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