medical countermeasures against terrorism

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MILITARY MEDICINE, 1 69. 11:8 50, 2 00 4

A Review of Multi-Threat Medical Countermeasures agaiChemical Warfare and Terrorism

Guarantor: William J, Smith, PhDContributors: Fred M. Cowan, BS*; ClarenceA. Broomfleld, PhD*; Milos P. Stojiljkovic,PhDf; William J, Smith, PhD*

The M ulti-Threat M edical Cou nteraieasure(MTMC) hypothesishas been proposed with the aim of developing a single coun-termeasure drug with efficacy against different pathologiescaused by multiple classes of chemical warfare agents. Al-though sites and mechanisms of action and the pathologiescaused by different chemical ins ults vary, common biochemi-cal signaling pathways, molecular m ediators, and cellular pro-ce sse s provide targets forMTMC dru gs. Th is article will reviewthe MTMC hypothesis for blister and nerve agents and willexpand the scope of the concept to include other chem icals aswell as briefly consider biological agents. The article will alsoconsider how common biochemical signaling pathways, mo-lecular mediators, and cellular processes that contribute toclinical pathologies and S3rndromes may relate to the toxicityof threat agents. Discovery ofMTMC provides the opportunityfor the integration of diverse researchers and clinicians, andfor the exploitation of cutting-edge technologies and drug dis-covery. The broad-spectrum nature of MTMC can augmentmilitary and civil defense to combat chemical warfare andchemical terrorism.

Introduction

T he list of military chemical threat agents has lengthenedover the last century. W orld WarI saw the development anddeployment of edemagenic and choking agen ts suc h a s chlorine,phosgene, and cyanide, and blister gases such as sulfur mus-tard (SM).'"^ World War II cultivated Germany's development ofnerve gases such as tabun , sarin, and soman, and this classof agentwas used in the 1980 to 1988 Iraq-Iranconflicf** and inthe 1994 to 1995 terrorist attacks in Japan.^"" The Cold Waryielded more lethality refmements in nerve agents to includedevelopment of VX.'^ Consistent with past experience, newthre at agents with novel mechanism s of toxicity may evolve.

Countermeasures for defending deployed military personnelagainst weaponized chemical warfare agents do not seamlesslytransition to military force protection an d civil defense againstchemical terrorism. Terrorist threat age nts include all classes ofchemical warfare agents, toxins, and a broader menu of toxicindustrial chemicals. The large number of threats and potentialfor use of multiple toxic substa nce s in combination can com pli-cate agent identification and medical response. A terrorist as -sault might more closely resemble the chemical accident atBhopal, India, than a chemical warfare attack. Symptoms may

*U.S, Army Medical Research Institute of Chemical Defense, Aberdeen ProvingGround, MD 21010-5400.

tMilitary Medical Academy, National Poison Control Centre, Belgrade, Serbia andMontenegro,

The opinions or assertions contained herein are the private views of the authorsand are not to be construed as official or as reflecting the views of the Department ofthe Army or the Department of Defense.

This ma nuscript w as received for review in February 2004, The revised m anuscrip twas accepted for publication in July 2004,

be closer to smoke inhalation and acute respiratory distrsyndrome (ARDS) than to the cholinergic crisis caused by neagent poisoning. Research into medical countermeasuragainst weaponized battlefield chemical warfare agents has cused on distinct classes of nerve, blister, choking, or edemgenic agents an d pathologies specific to the se ag ents, e.g., neagent-induced seizure, phosgene-induced ARDS, and SM bltering. The presen t challenge of defending against the myriadthreat chemicals and toxins necessitates a more collective acomprehensive strategy that more generally addresses tsymptoms and pathology of chemical toxicity rather thanspecific chemical mechanism.

The Multi-Threat Medical C ounterm easure (MTMC) hypotsis for chemical toxicity is analogous to the broad-spectruapproach used for protecting against infectious age nts auth orby Dr. Ken Alibek, former Deputy Chief of Biopreparat, tcivilian arm of the former Soviet U nion's biological weapoprogram.'^''* It may be possible to exploit the fact that tdiverse chemistry, sites, and mechanisms of action of toxchemicals often involve common underlying biochemical sigpathways. These common pathways are key in initiating tcellular processes that contribute to clinical pathologies causby chemical exposures. Clinically defined syndromes or symtoms that represent pathologies of respiratory, neuronal, cdiac, cutaneous, or other systems to include anaphylacshock, bro nchos pasm , ARDS, seizure, excitotoxin-like n eurodegeneration, and blistering are observed after exposure chemical warfare ag ents, haza rdou s chemicals, toxins, and evinfectious ag ents. TheMTMC hypothesis suggests th at commbiochemical pathways contribute to the toxicity that causes pathologies associated w ith different classe s oftoxic chemicalsMTMC drugs that target these key pathways might createphysiological "quiescent" state that protects against variochemical insults.'"*

MTMC and Inf lam m atory R espon se

The fact that inflammation causes or contributes to numous pathologies and that many toxic chemicals provoke an flamm atory respon se is well established (for review, see Re14-16). Although evidence for a signiflcantrole for inflammatioin chemical toxiciiy continues to accumulate, inflammatory sponse is still often regarded as merely collateral to chemiinsult and secondary to toxicity.'*"'^ The evolution over the ldecade of the concept that inflammatory response is a key ement of chemical toxicity that allows for the development anti-inflammatory drugs as multi-agent countermeasures unique to the MTMC hypothesis.'*""^ The MTMC hypotheencompasses the interaction of multiple toxic agents and

verse countermeasure drugs on mediators and signaling paways that cause or sustain inflammation. Whether inflamm


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Medical Countermeasures against Chemical Warfare and Terrorism 851

tion is a collateral biomarker or causative contributor tochemical toxicity is controversial. However, in either case in-flammation can provide a common denominator to facilitatedeciphering the relationships between agents, drugs, signalingpathways, and cellular processes pertinent to predicting candi-date MTMC drugs.'"

A major tenet of the pharmacology of anti-inflammatory drugsis that drug action can result from the specific inhibitionofmolecular m ediators of inflammation or from modulation of theunderlying biochemistry that initiates or sustains an inflamma-tory respo nse. Different inflammatory med iators, pathw ays, andcell populations can be inducedor recruited by different condi-tions or insults. This multifaceted nature of inflammation mayrequire the use of numerous pharmacologically distinct anti-inflammatory drugs to contend with the different manifestationsof inflammatory pathology. However, enough uniformity of bio-chemical pathways of inflammation existsto allow for develop-ment of broad-spectrum anti-inflammatory drugs.

The biochemical pathways associated with chemical toxicitycan involve proteases, inflammatory cytokines suchas tumornecrosis factor (TNF), interleukin(IL)-1, IL-8, and other mole-cules su ch as platelet activating factor (PAF), Af-methyl-D-aspar-tate (NMDA) glutamate receptors, acetylcholine (ACh),sub-stance P, and poly(ADP-ribose) polymerase (PARP)(for review,see Ref. 14). These mediatorsand receptors can influence in-flammatory responses associated with cellular processes suchas degranulation, apoptosis,and necrosis that contribute topathologies caused by chemical agents. Therefore, many classesof compounds used as countermeasures to chemical warfareagents such asPARP inhibitors, proteases inhibitors, adenosineagonists, and NMDA receptor antagonist, althoughnot chieflythought of as anti-inflammatory drugs, have anti-inflammatorypharmacology (Table I) (for review, see Ref.14).

The diverse biochemical pathways that influence inflamma-tory responses may explain why many pathologies associatedwith intoxication by chemical agents have an inflammatorycompon ent. Along this line of reasoning, it is not surprising tha tthe majority of coun terme asure drugs t ha t have shown efficacyagainst edemagenic, vesicant,and nerve agents have anti-in-flam matory pharmacology (for review, see Ref.14). The presenceof inflammatory responses and anti-inflammatory actionsof

TABLE I

PUTATIVE MEDIATORS OF INFLAMMATION AND POTENTIALTARGETS FOR MTMC DRU GS

Mediator (Siteof Action)

Proteases [proteolysis.proteases receptors(R)1

Inflammatory cytokinesPAF (PAFR)

Glutamate (NMDAR)

Acetylcholine(acetylcholineiJ

PARP

Candidate MTMC Drug

Protease inhibitors

Soluble cytokine receptorsPAFR antagonist (benzodiazepines)NMDAR antagonist

Anticolingerics (atropinc)

PARP inhibitors

countermeasures implicates inflammationas a cause or a re-sulting biomarker of the toxicity of these agents. The extenttowhich common inflammatory m echanism s are coupled to chem-ical agent toxicity will determinethe feasibility of developinganti-inflammatory MTMC.

In f la m m a t io n A s s o c i a t e d w i th Ed e m a g e n i c , B l is t e ra n d N e r v e A g e n t s

Inflammatory respons e induced by the prototypic edemagenicagent phosgene is the primary cause of the frequently lethalARD S."''^ ARDSis also associated with pulmonary toxicityofthe acetyl-cholinesterase-inhibiting organophosphorus insecti-cide thionazine,'^ SM,'"and other toxic chemicals,as well astoxins, infectious-agent pneumonia, shock, se psis, bum s,andother trauma (TableII). SM dermal-epidermal separation is sim-ilar to that caused by proteolysis and certain buUous diseases,and this h as fostered th e hypotheses thatSM vesication involvesproteolytic and/or inflammatory responses.'^^ Experimentalevidence has accumulated overthe last decade demonstratingSM-increased proteases and the expression of inflammatoryenzymes, gene p roducts, mediators,and receptors in tissue orcell cultures .'''15.19-23 inflammatory enzym es and cytokines havealso been reported in the skin of SM-exposed animals. "'^^

Cholinergic crisis is the paramount toxicological eventinnerve agent intoxication, causing acute toxicity and precipitat-ing seizure and neuronal degeneration.^^ However, along withcholinergic crisis anaphylactoid reactions, pathological proteo-lytic activity and inflammatory cytokines have also beenre-ported in nerve agent-intoxicated animals.'"^^"2' The initial ob-servations of anaphylactoid reactions associated with somanpoisoning reported by D oebler etal.^^ and Newball etal.^^ nearlya quarter century ago have recently again been consideredbyGilat et al.^" in sarin-intoxicated animals. Anaphylactoid reac-tions, by definition, occur upon initial exposureto a chemicalindependent of antibody production. Anaphylactoid reactionsand nerve agent intoxication can generate acute symptoms su chas convulsions, bronchoconstriction, respiratory failure, circu-latory collapse, and death withina few m inutes.'"'^ Thus, ana-phylactoid reactions,'"'^ likethe more extensively investigatedcholinergic crisis and excitotoxin-like neuronal degeneration,are a clinically well-defmed and potentially lethal syndromeassociated with nerve agent intoxication.

McLeod^^ noted neuronaland neurophil degenerationandnecrosis associated with soman-induced brain lesions. The pat-

tern of injury was similar to that caused by epilepsyand isch-TABLEn

CHEMICAL, TOXIN, AND INFECTIOU S AGENTS AND INSU LTS THATCAUSE ARDS

Other possible MTMC drugs with more general sitesof anti-inflammatory action include adenosine agonists, corticosteroids,andnonsteroidal anti-inflammatory drugs.Of particular interest are drugsthat have efTicacy against SM toxicity in the MEVM and also inhibitSM-increased IL-8in HEK cultures (for review, see Ref. 14).

Agent / Insul t

Organophosphate compoundsSulfur mustardPhosgeneMycotoxinAnthrax, smallpox, Ebola,and

severe acute respiratory syndromePneumonia, shock, sepsis trauma.

a n d b u m s

Classification

AntichloinesteraseBlisterInhalation edemagenicBiotoxinInfectious agents

Acute lung/organ

dysfunction


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85 2 Medical Countermeasures against Chemical Warfare and Terrori

emic brain injury. Some animals also had cardiac lesions char-acterized by acute necrosis with subsequent mild inflammationand flbrosis. Inflammatory cytokines such as TNF, IL-1, andIL-8 are associated with recruitment of inflammatory cells andcellular processes such as degranulation, apoptosis, and necro-sis. Inflammatory cytokines are causative factors in phosgene-associated ARDS, they contribute to SM injury, and they areimplicated in nerve agent seizure and neuronal degenera-jjQj^ 14,17,18,24,25.31,32 Skin from mice SM exposure sites and thebrains of soman-intoxicated rats demonstrate increased IL-lj3mRNA.^^'^^'^' IL-1 is an inflammatory cytokine that can precip-itate other cytokines such as TNF, IL-6, and IL-8, and such acytokine casc ade is implicated inSM toxicity. ^ Svensson et al.^'have demonstrated that soman induces the inflammatory cyto-kine IL-1(3 in rat b rain, and this activity is highly correlated withconvulsions. Williams et al.^^ confirmed IL-lj8, and further ob-served an acute and transient upregulation of other inflamma-tory gene respons e, i.e., TNF, IL-6, E-selectin, and intercellularadhesionmolecule-1 caused by exposure to soman. The authorssuggest that these m oleculesmay be involved in soman -inducedbrain injury. Eriksson etal.^* demonstrated thatNMDA antag-onists could suppress excitotoxin-induced IL-lj3 mRNA in therat brain. Furthermore, Vezzani et al.^^ have protected miceagainst NMDA receptor-depen dent seizures w ith soluble IL-1receptors tha t specifically antagonizeIL-1 activity. The authorssuggest that the interaction between IL-1 and IL-1 receptorsrepresents a crucial mechanism of seizure and a target for de-velopment of anticonvulsant drugs. The role of inflammatorycytokines in edemagenic, nerve, and blister agent toxicity sup-ports cytokine antagonists as candidate MTMC.

A n t i- In f l a m m a t o r y A c t i o n o f M e d i c a l

C o u n t e r m e a s u r e s t o E d e m a g e n i c , B li s te r , a n dNerve Ag ents

Anti-inflammatory dru gs su ch a s ibuprofen a re the drugs ofchoice in reducing phosgene toxicity.'^'^ The majority ofdrugs that have shown efficacy against SM in animal modelshave anti-inflammatory phannacology (for review, see Ref.14). Our institute has screened more than 400 com pounds inthe mouse ear vesicant model (MEVM) for cutaneous injury;19 compounds reduced SM histopathology greater than500/0 36-38 'pjjg jg compounds include seven listed as anti-inflammatory drugs, consisting of five capsaicin analogs, asingle cyclooxygenase inhibitor, indom ethacin, and a calmod-ulin antagonist, fluphenazine.^^'^^ The three protease inhibi-tors and three PARP inhibitors included in the list of antivesi-cant drugs also have the potential to inhibit inflammatoryresponses.''' The remaining six anti-vesicant drugs, sodium3-sulfonatopropyl glutathionyl disulfide,3% hydrogen perox-ide gel, dimercaprol, and three other mercaptopyridines ana-logs are listed as SM scavengers.^^'^^ However, mercaptopyri-dine-like com pound s have dem onstrated anti-inflammatoryphannacology to include inhibition of the cellular release ofthe inflamm atory cytokine IL -l."" Therefore, 17 of the 19compounds with efficacy against SM toxicity have anti-in-flammatory pharmacology, the exceptions being two of thelisted SM scavengers. Furthermore, antivesicant drugs withanti-inflammatory pharmacology generally demonstrate inhi-bition of HD-increased IL-8 in hum an epidermal keratinocyte

(HEK) cultures (Ref. 41; FM Cowan, CA Broomfleld, and WSmith, unpublished observations). Collectively, the MEVand in vitro SM-increased IL-8 HEK assays effectively screnot just for vesicant countermeasures, but also for anti-flammatory drugs th at inhibit IL-8. These mod els furthidentified drugs such as capsaicin analogs as better antivecants and anticytokine drugs than major classes of currenavailable corticosteroids and nonsteroidal anti-inflammatodrugs.

The anti-inflammatory action of nerve agent countermesures to include atropine, carbamates, and benzodiazepines hbeen extensively reviewed.'"' ''^ For exam ple, a role for synebetween mediators of anaphylactic response and cholinerstatus "hypersensitivity" is accepted for asfhma-related letbronchoconstriction, and has been implicated for nerve ageinduced lethal bronchoconstriction.''*'^*^'^ Kotev^"* has demstrated tha t soman-induced bronchial spasm was greatly intsified not only by ACh, bu t also by h istam ine. Hypersensitivto inhalation of the cholinergic compounds such as methylchline or the autacoid h istamine is a diagnostic test for asthmand anticholinergics are sometimes used as supplementatreatment.*^

Inflammatory, neurological, and tissue pathology pathwainvolve proteolyfic processes." Synthesized mediators suchPAF and serine proteases such as tryptase and tissue plasmogen activator (t-PA) in addition to autacoids such as histamare significant factors in infiammatoiy and anaphylactic sponses.'*'^*^ Carbamates can inhibit serine proteases tmediate anaphylaxis and prevent anaphylactic respon se.*' Tbenzodiazepine diazepam is Food and Drug Administration proved for the treatment of seizures associated with nerve agepoisoning.*^ Benzodiazepines can, in addition to acting 7-aminobutyric acid receptor agonists, also inhibit PAF recetors.*^ PAF is a dual proinfiammatory and neuromessenphospholipid molecule that participates in pathological phnomena that include protease synthesis, lethal anaphylaxvesication an d NMDA glutam ate receptor excitotoxicity, seizuand neu rona l degeneration (for review, see Ref 14). Mice protected from lethal anaphylaxis by serine protease inhibitor PAF antagonists.*^*^ Tlie y-aminobutyric acid receptor anist and PAF receptor antagonist actions of benzodiazepinmight synergistically protect against nerve agent cholinerand inflammatory toxicities. Furthermore, proteolytic and flamm atory pathw ays are also strongly implicated in NMreceptor-mediated seizure and neuronal degeneration. Knoout mice deficient in the p rotease t-PA were resis tant to seizuand neuronal pathology caused by excitotoxlns (for review, Ref. 50). Furthermore, the synthetic protease inhibitor tPSTOP (American Diagnostica, Greenwich,CY] suppressed extotoxin-induced seizure and neuro nal deg eneration (for revisee Ref 50).

E x p e r i m e n t a l E v i d e n c e f o r A n t i - I n f l a m m a t o r yM TM C D r u g s

Experimental evidence generated in in vitro and in vivo mels of chemical agent toxicity supports the concept of anti-flammatory MTMC drugs. SM exposure increases the inflamtory IL-8 in HEK and human small airway cell (HSAcultures.*"'^' SM-increased IL-8 in HEK cultu res is a biomar


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Medical Countermeasures against Chemical Warfare and Terrorism 85 3

of dermal inflammatory pathology that is used as an in vitrodrug screening and treatment model to complement in vivostudies in the MEVM."" Likewise, SM-increased IL-8 in HSACha s recently been developed as an invitro model for treatme ntofinhalation toxicity.^' HSAC cultures exposed to 25 to 200 /xMSM or 0.2 to 6.4 ppm/min phosgene demonstrated significantlyincreased IL-8.^^ A maximum increase of approximately 1,000pg/mL IL-8 in HSAC cultures exposed to phosgene or SM wasobserved.^^ The pattern ofIL-8 response, increase to maximumlevels followed by inhibition at higher cytotoxic doses, was sim-ilar for both a gen ts. Ibuprofen (62, 125, 250, 50 0, and 1,000jLiM) significantly diminished phosgene-increased IL-8 in SACcultures exposed to 2 ppm/min phosgene.^^ Furthermore, thedoses of ibuprofen that decreased phosgene-increased IL-8 ap-proximately 50% in HSAC (125 and 250iM ] also inhibitedSM-increased IL-8 in HEK cultures to about the same ex-

Serine protease inhibitors andPARP inhibitors can have anti-inflammatory pharmacology, and m embers of these two distinct

classes of comp ounds have shown efflcacy for nerve and b listeragents in vivo.'''-^'''"'-^^ Serine protease inhibitors can prolongthe survival of animals intoxicated with the nerve agent so-man,'" and can also protect against vesication caused by theblister age nt SM. ^ PARP inhibitors can reduce soma n-inducedneuronal degeneration^ and SM-induced epidermal necrosis.^^

F u tu r e M T M C D r u g s

Candidate anti-inflammatory MTMC drugs to include pro-tease inhibitors, PAF antagonists, PARP inhibitors, NMDA re-ceptor antagonist, and adenosine agonists have been suggested(Table I).'* Adenosine receptor agonists illustrate the potentialand the complexity ofMTMC drugs. Van Helden et al.^ used theadenosine Al receptor agonist N6-cyclopentyl adenosine as acountermeasure to soman poisoning. Without any supportivetreatment with atropine, oxime, or diazepam, N6-cyclopentyladenosine protected rats from convulsive activity and respira-tory distress and improved 24-hour survival.^ Reduced AChlevels in rat brains were reported in this study, and the protec-tion was attributed to cholinergic mechanisms wherein theadenosine Al receptor agonists binding to the Al adenosinereceptor caused inhibition ofACh release.^ However, the cho-linesterase-inhibiting nerve agents sarin, tab un, and som an caninteract directly with brain Al adenosine receptors and maycompetitively alter the action of these agents at adenosine re-ceptor sites.'"'^^

Adenosine receptors can moderate the activation of other re-ceptors that influence neu rotransmitter release and /or synaptictransmission, e.g., ACh and NMDA receptors.^"'^^ A2, A3, andAl adenosine receptor agonists can further influence mast celldegranulation, and adenosine-directed treatment modalitieshave been suggested for asthma.^^ Neutrophil infiltration of der-mal inflammatory sites, similar to that also observed in SMpathogenesis, was inhibited by adm inistration of adenosine Alreceptor agonists.'"'^^ This anti-inflammatory action of adeno-sine agonists was reversed by anNMDA agonist and was mim-icked by a glutam ateNMDA receptor antago nist.^ Hence, in thismodel, central NMDA receptor activity can control peripheral

neutrophil accumulation, and adenosine Al receptor agonistscan influence th is NMDA recep tor excitation-mediated inflam-

mation.^^ Virag and Szabo^^ have further demonstrated thatadenos ine c an inhibit th e activation of PARP, and they proposethat this may affect cell death and inflammation. Thus, adeno-sine agonists can influence multiple inflammatory biochemicapathways associated with nerve and blister agent toxicity andare candida te MTMC (Table III).

M T M C H y p o t h e s i s , B i o lo g i c a l A g e n t s , a n dI n f l a m m a t o r y S y n e rg y

The activation of inflammatory responses that contribute topathology is not restricted to chemical agents. T-2 toxin, as amajor trichothecene mycotoxin, has some radiomimetic proper-ties, and the results of its action, like the blistering induced bySM, can be alleviated by treatment with glucocorticoid hor-mones.^'^' Moreover, PAF seems to have an important role inthe pathophysiology of T-2 toxicosis beca use its selective an tag-onist BN 520121 can prolong survival of rats exposed to lethaldoses of this toxin. ^ Trichothecene mycotoxin a lso induc e m es-enteric^ and subcutaneous mast cell degranulation^ and in-creased secretion of interleuk ins IL-1^ and IL-6 in vitro. Thisuggests that superinduction of cytokines might be one of themec hanism s of T-2 toxin-induced tissu e damage. ^ The inflam-magenic prope rties of mycotoxin may further contribute to corepathologies such as ARDS. Likewise, inflammatory cytokinesand the complication ofARDS are associated w ith the pathologyof infectious agents such as anthrax, smallpox, Ebola, and, ofcourse, the corona virus infection that causes severe acute re-spiratory

The MTMC hypothesis suggests tha t inflammation is not ju sta biomarker, but is also a major cause of toxicity for manychemical warfare ag ents and toxic chemicals.As a counterpointto the anti-inflammatory MTMC drugs, substances that in-crease inflammation can synergistically augment chemical toxicity. Roth and coworkers (for review, see Ref. 69) demonstratedthat a small dose of the inflammagenic endotoxin lipopolysaccharide (LPS), which is without effect byitself, markedly en-hances the hepatotoxic effects of aflatoxinB,. A similar effect ofLPS endotoxin occurs with other toxic chemicals and other tar-get organs (for review, see Ref. 69). Stone etal.^" have reportedthat LPS or the inflammatory cytokines TNF orIL-1 enhancedthe cytotoxic effects of the SM stimulant 2-chloroethyl ethysulfide. Whether the results of coexposure to an infiammagensuch as LPS or an intrinsic property ofa toxic agent, the inflam-matory response can augment sensitivity to chemical toxicitiesThu s, inflammation associated w ith chemical toxicity is a targefor anti-inflammatory MTMC.

M TM C C o n c l u s i o n s a n d P r o s p e c t s

The MTMC hypothesis is supported by experimental evidencethat distinct classes of drugs such as protease inhibitors and

TABLEm

ACTION OF ADENOSINE AGONISTS ON BIOLOGICAL RESPONSE

Situation

Soman intoxicationNMDAp-initiated inflammationPARPAs thma

Response

ProtectionInhibitionInhibitionAnti-inflammatory


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85 4 Medical Countermeasures against Chemical Warfare and Terroris

PARP inhibitors have demonstrated efficacy against the nerveagent soman and the blister agent SM.^^^e.'H.sa Moreover, T-2mycotoxin and SM injury can be alleviated by treatment withglucocorticoid hormones.^"'^' By focusing on key biochemicalsignal pathways and cellular processes that ultimately contrib-ute to pathologies associated with chem ical toxicity, th e MTMChypothe sis provides th e possibility of developing single c ounter-me asure drugs with prophylactic or therapeutic efficacy agains tdistinct pathologies cau sed by multiple classes of toxic chem icalagents. '* Furthermore, theMTMC concept may n ot be limited tochemical agents. Many biological toxins and infectious agentscause inflammatory responses that contribute to pathology. Fi-nally, because MTMC addresses clinically recognized patholo-gies such as ARDS, collateral improvements in general healthcare and emergency medicine are possible.

Once onelooks pas t the diverse chemistry, sites of action, an dsymptoms, common biochemical pathways may exist for manychemical threat ag ents. Even when threats extend to mixturesofagents and toxic industrial chemicals, or new threat agentsevolve, such biochemical signaling pathways may remain moreconstant and amenable to medical intervention. Defining andinterdicting these pathways provide strategies for developingcivil defense and military preparedness against chemicalthreats. Of perhaps equal significance, theMYMC hypothesisprovides an incentive for dialogue and cross-fertilization be-tween diverse chemical defense, academic, clinical, and drugdiscovery research interests to combat chemical warfare andchemical terrorism. Using MTMC to blunt pathological actionsof chemical agents is an attractive possibility.

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