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8
Availability, Safety, and Efficacy of Drugs and Other Therapies

This chapter reviews current and potential countermeasures for the chemical and biological agents. Discussion of chemical agents includes assessment of availability at both the first responder and local treatment facility level because of the need for rapid action in many cases. Treatment of victims of most of the biological agents being considered in this report is not so time dependent (in most instances there will not be any first responders involved), and discussion of availability therefore focuses on the existence and ease of purchase of required drugs and supportive equipment.

The discussions and the respective tables that follow permit a detailed analysis of these chemicals and biological agents. In a world of infinite resources almost all of the antidotal interventions being pursued for these potential agents would be of scientific merit. Many of these interventions might substantially advance scientific thought, and most could play a limited role in improving care, but all will confront the problem of Investigational New Drug (IND) status and FDA approval in the face of a very low natural incidence and ethical barriers to controlled testing in human subjects. These investigations will be exceptionally expensive and it is not apparent that the commercial pharmaceutical industry would consider research in this domain profitable without military or governmental support. In our world of finite resources a more pragmatic approach has been chosen for suggestions for research and development of antidotal agents. In particular, interventions that have a demonstrated



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Page 110 8 Availability, Safety, and Efficacy of Drugs and Other Therapies This chapter reviews current and potential countermeasures for the chemical and biological agents. Discussion of chemical agents includes assessment of availability at both the first responder and local treatment facility level because of the need for rapid action in many cases. Treatment of victims of most of the biological agents being considered in this report is not so time dependent (in most instances there will not be any first responders involved), and discussion of availability therefore focuses on the existence and ease of purchase of required drugs and supportive equipment. The discussions and the respective tables that follow permit a detailed analysis of these chemicals and biological agents. In a world of infinite resources almost all of the antidotal interventions being pursued for these potential agents would be of scientific merit. Many of these interventions might substantially advance scientific thought, and most could play a limited role in improving care, but all will confront the problem of Investigational New Drug (IND) status and FDA approval in the face of a very low natural incidence and ethical barriers to controlled testing in human subjects. These investigations will be exceptionally expensive and it is not apparent that the commercial pharmaceutical industry would consider research in this domain profitable without military or governmental support. In our world of finite resources a more pragmatic approach has been chosen for suggestions for research and development of antidotal agents. In particular, interventions that have a demonstrated

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Page 111 benefit and might be improved upon are favored over novel approaches that have yet to be shown efficacious in human patients. In addition, research and development recommendations are based on the premise that the most valuable treatments will be those that will be (or might be) useful even if a biological or chemical assault does not occur. A third consideration in making recommendations was based on the committee's view that prophylactic interventions will rarely, if ever, be appropriate. The decision as to whether prophylactic therapy is appropriate for any of these biological or chemical agents must be based on several issues: risk to personnel, potential benefit for the individual and society, and extent of societal expenditure. The committee's view is that these considerations preclude any prophylactic interventions for the entire population, at least for the biological or chemical agents under consideration in this report. Certain prehospital first responders might be considered for prophylaxis against specific biological or chemical agents, but the scientific evidence in favor of prophylaxis of this smaller but still very large population is limited, and the risks and expenditures would still be substantial. In making this recommendation the committee's focus is purely civilian, and it should not be construed as discouraging the development of prophylactic interventions for use by the armed forces. The differences with regard to military and civilian prophylaxis strategies are substantial, encompassing not only the simple contrast of known threats at known times for military forces as opposed to unknown threats at unknown times for the civilian population, but also the levels of organization and systemic preparedness required and available. Two general and important conclusions will become obvious to the reader as he or she proceeds through this chapter. The first is that with a few exceptions, drugs, antitoxins, and supportive medical equipment are generally available in small quantities (although two recent surveys [Dart et al., 1996; Skolfield, 1997] by poison control centers report that very few hospitals in their service areas carried sufficient amounts of all recommended antidotes). Proper planning and coordination among area medical and veterinary facilities might yield sufficient quantities of these drugs and other supplies for a multiple-victim incident, but few locales will have adequate supplies for a true mass-casualty event. The second general conclusion is that many of the vaccines and therapeutics described below are only available under Investigational New Drug (IND) applications to the Food and Drug Administration (FDA). Such products are generally produced in limited amounts and can be used only in a research setting and with the informed consent of the recipient (i.e., the patient or a proxy must provide informed consent, and the FDA must be contacted for an IND number for the patient before the

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Page 112 manufacturer can provide the product). In some cases, a fully licensed FDA-approved product will emerge after the requisite evidence of safety and efficacy is accumulated. In the interim however, under current legal requirements, IND status will effectively preclude use in a mass-casualty situation. Furthermore, it will be difficult or impossible to collect the required evidence of efficacy for many INDs (randomized clinical trials in human patients), either because the disease is so rare that accumulating enough cases will take a very long time, or because the condition against which it is directed does not occur naturally (e.g., mustard poisoning). Earlier this year, FDA established rules making it easier to study investigational drugs and devices with patients in life-threatening situations and unable to give informed consent. However, these rules, which require extensive prior planning, are aimed at facilitating collection of efficacy data and do not directly address the mass-casualty situation, especially for terrorist acts involving chemical and biological agents. FDA recognized the difficulty IND status presented in potential mass-casualty situations during the Persian Gulf War and passed an interim rule waiving the requirement for the United States military to obtain informed consent in using two investigational products intended to provide protection against chemical and biological warfare agents (pyridostigmine bromide and botulinum toxoid vaccine). The FDA has recently solicited comments on the wisdom of revoking this interim rule as well as on the nature of the evidence that ought to be required when products cannot ethically be tested in humans (United States Food and Drug Administration, 1997). Chemical Agents Discussion of chemical agents is based upon an approach that integrates local, state, and federal systems for the delivery and stockpiling of antidotes for mass casualty events. This approach emphasizes which agents must be available locally, how much and under whose jurisdiction. The principle being that a plan should be developed to deliver large quantities of antidotes to any part of our country in a rapid organized fashion. Research and development should focus on models of storage and methods for deployment and delivery in a timely fashion. First responders from Emergency Medical Services and Hazmat Services cannot be expected to make definitive decisions and in general will not be stocked for population antidotal care, although they should have access to personal antidotal material for high-risk toxins so as to effectively complete scene assessment and victim rescue.

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Page 113 Nerve Agents The treatment for nerve agent poisoning recommended by the U.S. military involves the use of three therapeutic drugs: atropine, pralidoxime, and diazepam. Nerve agents act by binding to the enzyme acetylcholinesterase, thereby blocking its normal function of breaking down the neurotransmitter acetylcholine following its release at neuronal synapses and neuromuscular junctions throughout the peripheral and central nervous systems. Acetylcholine accumulates and overstimulates synapses throughout the brain, nervous system, glands, and skeletal and smooth muscles. Death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. Seizure activity also contributes to morbidity and mortality. Atropine sulfate is a drug that blocks muscarinic acetylcholine receptors, counteracting effects such as vomiting and diarrhea, excessive salivation and bronchial secretions, sweating, and bronchospasm. It is administered intravenously, if possible, in high doses at frequent intervals until signs of intoxication diminish. Pralidoxime chloride (2-PAM), a drug that reactivates the nerve agent-inhibited cholinesterase, is administered along with atropine. Diazepam, or another anticonvulsant, may be administered in severe cases to control seizures and thereby prevent seizure-induced brain damage. Appropriate adult doses of atropine sulfate, 2-PAM, and diazepam are packaged in autoinjectors issued to U.S. military personnel for self- or buddy-aid. A metered dose atropine methonitrate inhaler called the medical aerosolized nerve agent antidote (MANAA) has been approved by FDA and is being produced for DoD by 3M/Riker. However, it is intended for use, under medical supervision, as a supplement to injectable atropine, not as self/buddy aid. Except under special circumstances, utilization of these prepackaged autoinjectors should be limited to Hazmat and prehospital EMS staff for their own personal care and that of their coworkers. Consideration for use of these antidotes for the general public should be restricted to exceptional circumstances when patients cannot be expeditiously removed from the environment, decontaminated, and brought to an emergency department. None of these antidotes is ideally delivered intramuscularly, in the absence of intravenous fluids and control of the airway, or during a convulsion. If these are considered essential products for civilian care, the hospital emergency department is the ideal site for their use. In a nerve agent incident where a presumed exposed patient is to be decontaminated prior to transportation to an emergency department, it can be considered appropriate for prehospital medical personnel to utilize

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Page 114 prepackaged antidotes (atropine sulfate, diazepam and pralidoxime chloride) if and only if: 1. There are signs and symptoms indicative of nerve agent poisoning, namely, meiosis, rhinorrhea, shortness of breath, fasciculations, or seizures. 2. There is an initial intelligence basis for suspecting the presence of a nerve agent at the scene or a high quality detection system that indicates the presence of a nerve agent at the scene. 3. A qualified physician with skills in medical toxicology is actively involved in the management of the patient. 4. The antidotes are utilized before or during decontamination and in no way delay transfer to a health care facility or casualty collection point. If transfer to a health care facility subsequent to decontamination will exceed 30 minutes, it may be appropriate to treat additional civilians at the scene. The committee is aware of no studies performed comparing central nervous system levels and benefits achieved by intravenous administration of these antidotes with those achieved by intramuscular injection performed 15–45 minutes earlier. Such a comparison would be an important consideration in deciding upon expedient prehospital treatment. An alternative to extensive field treatment by Hazmat, EMS, and MMST teams in a particular region might utilize Hazmat and MMST teams as a mobile stockpile system delivering large quantities of antidotes to the EMS teams/ambulances (and individual hospitals as patients move there). This approach will ensure that patient load at a given hospital will be matched by antidote supply, thus expediting therapy and avoiding delays in delivery from a single central stockpile. Decisions on antidote stockpiling and control will involve geographic (rural vs. urban), financial, and other legitimate but nonscientific determinations, but in the proposed procedure, first responders would draw on established supplies of antidotes prepared for disaster management to ensure that patients transported to local emergency departments arrived with sufficient antidotes to begin treatment. Simultaneous communication with Regional Poison Control Centers and Poison Control Center-Emergency Department linkages to local and state health departments would track stockpile usage and allow for coordination with more distant sources, such as the Centers for Disease Control and Prevention. In nonhuman primate studies, the combination of atropine and 2-PAM will protect against up to five times the LD50 (the dose lethal to 50 percent of the population exposed)1 of all known nerve agents except 1LD50 is a statistical concept rather than a clinical one, so neither doses below the LD50 nor protection against doses even higher than the LD50 guarantee that everyone exposed will survive.

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Page 115 soman (GD). Soman is an exception, because 2-PAM acts by competitively binding to the organophosphate agent and thereby "reactivating" the acetylcholinesterase enzyme the agent had tied up. However, once the enzyme-agent complex has undergone an irreversible "aging" process, 2-PAM is unable to reactivate the enzyme. The aging process takes hours for VX and most of the G agents, but only minutes in the case of soman (GD). In most cases of domestic civilian terrorism involving soman intoxication, it will not be possible to administer 2-PAM this quickly. Additional limitations in the use of 2-PAM as an antidote in nerve agent toxicity include the fact that large doses may be necessary for protection and survival, but in such large doses 2-PAM itself can lead to significant side effects, most notably hypertension. In addition, because it does not readily cross the blood-brain barrier, 2-PAM is thought to have little action against the central nervous system effects of nerve-agent poisoning. Although 2-PAM and atropine sulfate have only limited efficacy against soman (GD), nonhuman primates given the peripherally acting carbamate pyridostigmine prior to exposure to the nerve agent and atropine sulfate and 2-PAM after exposure survived GD in doses up to 20 to 40 times the LD50. Pyridostigmine appears to be without comparable benefit in treatment of sarin or VX, however. Like the nerve agents, carbamates inhibit the enzymatic activity of acetylcholinesterase. In fact, carbamate-enzyme binding precludes organophosphate-enzyme binding. Unlike the nerve agents, however, the carbamate-enzyme bond is freely and spontaneously reversible. As a result, it is possible to protect acetylcholinesterase from irreversible inhibition by nerve agent by use of the reversible carbamate inhibitor. The use of pyridostigmine by large numbers of military personnel for periods of 6–7 days during the Gulf War resulted in uncomfortable but not disabling side effects (primarily gastrointestinal and urinary) in more than half of those taking the drug (Dunn et al., 1997). In most cases these effects subsided after a day or two. Numerous controlled studies in humans, as well as years of use in the treatment of myasthenia gravis, support claims for the safety of pyridostigmine. The utilization of prepackaged diazepam for intramuscular use is a poor parenteral therapeutic delivery technique for this anticonvulsant. The diazepam is dissolved in propylene glycol and is poorly and erratically absorbed following intramuscular use. Although the intramuscular route is considered to be the least effective route for seizure control, lorazepam can be used intramuscularly and could be preferred to diazepam for EMS and Hazmat use. Lorazepam, however, has several disadvantages. From a financial perspective it is more expensive than diazepam. Lorazepam is not stable at high temperatures and therefore cannot be as easily stored as diazepam. Finally, without preloaded syringes or

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Page 116 autoinjector packaging, intramuscular use will be difficult to accomplish efficiently while utilizing the protective clothing required at the scene. Organophosphate (OP) pesticides are widely used throughout the United States, and poisoning is common (Litovitz et al., 1997). Treatment is identical to that for nerve agents, and as a result, many emergency medical teams and most hospital emergency department staff have some familiarity with diagnosis and treatment of OP poisoning and have access to limited supplies of atropine and pralidoxime. However, multiple nerve agent victims may each need 10–50 milligrams (mg) of atropine sulfate, which would rapidly deplete supplies in receiving hospitals. Rural communities may be able to call on veterinarians, who sometimes hold substantial amounts of atropine to treat cattle or horses poisoned by organophosphate pesticides. They might also be sources of other drugs, resuscitation equipment. disinfectants, and other useful equipment and supplies (Schneider, 1987). The same general concern—treatment would be possible only for small numbers of patients—is also true with regard to availability of ventilators. As in many other disaster situations, intubated patients can be supported by bag valve mask ventilation until a ventilator is available. Bronchoconstriction and copious secretions are prominent effects of organophosphate poisoning, and therefore ventilation is likely to be required for up to several hours after exposure, even when appropriate drug therapy is available. Potential Advances Table 8-1 provides information on a number of treatments and prophylactic pretreatments in various stages of research and development. This table and those that follow contain the relativistic term "potential civilian utility" and employ a very liberal criterion in assessing products for such use. The accompanying text evaluates potential products in a more selective manner that emphasizes probability and priority. For example, various pralidoxime derivatives, such as Pro-2-PAM, P-2-S and the Hagedorn oximes such as HI-6, have been compared to 2-PAM. Although some of these products offer increases in efficacy under some circumstances, none are FDA approved and most have intrinsic formulation and stability problems. The committee recommends that no further investment be made in attempting to bring these or similar compounds to market and/or to establish stockpiles The potential cost appears far more substantial than the advantage they might provide over 2-PAM. Alternatives to atropine sulfate autoinjectors, such as the quaterary ammonium derivatives ipratropium bromide and atropine methonitrate, have the disadvantage of poor absorption across mucosae and the blood-brain barrier, resulting in prolonged local effects, but they have negligible

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Page 117 TABLE 8-1 Potential Antidotes for Nerve Agent Poisoning Antidote Efficacy Availability Potential Civilian Utility Stockpile Scopolamine Poorly absorbed through inhalation Yes Yes Hospitals, ED Ipratropium Bromidea A quaternary anticholinergic agent Yes for inhalation Yes Hospitals, ED 3-quinuclidinyl benzilate (BZ, QNB)b CNS effects Withdrawn None N/A N, N' trimethylene bis (pyridine-4-aldoxime bromide) combined with benzactyzine CNS effects Benzactyzine is a cholinolytic agent Benzactyzine withdrawn None N/A Benzodiazepines (Diazepam, Lorazepam, Midazolam)c,d Controls seizures Autoinjector: 10 mg/2-ml vials (convulsant antidote) Field: yes Lorazepam preferred Base: no Intravenous preferred Prehospital, Emergency, Hospitals Health Department Pro-2-PAM (Dihydropyridine derivative) Prodrug or drug carrier permits traversing blood brain barrier Experimental Inadequate evidence N/A Obidoxime (Toxogonin) Effective in rodent model European Countries Inadequate evidence N/A Continued on next page

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Page 118 TABLE 8-1 Continued Antidote Efficacy Availability Potential Civilian Utility Stockpile H Series of oximes TMB4 (Hagedorn) (HI-6 compounds)e–h Effective in rodent model Toxicity profile under study Direct central and peripheral anticholinergic activity Stability in question Inadequate evidence N/A Methanesulfonate salt of pralidoxime (P2S)   Standard in UK Inadequate evidence N/A Nicotine hydroxamic acid methiodide (NHA) Pretreatment of soman exposure in rhesus monkeys Research potential   N/A Monoisonitrosoacetone (MINA) May have 48 hr post-exposure utility Research potential   N/A Butyryl cholinesterase (BChE)i–k (Human BChE Mutants) Exogenous scavenger for highly toxic organophosphorus poisons. Equine BChE studied in rhesus monkeys Human BChE available (? FDA status) Prehospital: high-risk environment pretreatment essential personnel ED: no N/A Continued on next page

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Page 119 TABLE 8-1 Continued Antidote Efficacy Availability Potential Civilian Utility Stockpile Stoichiometric scavengers: acetylcholinesterasel,m and carboxylesterasen,o [fetal bovine products] Binds broad spectrum of nerve agents Longer half-life Pretreatment common disadvantage that they have high MW and react 1:1 with organophosphates. Effective at 1:1 concentration. Research Prehospital: high-risk environment pretreatment essential personnel ED: no N/A Catalytic scavengers: Organophosphorus acid anhydride hydrolase,p,q [parathionase] modified AChE, modified BChE Pretreatment: advantage small amount of effective enzyme to destroy large amounts of toxin. Research No N/A Catalytic monoclonal antibodiesr,s Mice hybridomas secret monoclonal antibodies which hydrolyze phosphonates. The antibody is an IgG2a with Kappa light chain character with activity against soman, but there is no cross reactivity against sarin or tabun. Rodent models   N/A Reactive topical skin protectants Protection against penetration and will detoxify nerve agents. Animal model Prehospital and ED personnel. Field use in high-probability zone N/A Continued on next page

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Page 120 TABLE 8-1 Continued Antidote Efficacy Availability Potential Civilian Utility Stockpile Memantinet May be neuroprotective in cell culture for soman but severe injury still noted. Antiparkinsonian agent No evidence N/A Thienylcyclohexylpiperidine (TCP)u Acts as a noncompetitive inhibitor of NMDA receptors. May prevent and interrupt soman-induced seizures. Better approaches available. Experimental No evidence N/A Dizocilpine (MK-801)v Act as a noncompetitive inhibitor of (N-Methyl-D-Aspartate) NMDA receptor channel during seizures induced by soman in guinea pigs. Adverse effects similar to those of PCP. Experimental No evidence N/A aGross, 1988; bWaelbroeck et al., 1991; cMartin et al., 1985; dMcDonough et al., 1989; eLundy et al., 1992; fKoplovitz and Stewart, 1994; gWorek et al., 1995; hKassa, 1995; iRaveh et al., 1993; jBroomfield et al., 1991; kMasson et al., 1993; lMaxwell et al., 1992; mVelan et al., 1991; nMaxwell et al., 1987; oDoctor et al., 1993; pLittle et al., 1989; qRay et al., 1988; rLenz et al., 1992; sLenz et al., 1984; tDeshpande et al., 1995; uCarpentier et al., 1994; vSparenborg et al., 1992.

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Page 154 Postexposure Therapy Activated charcoal lavage may be helpful immediately after ingestion of castor beans or ricin, but ricin acts rapidly and irreversibly, which makes treatment very difficult after signs and symptoms appear. Symptomatic care is the only intervention presently available to clinicians treating aerosol ricin poisoning. Additional information on ricin may be found in Franz and Jaax (1997). Potential Advances There are several investigational antiricin strategies being pursued (see Table 8-7), including passive immunization through antibodies and toxoid-stimulated immunization, although, as with SEB, the very rapid binding of ricin regardless of the route of challenge makes active immunization the preferred strategy. Both toxoids of the native toxin and a preparation of the A-chain fragment have been shown to provide mice with protection from lethal aerosolized doses. DoD is pursuing the testing of the A-chain antigen as a possible vaccine. USAMRIID has been unable to demonstrate effective passive (postexposure) immunization however, and an in vitro screening program has examined over 150 compounds of a wide variety, but has not found a compound that provides any protection to laboratory animals. Additional study of the toxin's mechanism of action may provide useful leads for specific mediator blocking agents, but these research ventures are in a very early stage and raise fundamental questions about risk, benefit, and potential utility, in view of the exceptionally low potential for mass exposure. R&D Needs 8-23 Continued investigation of antiricin antibodies as well as formalin-treated toxoid immunization is appropriate, but should be considered low priority for domestic preparedness due to the high cost of developing a licensed product, the limited potential of mass exposure to ricin, and the low probability of any potential means of developing a mass-exposure technique. T-2 Mycotoxin Mycotoxins are by-products of fungal metabolism. A wide variety of fungi produce substances that produce adverse health effects in animals and humans, but mycotoxin production is most commonly associated with the terrestrial filamentous fungi called molds. T-2 mycotoxin is one of a family of nearly 150 toxins produced by Fusarium and related fungi

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Page 155 TABLE 8-7 Potential Antidotes for Ricin Poisoning Antidote Efficacy Availability Potential Civilian Utility Stockpile Antiricin rabbit antibodies tested parenterally in mice following inhalation at 1 hour Produced by toxoid of native toxin or purified A chain Pretreatment at 1 hour protected mice from 5 × LD50 Preclinical testing Prehospital task force Poison center Health dept. Toxoid is micro-encapsulated in galactide-glycolyde microparticles Active immunization Preclinical testing Prehospital task force N/A Formalin treated toxoid Passive prophylaxis Preclinical testing Postexposure N/A a-deglycosylated A chain as antigen Effective in mice after one immunization Submitted to FDA as IND Pretreatment N/A Supportive chemotherapy Transition state inhibitors block enzymatic effects on A chain Preclinical testing Insufficient evidence N/A

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Page 156 that infect wheat and other grains that are important human foods (T-2 mycotoxin-contaminated grain is thought to have been responsible for the deaths of more than 10 percent of the population of the Russian town of Orenburg in the 1940s). These toxins are nonvolatile, low-molecular-weight (250–550) compounds that are insoluble in water and highly resistant to heat. T-2 toxin has been the most extensively studied. Its primary toxic effects appear to be caused by inhibition of protein synthesis. Clinical effects of acute exposure, in addition to local effects specific to route of exposure (unlike the other biological agents described here, T-2 mycotoxin can penetrate intact skin [Wannamacher et al., 1991; Wannamacher and Wiener, 1997]), include vomiting and diarrhea, weakness, dizziness, ataxia, and acute vascular effects leading to hypotension and shock. In the 1970s, the United States government accused the Soviet Union and its allies of using trichothecene mycotoxins as weapons in conflicts in Southeast Asia and Afghanistan (Ember, 1984). See Wannamacher and Wiener (1997) for additional details. Preexposure Prophylaxis No vaccine is currently available for protection against any of the trichothecene mycotoxins. Postexposure Therapy No specific therapy for trichothecene mycotoxin poisoning is currently available. Skin decontamination with soap and water or the hypochlorite- (M258A1) or resin-based (M291) military decontamination kits can effectively remove toxin up to six hours after exposure, although none of them neutralize the toxin. Treatment of respiratory, dermal, and GI effects currently must be symptom based and supportive in nature. Superactive activated charcoal, for example, a common treatment for many orally taken poisons, has been shown to bind 0.48 mg T-2/gm charcoal in mice and improve survival rates significantly. Potential Advances Two topical skin protectants in development by DoD have been shown to protect rabbits from the dermal effects of T-2 toxin for at least 2 hours, but neither is available for human use. An IND has been submitted to the FDA for the simpler of the two, which offers only passive protection from T-2 toxin and a number of other potential chemical and biological agents. Human safety has also been demonstrated for this product, a manufacturing contract awarded, and an NDA is being prepared in hopes

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Page 157 TABLE 8-8 Potential Countermeasures Against T-2 Mycotoxin Antidote Efficacy Availability Potential Civilian Utility Stockpile Topical skin Protectant (TSP) Passive protection Goal is FDA license by FY00 Prehospital high-risk personnel Health dept. Reactive TSP (decontaminates) Proof of principle Goal is FDA license by FY08 Prehospital high-risk personnel N/A Corticosteroids (systemic) High doses decreased primary injury and shock in animal studies Yes Possible supportive therapy N/A BN52021 (a platelet activating factor antagonist) Prolongs rat survival when given after a lethal dose Research Possible therapy N/A Despeciated monoclonal Anti-idiotype antibody 100% effective for rats 30 min before T2 exposure or 15 min after exposure Preclinical Prehospital high-risk personnel N/A Prophylactic enzyme induction: flavonoids, ascorbic acid, vitamin E, selenium Rodent studies only Preclinical Prehospital high-risk personnel N/A Prophylaxis: mycotoxins conjugated to a carrier protein creates immunogen Highly specific and not successful against other trichothecenes Preclinical Prehospital high-risk personnel N/A

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Page 158 of fielding the product in the next two years. However, it is difficult to envision a domestic civilian terrorism incident in which these skin protectants would play an important role. Unless police, fire, and rescue personnel were to use a protective lotion routinely, some preincident intelligence would be required, and that should rightly trigger the use of protective clothing and respiratory equipment. Other prophylactic measures that have some promise in preclinical studies are susceptible to the same criticism. Very few specific postexposure measures have received extensive study. To the committee's knowledge, none are currently being studied. R&D Needs 8-24 The committee considers the threat of a terrorist incident involving T-2 mycotoxin to be very low. In addition, its effects are not consistently fatal, nor are they so rapid that prehospital treatment is demanded. The committee therefore recommends that civilian medical personnel continue to rely on nonspecific treatment and supportive therapy. R&D in this area should be limited to screening antivesicant treatments for their efficacy in animal models of mycotoxin poisoning. Broad Spectrum Defenses Against Biological Agents As noted above in the sections on viral encephalitides and viral hemorrhagic fevers, research on a number of multiagent defense approaches is being sponsored by the Defense Advanced Research Projects Agency (DARPA) contract program on Unconventional Pathogen Countermeasures. Exploratory work is under way not only on new antiviral drugs but also on antibacterials, antitoxins, new types of immunization, and several multipurpose approaches to pathogen destruction. The first of the multipurpose approaches is a strategy that utilized the red blood cell membrane outer surface as a platform for enzymatic-based defenses against pathogens and toxins. Boston University researchers are mounting a toxin-specific enzyme on the surface of circulating red blood cells in order to encounter the toxin and destroy it before the infecting agent can reach the target cells. A similar tack is being taken by University of Virginia scientists, who are using pathogen-specific cross-linked, bispecific monoclonal antibody complexes bound to a red blood cell complement receptor (Taylor et al., 1997; Nardin et al., 1998). The modified circulating red blood cells then scavenge for the infectious agent and bind it. The pathogens and the complement receptor, but not the red blood cells to which they are bound, are rapidly cleared from the circulation and destroyed by hepatic macrophages. The third multi-purpose approach

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Page 159 (Osiris Therapeutics, Inc.) involves engineered human mesenchymal stem cells programmed to produce a specific signal in the presence of an infecting agent or a toxin. The resulting signal would then tell a secondary cell system (i.e., platelets) to release a genetically programmed detoxifying substance. The fourth multi-purpose approach (Genelabs) focuses on the development of self-assembling RNA and DNA binding agents with broad spectrum anti-pathogen effects These approaches are multipurpose in the sense that each can be tailored to any one of many potential agents, although the agent must be specified. Therefore, the approaches could be used prophylactically if there is prior knowledge of the infecting agent and could be used as treatment after the agent is detected and identified. Immunizations The human host's immunity can stop or slow the spread of infection if the immune system can be activated very rapidly after the exposure. Approaches include stem cells (Osiris) for delivery of several antigens, simultaneously or over time, to immunize against a broad range of potential agents and the use of peptides (University of Connecticut) attached to heat shock proteins that together efficiently elicit cytotoxic T-lymphocytes (killer white blood cells) against specific infectious agents (Blachere et al., 1997). Heat shock proteins are produced naturally when the body is stressed by heat or injury; they help cells repair damage from stress. The heat shock protein complexes can be extracted as noninfectious entities from infected cells in culture and used as a vaccine. One does not need to know the identity of the agent, because peptides of any pathogen will putatively work. Conventional immunization methods take days to weeks to induce protection. There is a race between the body's immune system and the infecting agent. If the development of immunity could be hastened, the body would have a better chance to win. In an attempt to do just that, the University of Texas, Southwestern proposes to remove antigen-presenting cells from the blood, inject them by a special gun with DNA encoding the pathogen's genes, then return them to the body to provide rapid protection (Barry and Johnston, 1997; Johnston and Barry, 1997). Another effort is a three-pronged attack on viruses at Massachusetts General Hospital, in which soluble factors from human immune cells are to be developed to induce antiviral defense; immune effector cells engineered to recognize and destroy virus-infected cells, and hematopoietic stem cells (immature cells from the bone marrow) engineered to give long-term pathogen immunity (Scadden, 1997; Gardner et al., 1997).

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Page 160 Antibacterial Drugs The development of new antibacterial compounds is of prime importance, especially for prevention of infection when a terrorist attack is suspected, and for treatment after an attack. New classes of drugs are especially needed to combat known bacteria that have been rendered resistant to currently available antibiotics by genetic engineering. The DARPA program is supporting several efforts, including combinatorial chemical technology at ISIS Pharmaceuticals to find decoys that will prevent bacterial RNA-protein interactions (Konings et al., 1997); a Stanford effort to develop decoys that will target a DNA methylating enzyme (McLane et al., 1995; LeBlanc et al., 1998); and gene products expressed early in infection that can be inhibited by decoy compounds (SmithKline Beecham). A new class of drugs is under development at Stanford University to render pathogenic bacteria nonpathogenic by inhibiting the type III secretory pathway (Mecsas et al., 1998). The drugs will not necessarily kill the bacteria, but will stop the transport of virulence-causing proteins destined to be secreted through the bacterial surface. Another approach (Harvard University) aims at blocking attachment of toxins, viruses, and bacteria to target cell surfaces. Organic synthesis of strings of polyvalent molecules that mimic specific receptors and that nonspecifically rely on hydrophobic or coulombic interactions is expected to yield compounds that can be administered to persons during a bioterrorist attack. Antiviral Compounds New approaches to broad-spectrum antiviral drugs were discussed above in the sections on viral agents and will not be reviewed again here, other than to note that a variety of approaches aimed at common elements of viral replication and pathogenesis are targeted. Antitoxins New antitoxins are proposed for development by researchers at Los Alamos National Laboratory, using structure-based design of compounds that block SEB-host interactions at the receptor site on the target cell. A second approach is designed to select low molecular weight peptides from random libraries and test by in vitro assays to detect inhibition of cholera toxin binding. Development of broad spectrum molecular antagonists and vaccines is also proposed by Hebrew University scientists working with SEB and other superantigen toxins. These antitoxins may be

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Page 161 useful to first responders or emergency departments in cases of toxin exposure, whatever the source. Finally, a Rockefeller University project seeks to express detoxifying enzymes and neutralizing antibodies on the surface or secreted from human commensal bacteria (e.g., S. gordonii). Feasibility and Utility of the DARPA Approaches DARPA projects are as a rule speculative, but with the potential for high yield when they succeed. All of these approaches are in the initial experimental stage, making it unlikely that the research will mature to an application for several years. Some of the approaches, especially those using combinatorial chemistry (e.g., SELEX, Systematic Evolution of Ligands by Exponential enrichment) for drug development, have already shown great promise in the development of HIV/AIDS drugs (e.g., Tuerk and MacDougal-Waugh, 1993). However, getting similar drugs for bioterrorist organisms to licensure is problematic. The FDA process as it is now structured will need to accept surrogate outcome measures for both bacterial and viral infections, because these infections are for the most part exotic and do not occur commonly in the United States. Furthermore, for the same reason, pharmaceutical manufacturers are not likely to invest heavily in drugs for which the demand is small or infrequent. R&D Needs 8-25 Development of new specific and broad-spectrum antibacterial and antiviral compounds should be encouraged through financial support, early and accelerated transition to the marketplace, and, where indicated, application of orphan drug coverage. Emphasis should be given to rational drug development through combinatorial chemistry and applied research on receptors, replication complexes, and host defense mechanisms, keeping in mind that for combating terrorist attacks, treatment rather than prevention will be the most practical approach. Summary Of R&D Needs Unlike the other chapters of this report, the committee's recommended R&D needs for drugs and other therapies have been agent-specific. This was necessary because the nature of research tends to be agent specific. Additionally, because research of each agent is at various stages, the committee has prioritized the R&D needs as listed below.

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Page 162 High Priority Nerve Agent • Antidote stockpiling and distribution system • Scavenger molecules for pretreatments and immediate postexposure therapies Vesicants • An aggressive screening program focused on repairing or limiting injuries, especially airway injuries Anthrax • Vigorous national effort to develop, manufacture, and stockpile an improved vaccine Smallpox • Vigorous national effort to develop, manufacture, and stockpile an improved vaccine • Major program to develop new antismallpox drugs for therapy and/or prophylaxis Botulinum Toxins • Recombinant vaccines, monoclonal antibodies, and antibody fragments Non-specific Defenses Against Biological Agents • New specific and broad-spectrum antibacterial and antiviral compounds Moderate Priority Nerve Agents • Intravenous or aerosol delivery of antidotes vs. intramuscular injection • Development of new, more effective anticonvulsants for autoinjector applications

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Page 163 Cyanide • Dicobalt ethylene diamine tetraacetic acid, 4-dimethylaminophenol, and various aminophenones • Antidote stockpiling and distribution system • Risks and benefits of methemoglobin forming agents, hydroxocobalamin, and stroma free methemoglobin Phosgene • N-acetylcysteine and systemic antioxidant effects Viral Encephalitides • Antiviral drugs Viral Hemorrhagic Fevers • Antiviral drugs Botulinum Toxins • Botulinum immune globulin Low Priority Brucellosis • Vaccine Pneumonic Plague • Second generation vaccine Q Fever • Genes and gene products involved in pathogenesis Staphylococcal Enterotoxin B (SEB) • Characterization if mechanism of action • Active immunization

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Page 164 Ricin • Antiricin antibodies and formalin treated toxoid immunization T-2 Mycotoxin • Screening antivesicant treatments in animal models