This is a program of the National Institutes of Health (NIH). The program is coordinated by NIAID, with the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, and several other NIH Institutes and Centers.
NIH Funds Development of New Broad-Spectrum Therapeutics—Oct. 13, 2011
All Biodefense and Related News
News From NIAID-Supported institutions
In recent years, toxic chemicals have attracted the attention of terrorists because of the potentially devastating effects that such weapons could have on the general population. In 1995, the Japanese terrorist cult Aum Shinrikyo used the nerve gas sarin in an attack in the Tokyo subway, killing 12 people and causing more than 5,000 people to seek medical attention following the incident. More recently in Iraq, the targeting of chlorine storage tanks and production facilities by Al Queda have demonstrated a committed interest in finding new ways to cause disruption and devastation in a community.
The number and variety of toxic chemicals that pose a health risk to the civilian population is extensive. The Occupational Safety and Health Administration has identified approximately 100 toxic industrial chemicals. The U.S. Environmental Protection Agency lists more than 600 chemicals in its Toxic Release Inventory. Animal, plant, and bacterial toxins that can be synthesized are also potential chemical threats, especially if they are produced in large quantities.
Terrorists could employ any of the traditional chemical warfare agents, ranging from nerve gas and cyanide to pulmonary or vesicating (blister) agents, to achieve their goals. Industrial targets or the combined use of chemicals with explosives only highlight the need to address such threats with safe and effective medical countermeasures.
For more than 75 years, the U.S. Department of Defense (DoD) has been addressing the threat of chemicals to military forces and has been developing countermeasures to such threats.
The United States Army Medical Research Institute of Chemical Defense (USAMRICD) has a long history of developing medical products against chemical warfare agents for military use. Until 2006, DoD efforts had been the only well-defined federally supported medical research effort addressing the medical effects of chemical warfare agents. In prior years, NIH had supported limited research on some of the symptoms possibly associated with chemical exposures. These have included studies on the etiology and physiologic changes associated with seizures and other neurologic effects of drugs and chemicals on the central nervous system.
NIH has also supported research on the environmental toxicologic effects on the body, but no program had focused exclusively on the terrorist threat posed by chemicals. NIAID-supported a Blue Ribbon Panel and several targeted workshops on specific chemical issues and assisted NIH in developing the medical research strategy and agenda. This new research, thrust on developing medical countermeasures that can be used in mass casualty situations, represents a new and important priority for NIH and the U.S. Department of Health and Human Services and its commitment to protect and maintain the health of the nation. This research has resulted in the development of an NIH Strategic Plan and Research Agenda on Medical Countermeasures Against Chemical Threats. This program, focusing on the medical aspects of chemical agents, is a part of the broad biodefense medical research program headed by NIAID across the Weapons of Mass Destruction threat spectrum.
With the support of NIAID and the NIH Biodefense Research Coordinating Committee, the National Institute of Neurological Disorders and Stroke has executed a research grant and contract program called the NIH Countermeasures Against Chemical Threats (CounterACT) Research Network. The CounterACT Research Network solicited proposals from academia, other governmental agencies, and industry. In Fiscal Year 2006, the CounterACT Research Network established four Centers of Excellence in Medical Chemical Research and more than two dozen research projects focusing on nerve agents, mustard, cyanide, and pulmonary agents. Several Small Business Innovation Research grants for therapeutics and diagnostics development were also established. NIAID also developed a strong research partnership through an interagency agreement with USAMRICD to focus on nerve agents, vesicants, cyanide, and pulmonary agents and to explore the civilian use of military products.
Achievements and Goals
Over the next several years, it is the intent of the NIH medical chemical research program to draw on the expertise in the appropriate research institutions comprising NIH and to strengthen the national research base with involvement of academia, government research laboratories, and industry in developing safe and effective medical products addressing all subsets of the U.S. population.
The Strategic National Stockpile (SNS) is maintained by the Centers for Disease Control and Prevention (CDC). SNS now contains CHEMPACKS which are located in secure, environmentally controlled areas throughout the United States and are available for rapid distribution in case of emergency. Many of the critical components of the CHEMPACKS are now available in adult and pediatric formulations. CDC has established a diagnostic response network for detecting nerve agents, mustard, cyanide, and toxic metals. NIH will continue to research, develop, and improve medical products that include chemical antidotes, drugs to reduce morbidity and mitigate injury, drugs to reduce secondary to chemical exposure, and diagnostic tests and assessment tools to be used in mass casualty situations.
Metabolic poisons, such as hydrogen cyanide and cyanogen chloride, inhibit cellular respiration, whereby cells extract oxygen from the blood and transform the energy in sugar molecules into a useful form of energy for cells. All systems of the body are ultimately affected by these metabolic poisons. The cardiovascular and central nervous systems are most strongly affected, due to their high demands for oxygen and energy and their limited ability to use alternative pathways for energy production. Exposure to metabolic poisons can quickly cause seizures, respiratory failure, cardiac arrest, and death. The long-term effects of these agents are poorly understood and may include gradual neurodegeneration.
Metabolic poisons can be inhaled or ingested. Exposure to high concentrations of hydrogencyanide gas (HCN) can cause death within minutes. This narrow therapeutic window presents a formidable challenge for treatment but emphasizes the need for immediate medical intervention. Inhalation of lower concentrations of cyanide vapor or the ingestion of cyanide salt may result in a slower development of symptoms.
No pretreatment for cyanide poisoning is available and may not be practical. Since 1933, a Cyanide Antidote Kit has been marketed for use in the United States but, as a kit, it has never received formal regulatory approval by the Food and Drug Administration (FDA). The Cyanide Antidote Kit includes crushable ampules of amyl nitrite, for inhalation, and sodium nitrite and sodium thiosulfate, which are administered intravenously. The nitrites bind with hemoglobin in the blood to produce methemoglobin molecules. The methemoglobin then binds with cyanide to produce a much less toxic compound, cyanomethemoglobin, which is eventually eliminated from the body. Sodium thiosulfate, often referred to as a sulfur donor drug, converts cyanide into non-toxic thiocyanate, which is then excreted by the kidneys.
Use of the Cyanide Antidote Kit can be very effective as a post-exposure treatment for cyanide poisoning, but it carries the risk of toxic side effects. High levels of methemoglobin can be lethal. Determining the correct dose is especially challenging for treating pediatric casualties. Individuals with pre-existing glucose 6-phosphate deficiency (G6PD deficiency, the most common inherited enzyme deficiency in humans) have a risk of red cell hemolysis if given sodium thiosulfate. Individuals with renal deficiency or anemia could also suffer toxicity from the treatment. Concern has been raised over the ability to quantify predictably the amount of amyl nitrite that would be absorbed through inhalation.
Recently, FDA approved Cyanokit (hydroxocobalamin for injection) for treating cyanide poisoning. It has not yet been determined how effective this new countermeasure would be in a mass casualty situation.
Administration of 10 percent (hyperbaric) oxygen is a major component in the treatment of cyanide poisoning and is typically used even before the administration of any cyanide antidotes. However, the value of hyperbaric oxygen has not been determined, especially with products that form methemoglobin.
Because ingredients in cyanide antidote kits can have toxic side effects, accurate diagnosis of cyanide poisoning is important. Currently, diagnosis is based on clinical evaluation, but the presenting symptoms may be confused with exposure to other agents including nerve agents, botulinum toxin, hydrogen sulfide, or carbon monoxide. No rapid diagnostic tests are available for any cyanide-containing compounds.
Cobinamide, one of the compounds in the biosynthesis pathway of hydroxocobalamin, is another promising drug that warrants further investigation. Cyanohydrin-forming compounds (e.g., alpha-ketoglutarate and pyruvate) and vasodilatory drugs that act similarly to nitrite compounds are potential new cyanide antidotes, as are drugs that act at the cellular level, such as synthetic S-substituted crystallized rhodanese (an enzyme that promotes the conversion of cyanide to non-toxic thiocyanate). Sulfur-containing medications may also have potential benefits in the treatment of cyanide poisoning, especially those that remain in circulation for longer periods of time than sodium thiosulfate. Drugs that form methemoglobin may have an advantage, but there are significant health risks associated with high levels of methemoglobin.
Several sophisticated cyanide detection methodologies have been developed but these are neither rapid nor widely available.
A variety of chemicals are known to affect the nervous system. Some directly target neural signaling pathways. These include the classic nerve agents (e.g., sarin, soman, tabun, and VX), organophosphate pesticides, and some animal toxins (e.g., botulinum toxin). Chemicals can also affect the nervous system indirectly. For example, metabolic poisons (e.g., cyanide) disrupt cellular respiration, which ultimately prevents the brain from getting sufficient oxygen and energy. Some vesicating agents (e.g., sulfur mustard) appear to have neurological effects as well, although the specific mechanism by which they affect the nervous system is poorly understood.
Neurological symptoms depend on the type of chemical, the level of exposure, and the time elapsed following exposure. Exposure to nerve agents, metabolic poisons, or high levels of sulfur mustard can trigger seizures and loss of consciousness. Other acute effects of nerve agent poisoning include muscle paralysis, cardiorespiratory depression, massive secretion from mucous membranes, eye irritation, and blurry or dim vision. Other acute effects of exposure to high doses of sulfur mustard include behavioral effects and cognitive difficulties. Nerve agents and metabolic poisons also appear to have serious long-term neurological effects, including neurodegeneration, but these have not been studied extensively.
The physical states of chemicals that affect the nervous system are an important determinant of the requirements for developing effective countermeasures. Although some chemicals that affect the nervous system exist primarily in the form of a vapor (e.g., hydrogen cyanide), others are oily liquids that are very difficult to remove from the environment and extremely toxic even at miniscule levels (e.g., VX). For these persistent agents, it would be ideal to have pretreatments with long-lasting protective effects that can be administered in advance of possible exposure to personnel who must enter contaminated sites.
Existing medical countermeasures target the molecular interactions between nerve agents and proteins involved in neural signaling. Neurons can communicate with each other or stimulate muscle cells by releasing a chemical called acetylcholine. Nerve agents and organophosphate pesticides bind and inhibit a protein called acetylcholinesterase (AChE), which normally breaks down acetylcholine after a stimulated neuron has released it. The acute symptoms of nerve agent and organophosphate exposure are due to excess acetylcholine that persists after its release and continues to stimulate nerve endings in the brain, muscles, and secretory glands. Although this route of nerve excitation is considered to be the major focus for drug intervention, other neurotransmission pathways in the body that can be affected by toxic chemicals may need to be assessed separately for the development of potential interventions.
The U.S. military adopted pyridostigmine bromide (PB), an FDA-approved treatment for myasthenia gravis (an autoimmune disease characterized by extreme muscle weakness), for the pretreatment of soman (a nerve gas) poisoning. PB competes with the nerve agent by reversibly attaching to AChE prior to nerve agent exposure, thus avoiding the toxic effects of excessive acetylcholine stimulation. PB has limited usefulness after exposure to a nerve agent and is approved for use in military populations against only one of several nerve agents that could be used in an attack.
The standard treatment for nerve agent and organophosphate poisoning includes a 2-PAM, and benzodiazepine anticonvulsants, such as diazepam. Atropine blocks acetylcholine receptors in certain tissues, drying secretions and reducing smooth muscle contraction. Oximes free AChE from the chemical nerve agent and have their most marked effect on skeletal muscle strength. The only oxime approved for use in the United States against nerve agents is pralidoxime chloride (2-PAM). This oxime is also indicated as an antidote for organophosphate insecticide poisoning and to control overdosage of anticholinesterase drugs in the treatment of myasthenia gravis. The Strategic National Stockpile CHEMPACKs, which have been distributed around the United States for deployment in case of a chemical attack or accident, contain military “Mark I” adult autoinjectors with atropine and 2-PAM, diazepam autoinjectors, pediatric atropine autoinjectors, and multi-use vials of 2-PAM and diazepam.
These current treatments for nerve agent or organophosphate exposure have significant disadvantages. Multiple doses of atropine and 2-PAM may be necessary in order to be effective. Atropine does not relieve nerve agent effects on skeletal muscles. Oximes are ineffective once the AChE-nerve agent complex has undergone “aging,” a chemical change that permanently inactivates AChE. Aging can happen within minutes of exposure to some of the nerve agents, such as soman. Although diazepam is an effective treatment for nerve agent-induced seizures during about the first 40 minutes after exposure, it is less useful later. Benzodiazepine anticonvulsants also carry risks of excessive sedation and respiratory depression. No treatments are currently available to prevent or reduce neurodegeneration resulting from prolonged seizures, anoxia, or the direct effects of chemical agents.
Diagnosis following an acute exposure to a nerve agent is generally based on clinical observations of specific symptoms. Environmental sensors may provide valuable information on probable chemical exposure. One of the greatest challenges in diagnosis is determining whether an individual exposed to a nerve agent is experiencing chemically induced seizure activity in the absence of visible convulsions, since the chemicals that trigger seizures may also cause unconsciousness or paralysis. Sustained seizure activity that is uncontrolled can result in permanent brain injury and death. The standard test for seizure activity involves placing electrodes on the scalp to record electrical activity in the brain using electroencephalography (EEG). Such devices are not portable and have limited practical value in evaluating patients in a mass casualty situation.
Alternative oximes, such as trimedoxime (TMB4), Toxogonin, and HI-6 (an H-series oxime), are available in other countries for the treatment of nerve agent-induced injuries. Some of these have been or are in the process of being evaluated for use by the U.S. military, but none have been evaluated for possible use in U.S. civilian populations. Several promising new oxime candidates also have been identified and will require further investigation.
Proteins such as the enzyme butyrlcholinesterase (BChE), which have a similar structure to AChE, represent another potential therapeutic approach. They can act as “bioscavengers,” sequestering nerve agent molecules in the bloodstream. Plasma-derived human BChE shows some promise as a prophylactic countermeasure for military personnel, but it remains uncertain whether this product can be administered efficiently in a large enough volume to be fully effective. Several studies are underway and more are needed to determine if this, and similar bioscavenger-like proteins, could be effective treatments for civilians after exposure to a nerve agent has already occurred. Alternative forms of BChE have been produced through genetic engineering. They appear to be effective as pretreatments in animal models, and it may be possible to develop these enzymes as treatments for the civilian population or pretreatments for first responders.
Several promising anticonvulsant drugs for the treatment of nerve agent poisoning are on the horizon. New anticonvulsant drugs that have been or are being developed for the treatment of epilepsy in pediatric and adult populations may also be useful for treating chemically induced injuries. Alternative or more expeditious delivery routes for anticonvulsant drugs already approved to treat seizures may also be desirable in the event of mass casualties.
The benzodiazepine midazolam, currently FDA-approved as an intravenous sedative and anesthetic, may also be very effective in the treatment of seizures. Midazolam is being investigated to replace diazepam as the immediate anticonvulsant treatment for nerve agent-induced seizures. The potential use of midazolam, administered intramuscularly, to treat nerve agent-induced seizures will require clinical trials to test its effectiveness and gain FDA approval. Different benzodiazepines and other classes of drugs that antagonize various neuronal excitation pathways mediated by the neurotransmitter glutamate and neurosteroids, are also candidates to treat chemically induced seizures. The development of these potential therapies will also require preclinical and clinical studies.
Other promising research strategies may lead to treatments for chemically induced, long-term damage to the nervous system, or neurodegeneration. Recent studies have shown that the immunosuppressant drug cyclosporine dramatically reduced organophosphate-induced seizures and brain damage, and preserved memory and learning ability in rodents. Clinical trials are planned or underway with several drugs that appear to slow or stop the process of neurodegeneration due to stroke, traumatic brain injury, and chronic nervous system diseases. Some of these drugs may be candidates to prevent chemically induced neurodegeneration.
Many toxic chemicals can damage the respiratory airways, with potentially life-threatening effects. Ammonia, various alkalis (e.g., bleach and sodium hydroxide), hydrochloric and sulfuric acid, vesicants (e.g., sulfur mustard) and other corrosive agents affect the upper airways, the portion of the respiratory tract that begins at the mouth and nose and ends at the larynx (voice box). Inhalation of these chemicals can cause acute inflammation, painful ulcerations, increased secretions, and difficulties in breathing and swallowing. Secondary bacterial infections may further exacerbate the initial injury. Damage to the upper airway can lead to respiratory failure and death. Exposure can also lead to long-term health problems. For example, chronic respiratory problems, such as scarring and narrowing of the trachea, have been observed in Iranians exposed to sulfur mustard during the Iran-Iraq War of the 1980s. (Vesicating chemicals is discussed in more detail in Skin, Eyes, and Mucous Membranes.)
Some industrial chemicals, including ammonia, chlorine, phosgene, and perfluoroisobutylene (PFIB), can cause lower respiratory tract injuries, particularly life-threatening pulmonary edema. Pulmonary edema—the leakage of fluid into the lungs—prevents oxygen delivery to the blood, ultimately preventing oxygen from reaching the brain, kidneys, and other organs. Symptoms may be immediate or delayed; chlorine causes immediate airway irritation and pain, whereas phosgene exposure may not be evident for 24 to 48 hours (see Resources: Names and Symbols). People who survive a single, acute exposure to respiratory airway toxins generally show little or no long-term health problems, although some may eventually develop asthma or chronic bronchitis. Individuals at greatest risk are those with pre-existing heart or lung disease.
Specific pretreatments, drugs to prevent chemically induced lung injuries due to respiratory airway toxins, are not available. Analgesic medications, oxygen, humidification, and ventilator support currently constitute standard therapy. Hemorrhaging, signifying substantial damage to the lining of the airways and lungs, can occur with exposure to highly corrosive chemicals and may require additional medical interventions. Treatment of injuries to the lower respiratory tract is also supportive and usually includes administration of oxygen, the use of mechanical ventilation to include positive airway pressure, and bronchodilators to treat bronchospasms. Drugs that reduce the inflammatory response, promote healing of tissues, and prevent the onset of pulmonary edema or secondary inflammation may be used following severe injury to prevent chronic scarring and airway narrowing.
Current diagnostic capabilities are limited. Exposure to chlorine, phosgene, or any of the major alkalis is determined based on clinical signs and symptoms. No screening tests are available to identify individuals exposed to low levels of chemicals.
Although current treatments can be administered in a controlled hospital setting, many hospitals are ill-suited for a situation involving mass casualties among civilians. Inexpensive positive-pressure devices that can be used easily in a mass casualty situation, and drugs to prevent inflammation and pulmonary edema are needed. Several drugs that have been approved by FDA for other indications hold promise for treating chemically induced pulmonary edema. These include β2-agonists, dopamine, insulin, allopurinol, and non-steroidal anti-inflammatory drugs, such as ibuprofen. Ibuprofen is particularly appealing because it has an established safety record and can be easily administered as an initial intervention. Studies have shown that ibuprofen improves survival and reduces lung fluid levels in mice exposed to phosgene. Inhaled and systemic forms of β2-agonists used in the treatment of asthma and other commonly used medications, such as insulin, dopamine, and allopurinol have also been effective in reducing pulmonary edema in animal models but require further study.
Other promising drugs in earlier stages of development act at various steps in the complex molecular pathways underlying pulmonary edema. Some of these potential drugs target the inflammatory response or the specific site(s) of injury. Others modulate the activity of ion channels that control fluid transport across lung membranes or target surfactant, a substance that lines the air sacs in the lungs and prevents them from collapsing. Mechanistic information based on toxicology, biochemistry, and physiology may be instrumental in determining new targets for therapy.
Mechanistic studies may also aid in the development of new diagnostic approaches. Some chemicals generate metabolic byproducts that could be used for diagnosis but detection of these byproducts may not be possible until many hours after initial exposure. Additional research needs to be directed at developing sensitive and specific tests to identify individuals quickly after they have been exposed to varying levels of chemicals toxic to the respiratory tract.
Skin, Eyes, and Mucous Membranes
Vesicating agents such as sulfur mustard, nitrogen mustard, lewisite, and caustic industrial chemicals can cause severe blistering and burns to the eyes, mucous membranes, skin, and upper airways, as well as chronic eye inflammation and blindness. The eyes are the organs most sensitive to these chemicals. Vesicants may also affect other parts of the body, including the respiratory tract, immune system, and bone marrow. Sulfur mustard can cause tissue damage within minutes of exposure. Physical injury from other vesicating agents may not be evident for several hours and may result in delayed recognition of exposure (see Names and Symbols of Classical Chemical Warfare Agents). In such situations, an exposed individual may put others at risk of secondary contamination.
Sulfur mustard is an oily liquid and is considered a “persistent” chemical agent, that is, it does not evaporate quickly and remains active for an extended time. Clothing, skin, and hair may remain contaminated with sulfur mustard for hours, presenting a challenge to healthcare providers. The military and first responders rely heavily on individual physical protection (e.g., protective masks and suits) to prevent exposure to vesicants. No pretreatment drugs are yet available.
Current treatment of vesicant-induced injuries is largely symptomatic and supportive. Eye injuries require the use of special eye drops, antibiotics, and other drugs to prevent secondary infection. Steroids are used to limit the inflammatory response and speed the healing process. Skin wounds, especially when severe with blister formation, require specific medical attention to reduce pain, prevent infection, and reduce inflammation. Debridement (removal) of a layer of the injured skin may be necessary to speed the healing process.
At this time, diagnosis of vesicant injury is based on clinical signs and symptoms and the detection of specific agents in the environment. There are no FDA-approved clinical laboratory tests for sulfur mustard in blood or tissue. However, compounds such as thiodiglycol are produced in the body after exposure to sulfur mustard and can be detected in blood, urine, and tissue. Analysis of these compounds requires the use of complex technologies, such as gas chromatography-mass spectrometry.
BAL may be useful in the topical treatment of non-blister injuries from other vesicants in addition to lewisite. Because of reported toxicities associated with BAL, however, this compound has not been considered to be a useful prophylactic drug. Other therapeutic compounds are needed that can prevent or quickly reduce the redness and deep tissue damage (blisters). Also needed are improved skin protectants, reactive skin protectants that can neutralize the agent, new skin and eye therapies, and improved healing techniques.
Names and Symbols
Table based on information in
Not included in this table are other chemical agents recognized by the military, such as BZ (incapacitating agent), CN and CS (tear gas products), and DM (adamsite), a vomiting gas.
NIH Strategic Plan and Research Agenda for Medical Countermeasures Against Chemical Threats (PDF 3 MB)
NIH Countermeasures Against Chemical Threats Research Network
Emergency Preparedness and Response
Strategic National Stockpile
Safeguard America and Its Allies From Weapons of Mass Destruction
United States Army Medical Research Institute of Chemical Defense
Ready America-Chemical Threat
Chemical Reactivity Hazards
OSHA/EPA Occupational Chemical Database
Salt Lake Technical Center Chemical Sampling Information
Last Updated November 29, 2011