Chemical and Biological Terrorism Research and Development to Improve Civilian Medical Response (1999) / Chapter Skim
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8 Availability, Safety, and Efficacy of Drugs and Other Therapies
8 Availability, Safety, and Efficacy of Drugs and Other Therapies
Pages 110-164
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From page 110... ...
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.
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From page 111... ...
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.
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From page 112... ...
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 masscasualty 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)
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From page 113... ...
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.
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From page 114... ...
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.
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From page 115... ...
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.
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From page 116... ...
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.
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From page 120... ...
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From page 121... ...
R&D Needs 8-1 Atropine sulfate, pralidoxime, and diazepam autoinjectors and stockpiles of these drugs should be available both for onsite self/buddy use by emergency medical personnel andfor delivery to hospitals or patient collection points with patients. In addition atropine, pralidoxime and diazepam should be readily available in large quantities from a stockpile controlled by the local health department to be brought to the site where EMS will bring the casualties.
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From page 122... ...
8-8 Research into the development of catalytic monoclonal antibodies against a broad spectrum of nerve agents may prove beneficial in the development of rapid diagnostic tests as well as in the development of potential new therapies. Vesicants Included in this category of chemical agents are various forms of "mustard," an arsenical compound called Lewisite, and phosgene oxime.
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From page 123... ...
route make decontamination an unsatisfactory strategy for civilians, and, as is the case with most of the agents being considered, pretreatments requiring any more than a few minutes lead time are not likely to be generally useful in coping with civilian terrorism incidents. Topically applied skin Protestants offer the possibility of protection from trace amounts of agent-penetrating protective garments or surviving decontamination of equipment, but certainly could not be counted on to replace chemical-resistant clothing in areas known to be contaminated.
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From page 125... ...
Cyanide is metabolized more readily than the other chemical agents, and as a result, if the initial dose is not so large as to kill the victim within minutes, supportive therapy may be sufficient for full recovery in a matter of hours. Amyl nitrite, sodium nitrite, and sodium thiosulfate are commercially available in standard doses in the Pasadena Cyanide Antidote Kit (formerly the Eli Lilly Cyanide Antidote Kit)
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From page 126... ...
R&D Needs 8-10 The organization of delivery and availability of adequate supplies of the cyanide antidote kit must be achieved. Studies of stockpile control and time necessaryfor the delivery to prehospital, hospital, and health departments should be performed for each region.
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From page 127... ...
8-13 Dicobalt ethylene diamine tetruacetic acid and the strong methemoglobin forming compounds 4-dimethylaminophenol and various aminophenones merit further investigation, but must be given a lower priority then hydroxocobalamin and stroma-free me/hemoglobin, which carry less risk of creating excessive and unpredictable levels of me/hemoglobin. Phosgene Although phosgene is not currently believed to be a significant threat as a military weapon, it was used in World War I artillery shells, and, more importantly to the present discussion, it is still a widely used industrial chemical, over a billion pounds of which are produced in the United States.
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From page 131... ...
Vaccines against biologic threat agents do, however, have some very important uses in the civilian response to the threat of biologic terrorism. Anthrax vaccine can be effectively used in conjunction with antibiotics to prevent the development of pulmonary anthrax in exposed individuals.
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From page 132... ...
In both of these cases, high risk will be a highly subjective judgment, given the lead time of weeks to months required for immunization to achieve its full effect. The value of vaccines, even in the limited uses described above, justifies an accelerated research effort to improve the licensed vaccines, such as the anthrax, plague, and smallpox vaccines, and to complete the development process and seek licensure for those vaccines still in IND status.
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From page 133... ...
This is only partially true in the case of potential drug treatments: antiviral drugs have proven to be highly specific, like vaccines, so development of a drug to treat Ebola virus, for example, is unlikely to be financially attractive to the private sector. Antibiotics, on the other hand, are generally effective against a wide variety of microbial infections, greatly increasing the potential market of any new product.
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From page 134... ...
Preexposure Prophylaxis A licensed vaccine with demonstrated efficacy against cutaneous anthrax is available from Michigan Biological Products Institute. This vaccine is the formalin inactivated filtrate from culture of nonencapsulated B
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From page 135... ...
Ciprofloxacin and doxycycline are prescribed far more often, but they are expensive, especially ciprofloxacin, which may limit supplies in any one locale. Potential Advances The utility, indeed necessity, of anthrax vaccination subsequent to exposure is unique among the biological agents on our list.
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From page 136... ...
A second-generation, highly effective, and easy to administer anthrax vaccine would substantially improve the nation's ability to protect both civilian and military personnel against the number one biological threat. R&D Needs 8-15 A vigorous national effort is needed to develop, manufacture, and stock pile an improved anthrax vaccine.
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From page 137... ...
USAMRIID conducts assays of second- and third-generation antibiotics as they come on the market, using all of the bacterial threat agents in animal models. R&D Needs No action is required at this time.
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From page 138... ...
USAMRIID conducts assays of 2nd- and 3rd-generation antibiotics as they come on the market, using all of the bacterial threat agents in animal models.
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From page 139... ...
USAMRIID conducts assays of 2nd and 3rd generation antibiotics as they come on the market, using all of the bacterial threat agents in animal models.
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From page 140... ...
For additional information see Byrne (1997~. Preexposure Prophylaxis Q fever vaccines in the United States are still investigational, although an effective vaccine, Q-Vax, is licensed in Australia.
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From page 141... ...
USAMRIID conducts assays of 2nd- and 3rd-generation antibiotics as they come on the market, using all of the nonviral threat agents in animal models. R&D Needs No action is required at this time.
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From page 142... ...
Antiviral drugs may be of value in dealing with infected patients, but expanding ring vaccination is the proven means of eradicating foci of infection. Smallpox vaccine is therefore the second (and last)
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From page 143... ...
Recent research by scientists at NIH and USAMRIID on antiviral drugs against orthopox viruses, including variola, have shown some promising leads, including antivariola activity by at least three classes of compounds (Hugging et al., 1996; 1998~. One of these includes a licensed drug, cidofovir (marketed as Vistide_)
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From page 144... ...
Preexposure Prophylaxis A live attenuated vaccine for VEE (TC-83) is immunogenic in 80 percent of recipients, but it causes more than 20 percent of recipients to experience high fever, malaise, and headache serious enough to require bed rest.
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From page 145... ...
Potential Advances As is the case with most of the other infectious diseases of concern to the biological defense program, the primary thrust of current R&D is on vaccine development, and several candidate vaccines using live attenuated VEE, WEE, and EKE viruses have been identified and tested in animal models at USAMRIID. Unlike the antibiotics used to treat bacterial infections, most antiviral drugs are highly virus-specific, so drugs like AZT and the protease inhibitors that have proven so successful in controlling HIV, for example, have not been useful against the viral encephalitides.
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From page 146... ...
R&D Needs 8-18 Supportfor broad-spectrum antiviral drugs for treatment of VEE, WEE, EKE and other viruses considered biological terrorism threats should be consid ered a high priority. Viral Hemorrhagic Fevers Viral hemorrhagic fever is a term indicating an acute febrile illness accompanied by circulatory abnormalities and increased vascular permeability.
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From page 147... ...
. Potential Advances CDC, USAMRIID, and NIH all support small programs of research on one or more of the hemorrhagic fever viruses, primarily basic research on mechanisms of pathogenicity and explorations of possible vaccine can
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From page 148... ...
Additionally, arenavirus anti-polymerase humanized monoclonal antibodies will be synthesized at the University of Wisconsin for evaluation as antiviral drugs and researchers at the University of Texas Medical Branch are attempting to find ways to inhibit the intracellular transcription factor NFkB to modulate cytokine effects that are associated with arenavirus pathogenicity. R&D Needs 8-19 Support for the discovery and development of antiviral drugs for treatment of viral hemorrhagic fevers and other viral diseases considered biological terrorism threats should be considered a high priority.
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From page 149... ...
Army specifically for aerosol exposures to serotypes A-G has IND status (Franz et al., 1997~. This antitoxin markedly reduces the chances of serum sickness by eliminating the species-specific antigens from the horse immunoglobin (the basic immunoglobulin molecule is altered by removing complement fixing (Fc)
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From page 152... ...
Preexposure active immunization might be beneficial for those with the potential to be placed at very high risk, such as Ha~mat or MMST teams, but this appears to be a very low-probability occurrence. Staphylococcal Enterotoxin B (SEB)
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From page 153... ...
The death rate in cases of castor bean ingestion has been low, under 10 percent (Rauber and Heard, 1985~. Preexposure Prophylaxis Although preclinical testing in animals has encouraged the U.S.
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From page 154... ...
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.
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From page 155... ...
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From page 156... ...
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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From page 158... ...
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.
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From page 159... ...
attached to heat shock proteins that together efficiently elicit cytotoxic T-lymphocytes (killer white blood cells) against specific infectious agents (Blachere et al., 1997~.
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From page 160... ...
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.
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From page 161... ...
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.
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From page 162... ...
, . 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 Nerve Agents Moderate Priority · Intravenous or aerosol delivery of antidotes vs.
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From page 163... ...
AVA~AB~ITY, SAFETY, AND EFFICACY OF DRUGS AND OTHER THERAPIES 163 Cyanide and various aminophenones · Dicobalt ethylene diamine tetraacetic acid, 4-dimethylaminophenol, · 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 Brucellosis · Vaccine Pneumonic Plague · Second generation vaccine Q Fever Low Priority · Genes and gene products involved in pathogenesis Staphylococcal Enterotoxin B (SEB) · Characterization if mechanism of action · Active immunization
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From page 164... ...
164 Ricin CHEMICAL AND BIOLOGICAL TERRORISM · Antiricin antibodies and formalin treated toxoid immunization T-2 Mycotoxin · Screening antivesicant treatments in animal models
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