2011 Report on Research Progress and Future Directions 1 

The NIH Medical Research 

Program Directed Against 

Chemical Threats 

2011 Report on Research Progress 

and Future Directions 

2011 Report on Research Progress and Future Directions 3 

The NIH Medical Research 

Program Directed Against 

Chemical Threats 

2011 Report on Research Progress 

and Future Directions 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

National Institutes of Health 

National Institute of Allergy and Infectious Diseases 
4 The NIH Medical Research Program Directed Against Chemical Threats

FOREWORD 

In August 2007, the National Institutes of Health (NIH) published the National Strategic Plan and 

Research Agenda for Medical Countermeasures against Chemical Threats. This plan defined a 

research strategy to (1) improve current approaches in the treatment of chemical casualties and (2) 

develop new countermeasures that could be used during and following an industrial accident or a 

chemical terrorist attack on civilian populations. The plan recognized that NIH-supported research 

should be conducted in parallel with the Department of Defense (DoD) because certain diagnostic 

tests and antidotes might be used in both military and civilian settings. 

The Department of Health and Human Services (HHS) mandated that the National Institute of 

Allergy and Infectious Diseases (NIAID), part of the NIH, execute the strategic biodefense medical 

research plan against weapons of mass destruction (WMD) through collaborations with other 

NIH Institutes and Centers, other federal agencies, academia and industry. The ensuing program, 

the NIH Medical Research Program Directed Against Chemical Threats, is funded by a special 

Congressional supplement to the NIH budget, and is integrated closely with HHS medical product 

development efforts. 

Impressive progress occurred in the three years after publication of the strategic plan and research 

agenda. This progress stems from convergence of several key elements, including sharing of 

expertise, information, and other resources from the NIH Institutes (ICs), such as the NIAID/ 

National Institute of Neurological Disorders and Stroke (NINDS) effort to establish a national 

research program to develop medical products to counteract chemical threats. Interagency 

agreements with the U.S. Army and the establishment of a national academic and industrial 

research base dedicated to product development against chemical threats also facilitated important 

progress toward advancing the research effort. Interest in chemical research and medical product 

development has fostered new careers in scientific research and enabled NIH to recruit talented 

scientists, including Nobel Laureates. These researchers bring invaluable expertise to an area of 

research previously limited primarily to military laboratories, and help to raise the level of science 

in the entire field through their numerous publications in the top peer-reviewed scientific journals. 
2011 Report on Research Progress and Future Directions 5 

The NIH research focus on Medical Countermeasures against Chemical Threats is managed 

by the NIAID and NINDS and draws on research strengths of both NIH scientists and top 

NIH-grant recipients at research institutions and centers nationwide. For instance, through the 

Countermeasures Against Chemical Threats (CounterACT) Program, the NINDS and NIH partner 

ICs including the National Eye Institute (NEI), National Institute of Arthritis and Musculoskeletal 

and Skin Diseases (NIAMS), National Institute of Child Health and Human Development 

(NICHD), National Institute of Environmental Health Sciences (NIEHS), National Toxicology 

Program (NTP), National Library of Medicine (NLM), and National Institute of General Medical 

Sciences (NIGMS) established Research Centers of Excellence at academic, commercial and 

federal laboratories across the United States. These research centers focus on the health effects 

of hazardous chemicals and the underlying pathology. The NINDS also utilizes its existing 

scientific infrastructure and research expertise in the area of neurological disorders to advance 

research on chemical nerve agents and their effects. Other NIH Institutes, such as the NIEHS 

and the NIAMS, also manage research protocols. The CounterACT program leverages many 

NIH resources, such as the NTP and NLM, to fill data gaps in our knowledge of chemical 

agents, and the NIH Molecular Libraries Program to screen for new therapeutic targets. Finally, 

the NIH medical chemical program also draws upon the vast knowledge of chemical warfare 

agents and toxic chemicals acquired by the DoD and other Federal agencies, as well as industry. 

Workshops sponsored by the NIH engage leading authorities and experts from many federal 

agencies and academia in providing guidance to the overall program. 

The chemicals of concern are based on assessments performed by the Department of Homeland 

Security (DHS) and progress reviews are conducted on a regular basis with the involvement of 

all appropriate federal agencies, including the NIH. Promising therapeutic compounds have now 

been identified, and studies have led to a deeper understanding of the causes of injury down to 

the molecular level. As this document shows, promising compounds discovered through the NIH 

CounterACT Program may prove to be useful in preventing or reducing morbidity and mortality 

from highly hazardous chemicals. 

Anthony S. Fauci, M.D. Francis S. Collins, M.D. 

Director Director 

National Institute of Allergy National Institutes of Health 

and Infectious Diseases 
6 The NIH Medical Research Program Directed Against Chemical Threats

TABLE OF CONTENTS 

Foreword ................................................................................................................................. 4
 

Introduction ............................................................................................................................ 7
 

The Chemical Threat ................................................................................................... 7
 

Addressing the Chemical Threat through Research ...................................................... 7
 

Building The Research Infrastructure..................................................................................... 8
 

Public Health Emergency Medical Countermeasures Enterprise ................................... 8
 

NIH Research and Development Program ................................................................... 8
 

The Chemical Countermeasures Research Community............................................... 10
 

The Trans-NIH CounterACT Program ........................................................................ 10
 

Research Accomplishments Resulting From NIH Support
 

of Chemical Threat Research .............................................................................................. 11
 

Progress Against Nerve Agents ................................................................................... 11
 

Progress Against Metabolic Poisons ........................................................................... 12
 

Progress Against Vesicants and Pulmonary Agents ..................................................... 13
 

Therapeutic Targets and Model Development ........................................................... 14
 

Looking To The Future ......................................................................................................... 15
 

Appendices: .......................................................................................................................... 17
 

Table 1: Examples of Highly Hazardous Chemicals................................................... 17
 

Table 2: Key Workshops and Expert Panels on Chemical Threats and

 Medical Countermeasures .......................................................................... 18
 

Table 3: 2006-2009 NIH CounterACT Funding Opportunity Announcements

 Soliciting Research Proposals ...................................................................... 19
 

Table 4: 2006-2010 CounterACT Centers of Excellence and Primary Investigators .... 21
 

Table 5: Interagency Agreements (IAAs) ................................................................... 22
 

Figure 1: Overview Diagram of Trans-NIH CounterACT Program .............................. 24
 

Figure 2: CounterACT Medical Countermeasures and Technical

 Readiness Levels (TRLs)............................................................................... 25
 

Figure 3: Publications Resulting from CounterACT Investments ................................. 26
 
2011 Report on Research Progress and Future Directions 7 

Introduction 

The Chemical Threat 

Historically, the Department of Defense (DoD) 

has been concerned about the use of chemical 

warfare agents (CWA), due to their potentially 

devastating effects on the battlefield. More 

recent events involving the expanded use of 

toxic chemicals as weapons has increased 

awareness of the effects such chemicals may 

have on both military and civilian populations. 

The procurement and preparation of chemical 

weapons is well-documented as a part of the 

doctrine of several radical terrorist groups. 

Additional evidence has been obtained that 

some terrorist groups are interested in staging 

chemical attacks on population centers, perhaps 

in combination with other weapons. 

Highly toxic chemicals are now recognized 

as serious public health threats for a variety of 

reasons. First, unlike infectious diseases where 

incubation periods may allow for prophylactic 

measures to be instituted, chemical incidents 

can occur quickly with immediate generation of 

casualties. Second, many of the toxic industrial 

chemicals or their precursors may be easily 

procured or manufactured without detection. 

Third, it may difficult to ascertain if a chemical 

incident was accidental or deliberate, since 

chemical accidents can occur without warning 

or be associated with another disaster, such 

as an explosion. Fourth, extremist groups or 

individuals with limited scientific knowledge may 

be able to manufacture dangerous compounds 

without detection. Finally, the deliberate release 

of chemicals into the environment may increase 

the likelihood of injuries or death. This may be 

through deliberate contamination of food or water 

supplies or atmospheric release of volatile agents 

in enclosed spaces or poorly ventilated areas. 

Much attention has now been directed at how and 

where chemicals are manufactured, transported 

and stored in the U.S., but this will not prevent 

the desire of terrorists to cause destruction or 

disruption. 

It is impractical to develop specific 

countermeasures against every dangerous 

chemical in the U.S. Hazardous acids, bases, 

and explosives alone represent chemical dangers 

for those working with such materials, and the 

importance of security and careful handling and 

storage cannot be overemphasized. 

From a public health perspective where mass 

casualties might result from deliberate or 

accidental release of a chemical, high priority 

chemical threats include: (1) CWAs such as 

the “nerve gases” Sarin, VX, Soman, or their 

derivatives and Sulfur Mustard; (2) toxic industrial 

chemicals, such as Cyanide, Chlorine, and 

Phosgene; and (3) toxic agricultural chemicals, 

such as highly toxic insecticides (Parathion, 

Chlorpyrifos,and Disulfoton) and rodenticides 

(Sodium Fluoroacetate, Tetramethylenedisulfotetr 

amine(TETS), and Strychnine). These categories of 

chemicals exert their toxic effects through different 

mechanisms and on different organs of the body 

and physiological systems. 

The Department of Homeland Security (DHS) 

Chemical Security Analysis Center has assisted 

in the analyses and prioritization of threats 

and has developed a “Chemical Terrorism Risk 

Assessment” (Appendix 1). Updates on risk based 

on modeling and other information are provided 

periodically. Response during and following 

events where chemicals are released are addressed 

under various emergency preparedness and 

response plans and include recommendations 

for employing specific medical interventions 

that could minimize the number and severity of 

casualties. 

Addressing the Chemical Threat through Research 

The DoD is a key element in the chemical 

countermeasures research effort since many 

military research and development priorities 

overlap with those of civilians, such as the 

needs of civilian first responders and health 

care providers in the event of a chemical agent 
8 The NIH Medical Research Program Directed Against Chemical Threats

exposure. Even though DoD research has 

improved our understanding of how CWAs 

cause injury, research must continue as the list 

of chemical threats grows ever longer. The NIH 

research efforts initially focused on addressing 

the underlying injury processes resulting from 

chemical agents, including the toxicological 

effects of chemical compounds and their varying 

effects on the human body. 

Advances in biotechnology, knowledge of host 

defenses, and human genomics has showed 

promise to counteract the threat of chemical 

compound exposures. These countermeasures 

would be important for protecting civilians, 

as many would not have access to personal 

protective equipment or pre-treatment medical 

countermeasures. In addition, these realizations 

directed attention towards development of 

immediate post-exposure interventions and the 

need to clearly understand how exposure to these 

compounds affects physiological, biochemical 

and immunological processes at all stages of life. 

Due to these issues and the growing awareness 

that chemical agents pose a threat to public 

health, the Federal Government launched a new 

biodefense research effort with a goal to develop 

medical interventions to counteract the threat. To 

accomplish this goal, basic research initiatives 

were created to inspire advanced research and 

development for promising products. Successful 

completion of these initiatives would require 

participation by pharmaceutical companies, as 

well as HHS, specifically the Food and Drug 

Administration (FDA) and the Biomedical 

Advanced Research and Development Authority 

(BARDA). Federal programs such as Project 

Bioshield and the Strategic National Stockpile 

(SNS) continue to be very important in meeting 

this goal in that they provide market incentives to 

industry, particularly the pharmaceutical industry. 

Building The Chemical Research 

Infrastructure 

Public Health Emergency Medical 

Countermeasures Enterprise 

Approximately five years ago, HHS established 

the Public Health Emergency Medical 

Countermeasures Enterprise (PHEMCE) Strategy 

to address the public health threat from chemical, 

biological, radiological and nuclear (CBRN) 

agents. The PHEMCE Strategy established the 

goals and objectives that the HHS would employ 

to ensure that medical countermeasures are 

available in their critical hour of need. The 

implementation plan employed a “Four Pillars” 

approach, including: (1) identify and assess 

CBRN threats by conducting both material 

threat determinations and population threat 

assessments; (2) assess civilian medical and 

public health consequence assessments based 

on DHS scenarios of CBRN threats; (3) establish 

concept of operations for medical countermeasure 

requirements; and (4) identify and prioritize 

near-, mid-, and long-term research development 

and acquisition programs. The NIH effort to 

understand the pathology related to chemical 

exposure and develop specific medical treatments 

is a part of the overall PHEMCE Strategy, along 

with the focus on biological and radiological/ 

nuclear research. 

NIH Research and Development Programs 

In support of the PHEMCE Implementation Plan, 

the NIH led the research and development of 

new medical countermeasures against CBRN 

threats. With regard to chemical threats, the NIH 

established a program to develop safer and more 

effective therapies and diagnostic technologies for 

treating victims of emergency incidents involving 

chemical threat agents as a part of an overall 

national biodefense research strategy. A series of 

workshops and expert panels have been held by 

the NIAID and NINDS to ascertain research gaps 

and develop priorities (Appendix 2). 
2011 Report on Research Progress and Future Directions 9 

In 2005, NIAID convened a NIAID Blue 

Ribbon panel to help define the parameters of a 

comprehensive biodefense research effort against 

chemical threats. The “NIH Strategic Plan and 

Research Agenda for Medical Countermeasures 

Against Chemical Threats”, published in 2007 

(http://www.niaid.nih.gov/topics/biodefenserelat 

ed/chemicalcountermeasures/Pages/defaultaspx), 

resulted directly from the discussions and 

recommendations of this Panel. Recognizing the 

neurological effects of many of the highest priority 

chemicals, NIAID asked the National Institute of 

Neurological Disorders and Stroke (NINDS) to 

develop a research program on chemical threats 

that engaged academia and industry. NINDS 

had an active translational research program 

focused on neurological disorders that resembled 

symptoms caused by nerve agents. 

To complement the expertise in neurological 

effects, NINDS and NIAID recruited other ICs to 

the NIH research program including the National 

institute for Environmental Health Sciences 

(NIEHS), the National Eye Institute (NEI), the 

National Institute for Child Health and Human 

Development (NICHD), the national Institute of 

General Medical Sciences (NIGMS), the National 

Institute of Arthritis and Musculoskeletal and 

Skin Diseases (NIAMS), the National Library of 

Medicine (NLM), and the National Heart, Lung 

and Blood Institute (NHLBI). Several other ICs 

participated in NIAID-sponsored biodefense 

related meetings where the overall strategy was 

discussed. 

In FY 2006, NINDS, with the encouragement 

and support of NIAID, established the NIH 

“Countermeasures Against Chemical Threats” 

(CounterACT (http://www.ninds.nih.gov/ 

counteract) research program to support basic, 

translational, and clinical research into chemical 

threat agents. The CounterACT network continues 

to be a critical piece of the NIH strategic plan and 

is aimed at the discovery and/or identification 

of better therapeutic and diagnostic medical 

countermeasures against chemical threat agents. 

The scope of research includes: 

• Mechanistic studies to identify targets for 

therapeutic development
 

• Development of in vitro and animal models 

for efficacy screening
	

• Efficacy screening of therapeutics using new 

and validated in vitro and animal models 

• Advanced efficacy studies with appropriate 

animal models using Good Laboratory 

Practices (GLP) 

• Clinical trials 

Beginning in Fiscal Year (FY) 2005, the NIH 

received supplemental funds to address the 

effect of radiation and nuclear threats on human 

health. In FY 2006, an additional supplement of 

$50 million was appropriated to address medical 

countermeasures against chemical terrorist threats 

to civilian communities. These supplemental 

funds were sustained until FY 2010. In FY 2011, 

the funding was reduced to $49.5M. At present, 

the FY 2012 funding and beyond has not been 

determined at the writing of this document. 

The need to utilize the expertise and investments 

of the Department of Defense is considered a 

key element in the overall biomedical research 

effort for the nation, since military research and 

development priorities overlap with those of 

civilians, including the needs of civilian first 

responders and health care providers. 

Interagency Agreements (IAAs) were initiated 

in 2006 with the U.S. Army Medical Research 

and Materiel Command (USAMRMC) and its 

subsidiary laboratory, the U.S. Army Medical 

Research Institute of Chemical Defense 

(USAMRICD). Subsequently, in 2011, NIH 

established IAAs with the U.S. Army Defense 

Technical Information Center (DTIC) and the U.S. 

Army Edgewood Chemical Biological Center. 

These IAAs expedite the production and use of 

restricted chemical warfare agents under DoD 

control. The IAA research agenda compliments 

the CounterACT grant program. 
10 The NIH Medical Research Program Directed Against Chemical Threats

The Chemical Countermeasures Research 

Community 

Since its creation, CounterACT has sought to 

engage high quality scientists in a variety of 

disciplines to include neuroscience. For example, 

CounterACT supported a Nobel Laureate to 

develop novel therapies to treat nerve agent 

poisoning. To recruit scientists, NIH uses a variety 

of funding announcements (Appendix 3). In 

2006, the NIH received over 100 applications 

for this research which were then evaluated by 

an external review panel of experts, in keeping 

with long-standing NIH practice and stated NIH 

peer review policy. Of these applications, more 

than 60 new investigators received funding in 

September 2006. Continuing to move the program 

forward, many new initiatives were released 

subsequently, including– 

• 2008 – two additional initiatives that funded 

seven additional projects and two Research 

Centers of Excellence. 

• 2009 – initiatives to foster partnerships with 

industry through the NIH Small Business 

Innovation Research/Small Business 

Technology Transfer (SBIR/STTR) program. 

• 2010 and 2011 – new and renewal proposals 

solicited by NINDS for research resulting from 

projects funded in 2006. (Appendix 3) 

The CounterACT Program 

The Trans-NIH CounterACT Program 

encompasses a network of milestone-driven 

cooperative projects, including six Research 

Centers of Excellence, 54 individual research 

projects, small business awards and six 

Interagency Agreements with the DoD. 

CounterACT sponsors annual meetings of the 

entire research network (see NIH Record article 

for a description- http://nihrecord.od.nih.gov/ 

newsletters/2009/06_26_2009/story5.htm) 

to foster collaboration, share information and 

resources, and to give federal officials a chance 

to see progress. Several CounterACT scientific 

specialty groups also hold workshops and 

meetings between annual meetings. 

The CounterACT program staff is in close contact 

with the Center for Scientific Review which 

receives, screens, and reviews more than 60,000 

investigator-initiated research proposals per year. 

Some grants from this pool that are relevant to the 

CounterACT mission have been funded through 

the CounterACT research network. 

The NIH Biodefense Research Coordinating 

Committee conducts regular reviews of the 

research investments for the program to ensure 

that resources are directed towards developing 

only the most promising countermeasures. 

Interim reviews of the CounterACT Program 

are conducted by an external panel of senior 

academic experts and government officials to 

ensure that CounterACT activities are in keeping 

with NIH standards of research excellence. 

A number of resources and facilities provide 

additional access and collaboration opportunities 

to CounterACT researchers: 

• The NIH-supported CounterACT Efficacy 

Research Facility at Battelle Laboratories in 

Ohio increases the capacity for conducting 

studies with restricted agents and those needed 

to fulfill FDA Animal Rule requirements. The 

facility has a long-standing partnership with 

the DoD. 

• The CounterACT Preclinical Development 

Facility developed with SRI International 

enables investigators to conduct preclinical 

studies needed for drug discovery and 

development and, ultimately, FDA approval. 

Studies approved by the NIH are performed at 

no cost to the researcher. 

• The NINDS Anticonvulsant Screening 

Program at the University of Utah has been 

supported for the past 30 years to screen for 

anticonvulsant compounds for treating seizures 

caused by epilepsy and other pathologies. 

CounterACT leverages the high level of 

expertise and experience at this facility in a 

separate tract to screen for new drugs to treat 

seizures caused by chemical threat agents. 
2011 Report on Research Progress and Future Directions 11 

 

This program works closely with the MRICD 

program to test promising compounds with real 

chemical warfare agents that cannot be tested 

or used elsewhere. 

• Researchers funded through the NIH can use 

the NIAID-supported Collaborative Research 

Facility at USAMRICD in Edgewood, Maryland. 

This controlled research laboratory, suitable 

for research on concentrated chemical agents, 

was built in partnership with the DoD. The 

facility allows collaboration between highly 

experienced biochemists, physiologists, 

veterinarians, and laboratory technicians at 

USAMRICD and investigators from academic 

institutions. 

Research Accomplishments 

Resulting from NIH Support of 

Chemical Threat Research 

The NIH primary research effort on exposure to 

chemicals, particularly agents identified as threats 

by DHS, has focused on their potential effects 

on public health. Despite the potential use of 

chemicals as terrorist weapons, NIH research into 

chemical agents has been labeled “unclassified.” 

This has allowed research, including studies 

conducted jointly by NINDS and DoD-supported 

scientists, to be published, presented at 

professional scientific conferences, and in cases 

of intellectual property, to be awarded patents 

(Fig. 3). The following section describes selected 

findings resulting from NIH support for research 

into chemical threat agents. 

Progress Against Nerve Agents 

Chemicals that have toxic effects on the nervous 

system represent one of the largest challenges 

in medical therapeutics. NIH has been in the 

forefront of research to develop safe and effective 

countermeasures to combat the effects of chemical 

nerve agents for the civilian population and has 

capitalized on existing research infrastructures to 

accomplish new goals 

CounterACT studies of nerve agents include the 

following examples: 

• Diazepam, a controlled anti-anxiety drug, 

which is used to treat seizures resulting from 

nerve agents and epilepsy. However, users 

can become habituated to diazepam. In 

partnership with the military, CounterACTsupported researchers are working to develop 

an anticonvulsant against nerve agents for use 

in place of diazepam. Midazolam has been 

approved by the FDA as an anesthetic. It is 

water soluble, more quickly absorbed, and 

effective more rapidly than diazepam. Now, 

researchers are developing midazolam in an 

intramuscular (IM) form and are evaluating 

its use in treating seizures caused by nerve 

agents like sarin or soman. Phase I studies for 

midazolam IM in humans are complete and 

final animal studies are being led by the DoD. 

Midazolam IM is expected to be approved and 

ready for procurement by the HHS and DoD in 

2013/2014. 

• The CounterACT Program supported a clinical 

trial to compare a midazolam IM auto-injector, 

which could allow for the delivery of 

midazolam to patients before they arrive at 

the hospital, with Lorazepam IV, another 

treatment for seizures in humans. This trial 

used the same drug and auto-injector device 

proposed for use in humans exposed to nerve 

agents. The goal was to determine whether 

the new drug (midazolam IM) was at least as 

good as the standard of care (lorazepam IV). 

The results of this study were published in the 

New England Journal of Medicine (2102) in a 

landmark study indicating that not only does 

midazolam IM work as well as Lorazepam IV, 

but in fact works better and faster in humans. 

This study will be essential for the 2012 New 

Drug Application to the FDA. Additional 

research into anticonvulsant drugs, through 

the IAAs with USAMRICD, is being performed 

to determine if the drugs can be administered 

as adjuncts (an additional drug) to nerve agent 

antidotes. This adjunct method would help 
12 The NIH Medical Research Program Directed Against Chemical Threats

 

enhance anticonvulsant efficacy (midazolam) 

when treatment is delayed following exposure. 

These results will complement the current 

CounterACT midazolam efforts and address 

HHS and DoD concerns. 

• Galantamine is an FDA-approved drug used 

to treat Alzheimer’s disease. Galantamine can 

“protect” the brain from nerve agents by a 

reversible, competitive acetylcholinesterase 

(AChE) inhibition mechanism, according to 

CounterACT-supported researchers. However, 

the specific actions of galantamine that 

contribute to its effectiveness as a therapeutic 

countermeasure against organophosphate 

(OP) poisoning still remain poorly understood 

are presently being studied. CounterACT 

is supporting advanced efficacy studies in 

small animals and non-human primates in 

preparation for human safety trials. 

• At the Uniformed Services University of the 

Health Sciences, researchers supported by 

CounterACT have discovered a new class of 

anticonvulsant and neuroprotectant drugs that 

prevents seizures and the damage caused by 

nerve agents. One drug identified reduced 

the damage caused by nerve agents even after 

the onset of seizures. The safety of the drugs 

in this class are being tested concurrently at 

the CounterACT preclinical contract facility. 

Preliminary results revealed that drugs in 

this class enhance anticonvulsant efficacy, 

minimize brain injury, and facilitate behavioral 

recovery. 

• Oximes are molecules that counteract the 

effects of nerve agents by reactivating an 

enzyme that nerve agents turn off. The FDA 

approved one such oxime as an antidote to 

most CW nerve agents, but it is less effective 

against other neurotoxins. Novel oxime 

compounds are needed that can cross the 

blood-brain barrier and that are effective 

against a broader range of nerve agents. Such 

antidotes have been developed in CounterACT 

laboratories and through the IAAs. The possible 

addition of a centrally active oxime to the 

current regimen of atropine sulfate and 2-PAM 

could prove to be beneficial in the treatment 

of nerve agent intoxication. Nobel Laureate 

researchers, in the CounterACT Program, have 

synthesized several compounds that are now 

being tested against a variety of nerve agents 

and will be further tested for their safety in 

preclinical studies. 

Progress Against Metabolic Poisons 

Chemicals, like hydrogen cyanide and the 

cyanide salts, can function as metabolic poisons 

that interfere with cellular respiration and starve 

the cell of oxygen. Symptoms can range from 

dizziness to unconsciousness, shallow breathing, 

low blood pressure, and death within minutes. 

Cyanide can be a major threat to public health 

when deliberately added to food and drink 

or released as a gas. Treatments for cyanide 

exposure must be quick and safe to administer 

without waiting for laboratory confirmation. 

Currently, there are FDA-approved drugs that 

help counteract the effects of cyanide. However, 

the treatment is complex, can be dangerous, 

and most antidotes need to be given IV. Health 

practitioners and the military need new drugs that 

are fast-acting, safe and easily administered in 

mass casualty situations. 

Advances for treating exposure to cyanide include 

the following: 

• Cobinamide is a chemical precursor in 

cobalamin (vitamin B12) biosynthesis. 

Cobinamide can bind cyanide with greater 

affinity than hydroxycobalamin, which is a 

different cyanide antidote that was recently 

approved by the FDA. In animal studies 

conducted through the CounterACT Program, 

cyanide research centers in Minnesota and 

California have shown that cobinamide has 

great potential as an antidote for lethal and 

non-lethal doses of cyanide poisoning in 

animals. Importantly, this compound can be 

rapidly administered intramuscularly with an 

auto-injector device. These initial results have 
2011 Report on Research Progress and Future Directions 13 

 

moved cobinamide to pre-clinical development 

and eventual licensure. This drug holds 

promise as a countermeasure against cyanide 

attacks and accidental exposures. 

• Compounds such as sulfanegen show promise 

as an antidote to cyanide exposure because 

they render the metabolic poison (cyanide) 

nontoxic in animal studies. This molecule 

has a different mechanism of action than 

cobinamide. Investigators at the CounterACT 

cyanide research center are investigating the 

possible use of cobinamide and sulfanegen 

together, and comparing the effectiveness 

of these combinations to existing cyanide 

countermeasures. 

• Researchers at the University of Pittsburgh 

identified a new mechanism of cyanide 

poisoning involving nitric oxide. The 

understanding of this mechanism could lead to 

more effective treatments. 

• A diagnostic assay developed through the 

CounterACT Program can detect cyanide 

exposure in humans. This assay capitalizes 

on the high affinity and binding capacity of 

cyanide to cobinamide. Its detection limit is 

similar to that of the existing standard clinical 

assay used at present. More importantly, 

one can obtain measurements immediately, 

rather than the current 24 hour time lag. The 

high affinity cobinamide assay was used in a 

successful clinical trial of a drug that generates 

cyanide in patients. Investigators in a parallel 

study are developing this assay as a hand-held 

device to be used in the field for real-time 

cyanide measurement. The prototype will be 

applicable to blood, urine, and saliva samples. 

Progress Against Vesicants and Pulmonary Agents 

Vesicants and pulmonary agents are common 

chemicals that cause injury to the skin and lungs 

following exposure. These agents include sulfur 

mustard and chlorine. Upon long-term exposure, 

the lungs will develop thick, fibrin clots which 

cause severe damage to the tissues. 

Advances against vesicants and pulmonary agents 

include the following: 

• CounterACT researchers from the National 

Jewish Medical and Research Center in 

Denver, CO, identified an antioxidant, AEOL 

10150, that can protect animals against 

exposure to vesicants and pulmonary agents. 

In combination with other therapy, AEOL 

10150 was shown to block the processes 

that damage lungs and other tissues. Other 

groups at the Center determined that the 

drug PEGylated Thrombopoietin-mimetic 

peptide (TPOmp) could serve as a therapy for 

chemically induced bone marrow suppression. 

The potential benefits of AEOL 10150 and 

TPOmp against chemical agent toxicity is 

complemented by the Radiological Nuclear 

Medical Countermeasures Program to develop 

them as a treatment for acute radiation 

exposure. This could lead to new drugs for use 

against both types of threats. 

• Doxycycline is a tetracycline antibiotic that 

has been shown to be protective in several 

models of sulfur mustard poisoning. Some 

promising studies indicate that it may be useful 

in treating vesicant-induced eye injuries. 

Preliminary data from a CounterACT-funded 

study also suggest that the cyclooxygenase 

(COX) inhibitor, indomethacin, may be 

effective in mitigating skin damage and 

lung injuries caused by sulfur mustard. 

Corticosteroids such as clobetasol propionate 

reduce the severity of superficial skin injuries 

induced by liquid sulfur mustard and bromine 

vapor. Indomethacin, in conjunction with the 

drug diclofenac, works well when given in the 

days following exposure. IAA studies show 

that valproic acid, vigabatrin, and ambrisentan 

therapies may significantly increase survival 

rates when administered 15-20 minutes after 

exposure. 

• CounterACT researchers at the University 

of Alabama at Birmingham, showed that 

the FDA-approved, B2-agonist, BrovanaTM, 

reverses chlorine-induced reactive airway 
14 The NIH Medical Research Program Directed Against Chemical Threats

syndrome in mice. Combined therapy with 

Brovana TM and antioxidant drugs such as 

N-acetylcysteine and ascorbate, appears highly 

effective in counteracting the pulmonary 

toxicity of chlorine. 

• IAA researchers have shown that anti-inflammatory treatment, soon after injury, may limit 

tissue damage and speed wound healing for 

both superficial and deep dermal injuries. 

IAA researchers at the USAMRICD has been 

working on drugs, such as etanercept, for 

systemic treatment of deep dermal injury 

with some promising results. When applied 

topically in combination with clobetasol 

propionate and diclofenac (non-steroidal 

anti-inflammatory drug), inflammation and 

fibroplasia have been reduced. 

Therapeutic Targets and Model Development 

Therapeutic targets and model development 

are primary goals for the NIH medical chemical 

defense program. Rapid medium and high 

throughput screening models are needed to 

screen various drugs and chemicals in order to 

develop antidotes for various countermeasures 

against threat agents. Targeted therapies are being 

funded by the NIH to develop strategies and 

identify mechanisms required for the development 

of medical countermeasures against terrorist 

chemical threats. 

NIH-supported Research Advances toward 

therapeutic targets and model development 

include the following: 

• CounterACT-supported investigators in Miami 

have identified a novel target and therapeutic 

approach for nerve agent poisoning. The 

approach stabilizes the expression of an 

enzyme–acetylcholinesterase which is critical 

to the interaction between nerves and muscles, 

and prevents its removal by natural processes. 

The resulting pool of active enzymes can be 

available when other enzymes are destroyed 

by nerve agents and pesticides. Follow-up 

studies targeted this stabilization process using 

a laboratory-generated protein that binds 

enzymes at the neuromuscular junction. These 

NIH-funded studies represent the first approach 

(in decades) to treat organophosphate and 

nerve agent poisoning. 

• Transient Receptor Protein Antigent-1 

(TRPA1) is a stress sensor involved in signal 

transduction and initial host responses 

to chemicals. This response includes the 

release of cytokines and other immunologic 

mediators. These mediators may lead to 

unintended damage to surrounding tissues. 

CounterACT-funded researchers have sought 

to identify strategies to diminish the collateral 

tissue damage induced by TRPA1 and related 

proteins. In these studies, TRPA1 deficient 

mice were exposed to a TRPA1-antagonist, 

HC-030031. These mice had a reduced 

response to toxic chemical challenges. The 

results strongly suggest that TRPA1 contributes 

to the development of acute inflammation. 

Other studies are underway to determine 

how cell injury occurs and how the signal 

transduction pathways leading to cell damage 

might be interrupted. CounterACT researchers 

at Yale have discovered that in signal 

transduction, the TRPA1 receptor is activated 

by diphosgene, chloropicrin, isocyanates and 

other chemicals. 

• NIH-supported researchers are investigating 

water soluble derivatized fullerene 

nanoparticles to reduce the effect of nerve 

agents. These researchers are performing 

experiments to learn if the nanoparticles 

are able to scavenge nerve agents. For 

example, at the University of Puerto Rico, 

studies have indicated that cembranoid 

compounds, isolated from the tobacco plant, 

offer protection to the nervous system from 

nerve agents. Additional compounds are 

being studied as possible neuroprotectants. 

Novel compounds being examined include 

the growth factor neuregulin, prostaglandin 

receptor ligands and glutamate receptor 

antagonists. 
2011 Report on Research Progress and Future Directions 15 

• Development of rapid medium- and 

high-throughput screening models for chemical 

medical countermeasures is a goal for the NIH 

program. One NIH funded study at Harvard 

has developed a new high-throughput screen 

for nerve agents and pesticides using zebra 

fish and two physiological responses that 

have been validated against higher order 

mammalian models. The same system is 

being used by another Harvard researcher in 

a separate project to screen for antidotes for 

cyanide. These studies have demonstrated that 

at different developmental stages, organisms 

vary in their sensitivity to cyanide. This may 

have implications as to susceptibility of 

children and may guide medical interventions. 

• A screening program supported by CounterACT 

is located at the NIH Molecular Libraries 

Screening Center at Scripps Institute in 

California. The purpose of this program is to 

find compounds that can serve as antidotes 

to the chemical threat agent anatoxin. This 

involves two prominent marine neurotoxin 

experts at the Scripps Ocenaographic institute 

and the best resources available at the Scripps 

Screening Center. 

Looking To The Future 

When the medical chemical defense NIH research 

program started five years ago, the national 

research infrastructure in the United States for 

medical chemical research community was 

largely limited to those institutions directly funded 

by DoD. That effort focused almost solely on the 

warfighter. With the development of a strategic 

plan and research agenda and the maturation of 

the NIH research effort against chemical threats, 

substantial progress has been made in developing 

scientific interest and expertise in the private and 

public research sectors. Partnerships between the 

Federal Government, academia and industry are 

well underway. A robust research effort involving 

universities and drug developers is now engaged 

in medical chemical defense research that 

addresses the needs of the civilian community. 

The program has attracted allies of the U.S. who 

have similar needs for safe and effective medical 

products for military and civilian use. Promising 

drugs in development under this program have 

potential applicability in both malicious and 

accidental events. 

Hazardous chemical threats continue to be a great 

concern. Knowledge of the toxicity of chemicals 

raise concern among those who have national 

security responsibilities and those health care 

providers who must care for the casualties, but 

unfortunately this knowledge has attracted the 

attention of extremists with thoughts on how 

such chemicals could accomplish their more 

sinister goals. More recently, attention has focused 

on widely available household chemicals that 

could be used in malicious ways and those toxic 

chemicals that have been used in suicide. 

From the onset of the program, the need for 

medical interventions that address all subsets of 

the civilian population was recognized. Special 

concerns for pregnant women, infants and 

children (where growth and development may be 

more affected by chemical exposure) means the 

development of appropriate animal models that 

simulate the human experience is of high concern 

to the public. A long-term goal addressed in the 

initial Strategic Plan alludes to understanding 

effects of chronic exposure and developing 

protective or preventive drugs administered 

concomitantly with initial therapy. To achieve 

this, animal models will need to be developed that 

mimic the human experience. Research tools are 

needed to study the chronic effects of exposure. 

The NIH CounterACT program has engaged the 

varied strengths of the agency. This emphasis 

will continue at the NIH and also with other 

governmental departments and agencies to 

include the military, as well as all disciplines of 

science and medicine. 
16 The NIH Medical Research Program Directed Against Chemical Threats

Toxic industrial chemicals (TICs) are of increasing 

importance due to their ready availability and 

high toxicity. Most highly toxic TICS fall outside 

the purview of the Chemical and Toxins Weapons 

Convention. These chemicals may have damaging 

effects on the body via direct contact with skin 

and mucous membranes or through inhalation 

as a gas, vapor, or aerosol. Some TICs, such as 

household chemicals or poisons, have been used 

in small quantities in suicide or assassination. It 

is important to note that TICs could be employed 

on a larger scale. Therefore, NIH interaction with 

poison control centers across the nation is another 

partnership that has evolved through this ongoing 

research effort. 

Research into nerve agents remains a high priority 

for the NIH, especially because adversaries could 

potentially use new neurotoxic agents against 

civilian populations. It is now recognized that 

many toxic chemicals affect neurotransmission via 

different pathways. Because many toxic chemicals 

affect neurotransmission via different pathways, 

new treatment modalities likely will involve new 

combinations of drugs. The central nervous system 

has several important neurotransmitters other than 

acetylcholine, to include some that are excitatory 

(e.g., glutamate), and others that are inhibitory 

(e.g., GABA). Specific receptors determine the rate 

and severity of neurotoxicity. Organophosphate 

research is necessary to extend the understanding 

of how toxic chemicals affect different neurotransmission pathways, as well as other organ systems 

of the body. 

The CounterACT research efforts will continue 

to focus on medical product development using 

the existing mechanisms supporting research. 

The goals and objectives of the 2007 National 

Strategic Plan and Research Agenda for Medical 

Countermeasures against Chemical Threats 

remain largely unchanged, with the exception of 

a growing emphasis on TICs. Emphases include 

efforts to: 

• Integrate into standards of emergency care 

of products that meet the needs of the 

community. 

• Continue assessing whether medical products 

already licensed for use in the United States 

are applicable to chemical casualty care. 

• Assess products for civilian applications which 

are developed for military use; this is part of 

the overall HHS preparedness and response 

strategy. 

• Develop or improve medical diagnostic tests 

and assays that detect the presence of specific 

chemicals or their metabolities in body fluids. 

Much more needs to be accomplished through the 

NIH medical chemical countermeasures research 

programs. Since its inception, the research effort 

have invested heavily in addressing well-established chemical threats of concern, but many 

other toxic chemicals have yet to be studied in 

terms of their mode of injury and opportunities for 

therapeutic intervention. Much is still unknown 

of long-term consequences of exposure of most 

chemicals. With a viable research community 

now established through the NIH program, a 

strong partnership has been established between 

the NIH and academia, industry and the 

government. The NIH efforts will continue to be 

directed at discovery and development of safe and 

effective interventions that address the greatest 

terrorist threats. 
2011 Report on Research Progress and Future Directions 17 

 

 

Appendix 1. Examples of Highly Hazardous Chemicals
 

Chemicals Affecting the Nervous System 

(toxicity on the central and/or peripheral 

nervous system) 

Tabun (GA) 

Sarin (GB) and related derivatives 

Soman (GD) and related derivatives 

Cyclosarin (GF) 

VX and related chemicals 

R-33 (R-VX) 

TETS (2,6-dithia-1,3,7,7 tetraazadamantane 

2,2,6,6 tetraoxide) 

Anatoxin (algal toxin) 

Mercury compounds (e.g., methyl and 

dimethyl mercury) 

Aldicarb (pesticide) 

Brodifacoum (pesticide) 

Chlorpyriphos (pesticide) 

Parathion 

Fentanyl and related compounds (opiates) 

Chemicals Affecting the Skin, Eyes and Mucous 

Membranes (often referred to as irritants) 

Sulfur Mustard (HD) (vesicant) 

Nitrogen Mustard (vesicant) 

Lewisite (L) (vesicant) 

Phosgene Oxime (CX) 

Hydrogen Selenide 

Hydrogen Chloride 

Fuming Sulfuric Acid 

Hydrogen Fluoride (anhydrous form) 

Sodium Azide 

Arsenic Compounds (trivalent forms, e.g., 

Arsenic Trioxidc) 

Chloropicrin 

Ammonia 

Mercury (vapor form) 

Chemicals Affecting the Lower Respiratory 

Tract (capable of causing lung injury, i.e., 

pulmonary edema) 

Chlorine
 

Phosgene
 

Diphosgene
 

Perfluoroisobutylene (PFIB) 

Phosphine (rodenticide) 

Note: Many irritant chemicals deeply inhaled 

in high concentrations may cause pulmonary 

edema 

Chemicals Affecting Cellular Respiration 

(poisons damaging cellular metabolic 

enzyme systems) 

Hydrogen Cyanide (AC)
 

Potassium Cyanide 

Cyanogen Chloride (CK) (irritant also)
 

Hydrogen Sulfide 

Thalium Sulfate (especially chronic 

exposure) 

Acrylonitrile (metabolized to cyanide) 
 The NIH Medical Research Program Directed Against Chemical Threats

Appendix 2. Key Workshops and Expert Panels on Chemical Threats 

and Medical Countermeasures* 

Title Location Year Goals 

NIAID Expert Panel 

Workshop on Chemical 

Threats and Medical 

Countermeasures 

Washington, D.C. 2004 Identify research gaps and priorities for chemical 

threat agents (first NIH meeting to determine the 

scope of future NIH research investments). 

NINDS Counterterrorism and Neuroscience 

Workshop 

Washington, D.C. 2004 Identify research gaps and priorities for chemical 

threat agents that target the nervous system. 

NIH Anticonvulsant Expert 

Panel 

Bethesda, 

Maryland 

2005 Identify potential anticonvulsant agents that 

could be used to treat seizures caused by nerve 

agents; set research priorities. 

NIH Cyanide Expert Panel Bethesda, 

Maryland 

2005 Identify gaps and priorities for research on 

cyanide toxicity and medical interventions. 

NIH Pulmonary Agents 

Expert Panel 

Bethesda, 

Maryland 

2005 Identify research gaps and priorities for chemical 

threat agents that target the airways. 

NIH Blue Ribbon Panel 

on Chemical Threats and 

Medical Countermeasures 

Bethesda, 

Maryland 

2006 Develop consensus set of recommendations 

related to research gaps and research priorities 

for chemical medical countermeasures. 

NINDS Research Centers 

of Excellence Technical 

Assistance Workshop 

Rockville, 

Maryland 

2006 Provide information and answer questions 

regarding preparation of proposals in response 

to the NIH Research Centers of Excellence 

request. 

NIH Expert Panel on Toxic 

Vesicants 

Rockville, 

Maryland 

2007 Identify gaps and priorities for research on sulfur 

mustard toxicity and medical interventions. 

NIH Expert Panel 

Workshop on Toxic 

Industrial Chemicals -

Pesticides and Pulmonary 

Edemagenic Chemicals 

Bethesda, 

Maryland 

2009 Identify gaps and priorities for research on toxic 

industrial chemicals and pesticides, and on 

chemicals that cause pulmonary edema. 

NIH Expert Panel 

Workshop on Cyanide 

San Francisco, 

California 

2010 Review the current status of research and 

development regarding medical interventions for 

CN exposure; identify needs for future research, 

diagnostics, and methods of treatment suitable 

for different populations. 

*This list does not include regularly scheduled meetings to review CounterACT Program grants, progress 

reports with IAAs (U.S. Army), interagency meetings, threat assessment determinations, or meetings with 

BARDA/ASPR/HHS. 

18 
2011 Report on Research Progress and Future Directions 19 

Appendix 3. NIH CounterACT Announcements Soliciting Research 

Proposals 

2006 ....................................................................................................................................................................... 

RFA-NS-06-004 Countermeasures Against Chemical Threats (CounterACT) Research Projects (U01) 

RFA-NS-06-005 Countermeasures Against Chemical Threats (CounterACT) Research Centers of Excellence 

(U54) 

RFA-NS-06-006 Countermeasures against Chemical Threats (CounterACT) Small Business Innovation 

Research (SBIR/U44) Awards for Therapeutics Development (U44) 

RFA-NS-06-007 Diagnostic Technologies for Chemical Threat Exposure Small Business Innovation Research 

(SBIR/U44) Awards 

RFP–NS-04-01 Identification and Characterization of Novel Therapeutics for the Treatment and Prevention 

of Epilepsy (for nerve agent anticonvulsant – see below) 

RFP-NS-06-04 Countermeasures Against Chemical Threats (CounterACT) Preclinical Development Facility 

2008 .......................................................................................................................................................................
 

RFA-NS-08-003 	 Countermeasures Against Chemical Threats (CounterACT) Advanced Development 

Cooperative Agreements (U01) 

RFA-NS-08-004 	 Limited Competition for Countermeasures Against Chemical Threats (CounterACT) Research 

Centers of Excellence (U54) 

2009 .......................................................................................................................................................................
 

PA-09-080 PHS 2009-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business 

Innovation Research Grant Applications (Parent SBIR [R43/R44]) 

PA-09-081 PHS 2010-02 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant 

Applications (Parent STTR [R41/R42]) 
20 The NIH Medical Research Program Directed Against Chemical Threats

2010 ........................................................................................................................................................................ 

NOT-NS-10-011 Notice of Intent to Publish Funding Opportunity Announcements for Countermeasures 

Against Chemical Threats (CounterACT) Cooperative Research Projects (U01) and Research 

Centers of Excellence (U54) 

PAR-10-019 Countermeasures Against Chemical Threats (CounterACT) Exploratory/Developmental 

Projects in Translational Research (R21) 

PAR-10-180 Countermeasures Against Chemical Threats (CounterACT) Cooperative Research Projects 

(U01) 

PAR-10-181 Countermeasures Against Chemical Threats (CounterACT) Research Centers of Excellence 

(U54) 

PA-10-050 PHS 2010-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business 

Innovation Research Grant Applications (Parent SBIR [R43/R44]) 

PA-10-051 PHS 2010-02 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant 

Applications (Parent STTR [R41/R42]) 

2011 ........................................................................................................................................................................
 

PAR-11-155	 Countermeasures Against Chemical Threats (CounterACT) Cooperative Research Projects 

(U01) 

PA-11-096 	 PHS 2011-02 Omnibus Solicitation of the NIH, CDC, FDA and ACF for Small Business 

Innovation Research Grant Applications (Parent SBIR [R43/R44]) 

PA-11-097 	 PHS 2011-02 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant 

Applications (Parent STTR [R41/R42]) 
2011 Report on Research Progress and Future Directions 21 

Appendix 4: 2006-2010 CounterACT Centers of Excellence and 

Primary Investigators 

Lovelace Biomedical & Environmental Research Institute 

Albuquerque, New Mexico 

Mohan Sapori, Ph.D. 

“Identification of Therapeutics for the Treatment of Sulfur Mustard Injury” 

University of Medicine and Dentistry of New Jersey - Rutgers University 

Piscataway, New Jersey 

UMDNJ - Robert Wood Johnson Medical School 

Jeffrey D. Laskin, Ph.D. 

“Sulfur Mustard Research and Medical Countermeasures”
 

U.S. Army Medical Research Institute of Chemical Defense 

Edgewood, Maryland 

David E. Lenz, Ph.D. 

“Catalytic Bioscavengers Against Nerve Agents” 

University of Alabama at Birmingham 

Birmingham, Alabama 

Sadis Matalon, Ph.D. 

“Novel Treatments of Chlorine Induced Injury to the Cardio-Respiratory Systems” 

University of Minnesota Center for Drug Design 

Minneapolis, Minnesota 

Steven Patterson, Ph.D. 

“Combined Use of Cobinamide and a 3-Mercaptopyruvate Prodrug for Cyanide Poisoning”
 

National Jewish Medical and Research Center 

Denver, Colorado 

Carl W. White, M.D. 

“Novel Antioxidant Therapeutics for Sulfur Mustard Toxicity” 
22 The NIH Medical Research Program Directed Against Chemical Threats

Appendix 5: Interagency Agreements (IAAs)
 

5.1. Anticonvulsant research: funded through the “Chemicals Affecting the 

Nervous System – Anticonvulsants / Neuroprotectants” program: 

• 2011-2012: Y1-OD-1563-01: Received by USAMRICD 

• 2010-2011: Y1-OD-0692-01: Received by USAMRICD 

• 2009-2010: Y1-OD-9613-01: Received by USAMRICD 

• 2008-2009: Y1-AI-6178-03: Received by USAMRICD 

• 007-2008: Y1-AI-6178-02: Received by USAMRICD 

• 2006-2007: Y1-AI-6178-01: Received by USAMRICD 

5.2. Cyanide research: funded through the “Cyanide Diagnostics and Efficacy 

Testing of Next Generation Cyanide Antidotes” program: 

• 2011-2012: Y1-OD-1561-01: Received by USAMRICD 

• 2010-2011: Y1-OD-0690-01: Received by USAMRICD 

• 2009-2010: 

− Y1-OD-9611-01: Received by USAMRICD
 

− Y1-OD-9611-02: Received by USAMRICD
 

• 2008-2009: Y1-AI-6176-03: Received by USAMRICD 

• 2007-2008: Y1-AI-6176-02: Received by USAMRICD 

• 2006-2007: Y1-AI-6176-01: Received by USAMRICD 

5.3. Pulmonary research: funded through the “Chemicals Affecting the 

Respiratory Tract – Pulmonary Toxicant Gases” program: 

• 2011-2012: Y1-OD-1564-01: Received by USAMRICD 

• 2010-2011: Y1-OD-0693-01: Received by USAMRICD 

• 2009-2010: Y1-OD-9614-01: Received by USAMRICD 

• 2008-2009: Y1-AI-6179-03: Received by USAMRICD 

• 2007-2008: Y1-AI-6179-02: Received by USAMRICD 

• 2006-2007: Y1-AI-6179-01: Received by USAMRICD 
2011 Report on Research Progress and Future Directions 23 

 

5.4. Vesicant research: funded through the “Chemicals Affecting the Skin, Eyes, 

and Mucous Membranes – Toxic Vesicants and Industrial Chemicals” program: 

• 2011-2012: 1-OD-1562-01: Received by USAMRICD 

• 2010-2011: 1-OD-0691-01: Received by USAMRICD 

• 2009-2010: 1-OD-9612-01: Received by USAMRICD 

• 2008-2009: Y1_AI-6177-03: Received by USAMRICD 

• 2007-2008: Y1-AI-6177-02: Received by USAMRICD 

• 2006-2007: Y1-AI-6177-01: Received by USAMRICD 

5.5. Chemical Countermeasures: Studies to Support Countermeasures for Highly 

Toxic Materials Including Chemical Agents and Toxins 

• 2010-2011: Y1-OD-0387-01: Received by DTIC 

IAA Recipients: 

DTIC: Defense Technical Information Center 

USAMRICD: U.S. Army Medical Research Institute of Chemical Defense 

5.6 Chemical Countermeasures Collaboration 

• 2011-2012: DOD/NIH InterAgency Agreement: Received by DoD 

IAA Recipients: 

DoD: Office of the Assistant to the Secretary of Defense for Chemical and 

Biological Defense and Chemical Demilitarization (DATSD(CBD/CD)), 

Washington, DC 

ECBC: U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving 

Ground, MD 
 The NIH Medical Research Program Directed Against Chemical Threats

Figure 4.1. Overview diagram of CounterACT Program 

Basic Translational Clinical 

Clinical 

trials 

Pre-IND/IDE 

studies 

Optimization/ 

preclinical 

efficacy 

Proof of 

principle 

Target 

ID 

Assay 

development Screening 

NIH BARDA
 

Centers of Excellence and Individual Projects 

Anti-convulsant 

Screening Program 

DoD Laboratories 

Medicinal 

Chemistry 

Contract 

Facility 

Preclinical 

Contract 

Facility 

Clinical Trial 

Networks 

Industry Partners (SBIRs) 

Regulatory Affair Consultative Bureau 

The CounterACT Network 

Government 

Labs 

Research 

Centers 

Contracts Projects 

24 
2011 Report on Research Progress and Future Directions

Figure 4.2. Examples of NIH CounterACT Medical Candidate 

Countermeasures and Department of Health and Human Services 

Technical Readiness Levels (TRLs) 

Activities TRL 

Target 

identification 

1 

Validated 

screening tool 

2 Basic (NIH) 

“Hit” identification 3 

Preliminary leads 

(proof of concept) 

4 

Optimized leads 

(pre-clinical) 

5 Applied (NIH) 

Candidate drug 6 

IND ready 7 

Phase 1 8 

Phase 2 9 Advanced 

(NIH & BARDA) 

Phase 3 (definite 

animal efficacy) 

10 

Licensure, 

approval, 

clearance 

11 

Post-licensure 

and post-approval 

activities 

12 Acquisition 

(HHS) 

Expanded efficacy 

(if appropriate) 

13 

Specific Candidate 

Countermeasures 

Over 30+ “hits” 

and/or targets 

identified 

Neuregulin; 

AEOL 10150 

Brovana*; 

Sulfanogen 

Cobinamide; 

Galantamine* 

Midazolam* 

*Denotes FDA-approved compound 

25 
26 The NIH Medical Research Program Directed Against Chemical Threats

23 

22 Toxicol App Pharmacol 

21 

20 

19 

18 Chem Biol interact 

17 

16 

Am J Respir 

Cell Mol Biol 

15 

Biochemistry

# of Publications14 

13 

12 

11 

10 

9 

J Mol 8 

Neurosci 7
 

6
 

5
 

4
 

3
 

2
 

1
 

0
 

Epilepsy
 

Research
 

JBC 

Anal Chem 

PNAS 

Nature 

Physiol
 

Rev
 

0.561.071.431.731.831.932.092.222.282.522.612.782.882.953.083.233.493.563.623.933.984.104.494.635.045.145.335.646.957.619.64

15.4824.0033.0047.98 

Journal Impact Factor 

Figure 4.3. Publications Resulting from CounterACT Investments. 

(345 total as of May 2011) 

Impact Factor of CounterACT Publications 

(2006-Current) 

The impact factor of CounterACT publications from 2006 to the present has been noteworthy. The 

impact factor represents a measure reflecting the average number of citations to articles published 

in science and social science journals and is frequently used as a proxy for the relative importance 

of a journal within its field. The quality and volume of publications in peer-reviewed journals is 

indicative of the high quality of research (and researchers) which are involved in the NIH medical 

chemical defense program. The figure displays the # of publications and the quality of journal. 

The publication record is a critical product of the program and should be used as a criteria for 

success for the CounterACT program. 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institute of Allergy 

National Institutes of Health and Infectious Diseases 

NIH...Turning Discovery into Health	 NIH Publication No. 12-6212 

May 2012 

www.niaid.nih.gov