caused by non-lethal exposures. There is also an effort to understand the mechanisms of toxicity and treatments for other neuro-active agents such as tetramine and hydrogen sulfide. A robust translational research effort on nerve agents is essential for being better prepared with an effective medical response capability during chemical emergencies.

Females of a gift-giving spider do not trade sex for food gifts: a consequence of male deception?

BACKGROUND: Polyandry is commonly maintained by direct benefits in gift-giving species, so females may remate as an adaptive foraging strategy. However, the assumption of a direct benefit fades in mating systems where male gift-giving behaviour has evolved from offering nutritive to worthless (non-nutritive) items. In the spider Paratrechalea ornata, 70% of gifts in nature are worthless. We therefore predicted female receptivity to be independent of hunger in this species. We exposed poorly-fed and well-fed females to multiple males offering nutritive gifts and well-fed females to males offering worthless gifts. RESULTS: Though the treatments strongly affected fecundity, females of all groups had similar number of matings. This confirms that female receptivity is independent of their nutritional state, i.e. polyandry does not prevail as a foraging strategy. CONCLUSIONS: In the spider Pisaura mirabilis, in which the majority (62%) of gifts in nature are nutritive, female receptivity depends on hunger. We therefore propose that the dependence of female receptivity on hunger state may have evolved in species with predominantly nutritive gifts but is absent in species with predominantly worthless gifts.

The NIH Countermeasures Against Chemical Threats Program: overview and special challenges.

Intentional exposures to toxic chemicals can stem from terrorist attacks, such as the release of sarin in the Tokyo subway system in 1995, as well as from toxic industrial accidents that are much more common. Developing effective medical interventions is a critical component of the overall strategy to overcome the challenges of chemical emergencies. These challenges include the rapid and lethal mode of action of many toxic chemicals that require equally fast-acting therapies, the large number of chemicals that are considered threats, and the diverse demographics and vulnerabilities of those who may be affected. In addition, there may be long-term deleterious effects in survivors of a chemical exposure. Several U.S. federal agencies are invested in efforts to improve preparedness and response capabilities during and after chemical emergencies. For example, the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) Program supports investigators who are developing therapeutics to reduce mortality and morbidity from chemical exposures. The program awards grants to individual laboratories and includes contract resource facilities and interagency agreements with Department of Defense laboratories. The range of high-quality research within the NIH CounterACT Program network is discussed.