effect on compensatory reflex changes in heart rate as determined by the magnitude of the ratio of the longest to the shortest R–R intervals with each of the maneuvers. The authors concluded that despite tonic, dynamic reflex responses remain intact, suggesting a possible cardioprotective role for PB on post-myocardial infarction patients.

Harriman and colleagues (1990) designed a study to assess the possibility of PB treatment-related decrements in psychophysiological performance. Their preliminary publication dealt with the measurement of physiological parameters, including cardiovascular effects. A double-blind placebo-controlled crossover study of 24 male, trained A-10 pilots (mean age = 29) was carried out in flight simulators (with 12 pilots wearing chemical defense garments) after administration of either placebo or the standard PB regimen (30 mg every 8 hours) for 3 days. The pilots were first screened by measurement of plasma ChE inhibition after 30 mg of oral PB. Although there was marked individual variation of levels, in none of the pilots was ChE inhibition greater than 40 percent. Respiratory rate was not affected by PB. Heart rate and heart rate ratio (beats per minute/respirations per minute) were both decreased by PB. PB treatment also led to reports of 27 symptoms among 12 (50 percent) of the pilots. In contrast, placebo treatment resulted in only five (20 percent) pilots reporting six symptoms. The most common symptoms among PB-treated subjects were gastrointestinal upset, fatigue, confusion or giddiness, and headache. The authors concluded that the standard chemical warfare pretreatment regimen is safe for personnel who are prescreened for PB sensitivity.

In summary, in one small study (Izraeli et al., 1991), using relatively low doses (30 mg every 8 hours) of PB and causing no symptoms in healthy volunteers, subtle changes in heart rate and its normal respiratory fluctuations were observed. Another small study (Nobrega et al., 1996) of healthy subjects revealed slight negative cardiac chronotropic effects shortly after a single 30-mg oral dose of PB. However, this finding did not seem to be clinically significant because it was asymptomatic and autonomic reflex mechanisms easily compensated for the mild slowing in heart rate. The study of mission-ready pilots (Harriman et al., 1990) treated with the standard chemical warfare pretreatment regimen demonstrated gastrointestinal upset, fatigue, confusion or giddiness, headache, and decreases in heart rate and in the ratio of heart rate to respiratory rate without clinically significant cardiovascular symptoms.

These studies in healthy volunteers are limited because of the small number of participants and the brief duration of therapy without follow-up. It is, therefore, difficult to determine the significance of the findings or to compare their results to individuals with chronic illnesses or with genetically determined variations in cholinesterase activity.

Respiratory Studies in Healthy Volunteers

A study of FEV1 was done on six, healthy male volunteers with no history of asthma following intravenous (i.v.) administration of PB (0.143 mg/kg,



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