stressors. However, this statement must be understood to carry some important caveats:

  • Most subjects were extremely young males (<30 years) in exemplary physical condition (flight-ready pilots, Navy divers, medically screened volunteers). Whether the mild and/or equivocal performance effects (such as possible decrease in ability of pilots to avoid SAM attack in one simulation study) or the slight physiological changes or symptoms noted in others are clinically important in older or less well-screened individuals remains to be determined.

  • Long-term studies are unavailable at this time. In the longest of the above-cited investigations (Cook et al., 1992), a trend for decrease in hand strength became significant only after the full 7 days of PB treatment. The possibility exists that this change represents a downregulation of the ACh receptor after excessive stimulation by PB block of AChE. Long-term follow-up is needed to determine the possibility of a chronic adverse neuromuscular effect.

  • The number of subjects in each study is small and may not identify a sensitive subpopulation of individuals who might respond with greater adverse effects due to genetic variability (e.g., variants of BuChE activity).

Genetic and Population Pharmacokinetics and Pharmacodynamic Studies

Clinical Research Services, Inc. (1996), studied the safety, tolerance, and pharmacokinetics or pharmacodynamics (PK/PD) of PB in 45 male and 45 female healthy volunteer subjects in a randomized, placebo-controlled study. Subjects were divided into six groups by gender and weight (low, medium, and high weights for both sexes), with 15 subjects in each group. Within each group, 10 subjects received 30 mg of PB three times daily for 21 days and 5 subjects received placebo on the same schedule and for the same duration. Side effects were mild and similar between PB- and placebo-treated subjects except for mild gastrointestinal muscarinic symptoms that occurred with greater frequency among the PB-treated group. Blood chemistry, hematology, hormone levels, and electrocardiography showed no significant changes between those receiving PB and those on placebo. Plasma concentration of PB showed gender and weight effects early in the study, and maximum concentration of PB was significantly associated with weight (lower weights associated with higher serum concentrations).

Marino and colleagues (1998) describe a 1998 population PK/PD analysis of PB: 60 healthy men and women between 18 and 45 years of age received either 30 mg PB or placebo orally every 8 hours for 21 days (30 PB subjects and 30 placebo subjects). The PK model that best fit plasma PB levels was a two-compartment open model with first-order absorption and first-order elimination from the central compartment. The PD model that best fit RBC AChE activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results of this study show that the pharmacokinetics of PB are both gender and weight dependent. Due to wide individual variations, 30 percent



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