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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
4
Strategy for Identifying and Dealing with Interactions
Although the committee clearly sees the value of investigations of the entire dose-response surface, that is, of all the responses to all the combinations of all the agents to which military personnel might be exposed (see discussion in Chapter 1), the virtually infinite number of interactions of the many drugs, biologics, and chemicals makes it practically impossible to study and define all of them at once. Because of this it is not feasible to predict and eliminate all potentially adverse interactions. Therefore, the committee urges that studies be focused on those interactions that are likely to occur, that may compromise military unit or individual effectiveness, or, although rare, that may cause severe consequences. Although numerous schemes to categorize such interactions can be devised, the committee chose to categorize interactions in three ways: (1) those which are known from properly conducted and documented human investigations; (2) those which may be potential because of the individual characteristics of the agents, such as their known target organ toxicities, pharmacokinetics, or mechanisms of action in animals or other nonhuman systems; and (3) those which, given the present state of understanding, are unknown.
The committee proposes using these three categories to facilitate study, discussion, and action. To place various combinations of agents into one of the categories, the committee proposes constructing and then using a matrix (described later in this chapter). Finally, the committee proposes planning a research agenda in tiers, by category, using surveillance, toxicology, and epidemiology tools and approaches. Table 4-1 illustrates the varied research
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
4
Strategy for Identifying and Dealing with Interactions
Although the committee clearly sees the value of investigations of the entire dose-response surface, that is, of all the responses to all the combinations of all the agents to which military personnel might be exposed (see discussion in Chapter 1), the virtually infinite number of interactions of the many drugs, biologics, and chemicals makes it practically impossible to study and define all of them at once. Because of this it is not feasible to predict and eliminate all potentially adverse interactions. Therefore, the committee urges that studies be focused on those interactions that are likely to occur, that may compromise military unit or individual effectiveness, or, although rare, that may cause severe consequences. Although numerous schemes to categorize such interactions can be devised, the committee chose to categorize interactions in three ways: (1) those which are known from properly conducted and documented human investigations; (2) those which may be potential because of the individual characteristics of the agents, such as their known target organ toxicities, pharmacokinetics, or mechanisms of action in animals or other nonhuman systems; and (3) those which, given the present state of understanding, are unknown.
The committee proposes using these three categories to facilitate study, discussion, and action. To place various combinations of agents into one of the categories, the committee proposes constructing and then using a matrix (described later in this chapter). Finally, the committee proposes planning a research agenda in tiers, by category, using surveillance, toxicology, and epidemiology tools and approaches. Table 4-1 illustrates the varied research
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
approaches based on the three categories. Chapter 5 gives details of the tiered approach.
KNOWN INTERACTIONS
Only a relatively small number of the total number of possible interactions of various agents have been studied. Examples include protein binding displacement interactions (Udall, 1974); the interaction of acetaminophen and ethanol (McClain et al., 1980); and the role of the hepatic cytochrome P450 enzyme system in metabolizing compounds, thereby modulating their pharmacokinetics or organ toxicities (Levy and Bajpai, 1995). An example of military medicine drawing on current knowledge of interactions in its decisions is its procedures concerning vaccines. Live vaccine is not given soon after the administration of another live vaccine because of known interference with effectiveness; multiple live vaccines are given either concurrently or separated by more than 30 days.
Various strategies have been devised to alert decisionmakers to known interactions and to reduce the risk of such interactions. However, it is reasonable to assume that military operational requirements may necessitate the use of those substances that are known to result in increased toxicity on the basis of a significant positive risk-benefit ratio. For example, troops in the Balkans during the spring-summer season wore permethrin-impregnated uniforms and topically applied DEET to exposed skin when tick-borne encephalitis posed a significant hazard. In such instances, surveillance to detect, minimize, or prevent progressive toxicity should be established.
TABLE 4-1 Categorical Approach
Interaction Type
Recommended Approaches
Known
Avoid unless benefit outweighs risk
Use surveillance to monitor outcomes and implement appropriate intervention
Study in depth
Potential
Use matrix approach to predict or identify the interaction
Conduct studies (in vitro, animal, or human volunteer)
Use surveillance
Unknown
Put in place surveillance systems to detect sentinel events and do follow-up studies
Do prospective screening studies of important combinations
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
POTENTIAL INTERACTIONS
Some potential interactions, although not yet defined, can be suspected on the basis of similar target organ toxicities, toxicokinetic patterns, pharmacokinetics, or pharmacodynamics. Building on its understanding of the literature on interactions, in which agents X and Y have been shown to manifest common toxicities, toxicokinetics, or mechanisms of action, the committee recommends the development and use of a matrix system to identify potential but untested interactions. Examples of such matrices are provided in Table 4-2 and Table 4-3. The outline of the matrix is formed by listing the drugs, biologics, and chemicals to which troops may be exposed on one axis and listing known target organ toxicities, mechanisms of action, and toxicokinetic properties on the other. Then, for each row and column, the particular properties of the agent are entered. For example, fluoroquinolones and acetylcholinesterase inhibitors both express neurotoxic effects.
Once the matrix has been generated, one may look down the columns and identify commonalities between agents that may predispose them to interact. For example, the common neurotoxicities of permethrin and DEET suggest that they may interact (Table 4-2).
Table 4-3 demonstrates how a matrix could operate in assessing various classes of agents (e. g., antiparasitic or antidiarrheal agents) for overlapping sites of action or toxicities. When fully developed, these cross-comparison matrices should permit a more focused approach to the consideration of the potential interactions of multiple agents. For example, agents that express neurotoxic effects, such as fluoroquinolones and the acetylcholinesterase inhibitors (i.e., pyridostigmine) or Japanese encephalitis virus vaccination (Piesner et al., 1996), might be suspected of demonstrating interactive neurotoxicities. Moreover, new knowledge about the liver cytochrome P450 isozymes, enzymes involved in the metabolism of chemicals, may enable prediction of such interactions.
The matrix approach described in this chapter would serve as a screening step. Determining that toxic interactions between combinations of agents actually occur requires appropriate in vitro, animal toxicity, human volunteer, or epidemiologic studies for validation. Identification of potential interactions using available methodologies, including the matrix, could prompt the initiation of assessment programs (see Chapter 5). Once alerted to potential interactions, decisionmakers can prioritize studies of the potential interactions that could cause severe health consequences or impair troop effectiveness, or studies of the agents to which large numbers of individuals will be exposed. Continued improvement and updating of such a matrix is expected to further enhance its utility and validity.
The committee emphasizes that this approach is just one practical method that can be used to grapple with a difficult subject; there are no completely fail-
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
safe methods. Even if it were possible to study all combinations of agents in epidemiologic or animal model systems, it is unlikely that such a strategy would work. Many confounding factors would be encountered in epidemiologic studies; for example, host susceptibility factors such as age, race, sex, and comorbid conditions could affect the results. In the case of experimental studies, although randomization minimizes the effects of confounding variables, there remain the problems of multiple comparisons and sample size considerations.
Finally, although epidemiologic studies are more likely to involve exposures of humans to mixtures of chemicals or other toxic agents and could thus provide a more reliable basis for risk assessment than toxicologic studies with animals, epidemiologic data are rarely available for the specific mixtures of agents and exposure situations of interest. Thus, the committee proposes an additional series of prospective animal toxicity studies (Chapter 5).
UNKNOWN INTERACTIONS
Despite a thorough literature review and the development and use of a matrix such as the one proposed by the committee, unpredictable interactive toxicities are certain to occur. The unpredictable and severe toxicities of thalidomide, benoxaprofen, temafloxacin, and FIAU/FIAC (Fialuridine) used as single agents provide such examples (Strom, 1994). Even less predictable toxicities should be expected when complex mixtures of agents are used together. Early identification of such unusual or unpredictable events will require the use of a variety of toxicologic and epidemiologic tools. The surveillance tools that are required to investigate hitherto unknown interactions and that are currently available to the military were described in Chapter 3. Chapter 5 expands the discussion to specific toxicology and epidemiology approaches.
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
TABLE 4-2 Organ Toxicities, Pharmacodynamic, and Pharmacokinetic Properties of Drugs, Biologics, Chemicals, Recreational Substances, and Environmental Factors to Which Deployed U.S. Military Personnel May Be Exposed
Class of Agent
Specific Agent
Site of Action or Toxicity
Pharmacodynamic or Pharmacokinetic Characteristics
Smokes, obscurants
Diesel fuel
Fog Oil
Red phosphorous
Hexachlorethane
Zinc chloride
Titanium dioxide
Airways
Airways
Airways
Airways
Airways
Airways
Riot control agents*
CN (mace)
CS (O-chlorobenzylidene malonitrile)
Mucous membranes (eyes, nose, mouth, lung), skin
Mucous membranes (eyes, nose, mouth, lung), skin
Chemical warfare weapons*
Nerve agents: GA (tabun), GB (sarin), GD (soman), GF, VX
CNS, lung
Cholinesterase inhibitor (butyrylcholinesterase, acetylcholinesterase)
Vesicants: HD (distilled mustard), HL (mustard-lewisite mixture), HT (mustard-T mixture)
Skin, airways, eyes, CNS (poorly defined)
DNA alkylation and cross-linking in rapidly dividing cells
Cyanide: AC (hydrogen cyanide), CK (cyanogen chloride)
CNS, heart
Binds to Fe3+, inhibits cytochrome, prevents intracellular oxygen utilization
Pulmonary agents: CG (phosgene), PFIB (perfluoroisobutylene: pyrolysis of Teflon)
Lung
Acylation of cells at alveolar-capillary membranes with pulmonary edema
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Biologics/vaccines
Live-attenuated vaccines, routine
Adenovirus types 4 and 7
Measles, mumps, rubella
None recognized
None recognized
Poliovirus, oral
Typhoid
CNS
None recognized
Paralysis, 1:2,000,000
Varicella-zoster virus
Skin (liver)
Varicella-zoster virus-like rash (5%); Reye syndrome occurs with varicella-zoster virus infection and aspirin; not reported with vaccine, but warning to avoid aspirin for 2 weeks after vaccination
(Vaccina virus)
Killed vaccines, routine Tetanus, diphtheria
Hepatitis A and B viruses
Influenza virus
Menigococcal (groups A, C, Y, and W-135)
Area of operation-specific vaccines, killed
Skin
None recognized
None recognized
None recognized
None recognized
Cholera
Japanese encephalitis
Plague
Rabies
Yellow fever
Tick-borne encephalitis
None recognized
Anaphylaxis (rare), CNS
None recognized
None recognized
CNS
None recognized
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Class of Agent
Specific Agent
Site of Action or Toxicity
Pharmacodynamic or Pharmacokinetic Characteristics
Biological weapon vaccines
Anthrax
Botulinum
Immunoglobulins
None recognized
None recognized
Serum immune globulin
Hepatitis B virus Ig
Rabies IG
CNS
None recognized
None recognized
Large intravenous doses, aseptic meningitis
Drugs, commonly used, prescription
NSAIDS
Antibiotics, oral
Analgesics
Decongestants
CNS, renal, gastrointestinal
Multiple organs, depends on specific agent
Dizziness, headache (>3%), aseptic meningitis (<1%)
Antihistamines
Airways
Contraceptives, oral
Vitamins
Liver, skin
None at usual dosage
Induce cytochrome P450 enzymes
Iron
Antifungal agents (oral)
None at usual dosage
Liver
Blocks absorption of some oral antibiotics
Induce cytochrome P450 enzymes
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Drugs, area of operation, for prophylaxis (P) or therapy
Antimalarial agents
Chloroquine (P)
Primaquine (P)
Mefloquine (P)
Halofantrine
Doxycycline (P)
Quinine, quinidine
Artemisins
Antidiarrheal agents
CNS, hematologic
Hematologic, CNS, cardiac, central cholinergic system
CNS, cardiac
Cardiac, CNS
Skin, liver, CNS
Ototoxicity, CNS
Cardiac
Fluoroquinolones(ciprofloxacin)
Trimethoprim-sulfamethoxazole
Loperamide
Atropine sulfate-diphenoxylate
(Lomotil)
Antifungal agents
CNS, musculoskeletal, liver
Skin, CNS
Skin
Liver
GABA inhibitors, liver failure
Topical
None recognized
Azoles (oral)
Antiviral agents
Liver
Induce cytochrome P450 enzymes
Acyclovir
Ribavirin (intravenous)
Antiparasitic agents
Renal
None recognized
Metronidazole
Trimethoprim-sulfamethoxazole
Mebendazole
CNS, skin
Skin, CNS
Liver, hematologic
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Class of Agent
Specific Agent
Site of Action or Toxicity
Pharmacodynamic or Pharmacokinetic Characteristics
Praziquantel
Ivermectin
CNS, liver
CNS
Permethrin cream
CNS
Concentrated in fat; acute CNS toxicity
Antibacterial agents
Penicillin V (oral)
Amoxicillin (oral)
Cephalexin (oral)
Skin
Skin
Skin
Erythromycin (oral)
Skin, liver
Induces cytochrome P450 enzymes
Trimethoprim-sulfamethoxazole (oral)
Clindamycin
Metronidazole (oral)
Skin, CNS
CNS, skin
CNS, skin
Ceftriaxone (intramuscular, intravenous)
Doxycycline (oral)
Skin, liver
Skin, liver
Pseudocholelithiasis
Drugs, anti-biological warfare
Fluoroquinolone (ciprofloxin)
CNS, musculoskeletal, liver
Drugs, chemical warfare prophylaxis and treatment
Pyridostigmine
Atropine
Pralidoxime chloride
Diazepam
Nervous system
Skin (decreased sweating)
—
CNS
A cholinesterase inhibitor
An anticholinergic agent
Breaks the nerve agent–enzyme bond
Anticonvulsant
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Recreational drugs
Caffeine (coffee, soft drinks)
Nicotine (smokeless tobacco)
Alcohol
CNS
CNS
Liver
Occupational exposures
Noise
Carbon monoxide
Exercise
Heat
Cold
Ototoxicity
Ototoxicity
Musculoskeletal
Musculoskeletal, CNS, liver
Skin, musculoskeletal
Insect repellants
DEET
Permethrin
CNS
CNS
NOTE: CNS = central nervous system; Ig = immunoglobulin; NSAIDs = nonsteroidal anti-inflammatory drugs; and GABA = γ-aminobutyric acid.
*Identified using standard military terminology for chemical agents (see Chemical Casualty Care Office, 1995).
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
TABLE 4-3 Potential Interactions of Drugs, Biologics, Chemicals, Recreational Substances, and Environmental Factors
Chemical Agents
Site of Action, Toxicity
Smokes, Obscurants
Riot Control Agents
Nerve Agents
Vesicants
Cyanide
Phosgene, PFIB
Nervous system (central, peripheral)
+
?
+
Ototoxicity
Mucous membranes, conjunctiva
+
+
Airways, lungs
+
+
+
+
+
Cardiac
+
Cutaneous, skin
+
+
Hepatic
Renal
Musculoskeletal
Hematologic, lymphoid
Immunologic
Gastrointestinal
Reproductive, endocrine
NOTE: PFIB = perfluoroisobutylene (Teflon pyrolysis); NSAIDs = nonsteroidal anti-inflammatory drugs; beta-lactams are penicillin and cephalosporin; “+” denotes that the specified agent is active at the specified site. “?” denotes that the association of agent and site is ill-defined.
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Vaccines
Site of Action, Toxicity
Live Attenuated, Routine
Killed, Routine
Area-of-Operation Specific
Biological Weapons-Specific
Immunoglobulins
Nervous system (central, peripheral)
+
+
+
Ototoxicity
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
Cutaneous, skin
+
Hepatic
+
Renal
Musculoskeletal
Hematologic, lymphoid
Immunologic
+
Gastrointestinal
Reproductive, endocrine
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Commonly Used Prescription Drugs
Site of Action, Toxicity
NSAIDs
Antibiotics
Analgesics
Decongestants
Antihistamines
Contraceptives, Oral
Vitamins
Iron
Antifungal, Agents, Oral
Nervous system (central, peripheral)
+
+
Ototoxicity
+
Mucous membranes, conjunctiva
Airways, lungs
+
Cardiac
Cutaneous, skin
+
+
Hepatic
+
+
+
Renal
+
+
Musculoskeletal
+
Hematologic, lymphoid
+
Immunologic
Gastrointestinal
+
+
Reproductive, endocrine
+
+
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Antimalarial Agents
Site of Action, Toxicity
Chloroquine
Primaquine
Mefloquine
Halofantrin
Doxycycline
Quinine
Artemisins
Nervous system (central, peripheral)
+
+
+
+
+
+
Ototoxicity
+
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
+
+
+
+
Cutaneous, skin
+
Hepatic
+
Renal
Musculoskeletal
Hematologic, lymphoid
+
+
Immunologic
Gastrointestinal
Reproductive, endocrine
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Antidiarrheal Agents
Antiviral Agents
Site of Action, Toxicity
Fluoroquinolones
Trimethoprimsulfamethoxazone
Loperamide
Lomotil
Acyclovir
Ribavirin
Nervous system (central, peripheral)
+
+
Ototoxicity
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
Cutaneous, skin
+
+
Hepatic
+
+
Renal
+
Musculoskeletal
+
Hematologic, lymphoid
Immunologic
Gastrointestinal
Reproductive, endocrine
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Antiparasitic Agents
Insert Repellants
Site of Action, Toxicity
Metronidazole
Mebendazole
Praziquante
Permethrin
DEET
Nervous system (central, peripheral)
+
+
+
+
Ototoxicity
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
cCutaneous, skin
+
Hepatic
+
+
Renal
Musculoskeletal
Hematologic, lymphoid
+
Immunologic
Gastrointestinal
Reproductive, endocrine
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Antibacterial Agents
Nerve Agents
Site of Action, Toxicity
Beta-Lactams
Erythromycin
Clindamycin
Pyridostigmine
Atropine
Pralidoxime
Nervous system (central, peripheral)
+
+
Ototoxicity
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
Cutaneous, skin
+
+
+
+
Hepatic
+
Renal
Musculoskeletal
Hematologic, lymphoid
Immunologic
+
+
Gastrointestinal
Reproductive, endocrine
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Interactions of Drugs, Biologics, and Chemicals in U.S. Military Forces
Miscellaneous Agents
Site of Action, Toxicity
Caffeine
Nicotine
Alcohol
Noise
Carbon Monoxide
Nervous system (central, peripheral)
+
+
Ototoxicity
+
+
Mucous membranes, conjunctiva
Airways, lungs
Cardiac
Cutaneous, skin
+
Hepatic
+
Renal
Musculoskeletal
Hematologic, lymphoid
Immunologic
Gastrointestinal
Reproductive, endocrine
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