The study of navy divers (Thomas et al., 1990) under heat stress conditions showed no effect of PB on neurobehavioral parameters. Unfortunately, the dose of PB is not stated, making these results difficult to interpret. Again, no long-term follow-up was reported. Thus, these studies offer little evidence with which to predict possible long-term effects of PB on normal patients.
It has been suggested that acute or chronic low-dose exposure to anticholinesterase compounds may cause subtle, subclinical effects that might be masked by tolerance or by CNS compensatory mechanisms. Izraeli and colleagues (1991) proposed that pharmacological challenge with a cholinomimetic agent (atropine) could prove useful in unmasking the latent muscarinic effects of AChE inhibitors such as PB.
To this end, eight healthy male subjects (mean age 29) were enrolled in a placebo-controlled, single-blind crossover study in which a 30-mg oral dose of PB or a placebo was administered every 8 hours for a total of four doses. Dosing began 24 hours before the commencement of noninvasive cardiopulmonary monitoring, with the fourth and final dose given 75 minutes before the monitoring session. After baseline recording of electrocardiogram (ECG), respiratory rate, and cardiac power spectra, these parameters were measured for 7 minutes after each of nine consecutive increasing intravenous doses of atropine. Volunteers reported no symptoms; no changes in mean heart rate or heart rate power spectrum were noted after PB treatment alone. The usual bimodal effect of atropine on heart rate (low doses ordinarily cause bradycardia, whereas higher doses cause tachycardia) occurred, but PB at the higher doses of atropine blunted this expected effect. The expected inverse effect on the respiratory peak (mediated mainly by parasympathetic input) was also observed, with the respiratory peak increased at the low dose of atropine and decreasing incrementally at higher atropine doses. Moreover, analogous to the findings for heart rate, this expected atropinic effect was attenuated by pretreatment with PB. These results indicate that PB-mediated cardiac rate effects are “unmasked” by interaction with atropine and that such effects are present even at asymptomatic dose levels of PB.
Another study of healthy volunteers by Nobrega and colleagues (1996) was designed to explore the effects of PB on cardiac cholinergic responses. Eight healthy volunteers (five men and three women, mean age 27) participated in a randomized, double-blind crossover trial comparing cholinergic effects of PB as a single 30-mg oral dose to placebo. Each subject underwent a 12-lead EKG, and three noninvasive cardiovascular maneuvers (respiratory sinus arrhythmia, Valsalva maneuver, and 4-second exercise test) were performed before and 2 hours after taking PB or placebo. PB was found to have a negative chronotropic cardiac effect (i.e., slowing of the heart rate) as evidenced by increased R-R intervals7 at rest and during the three autonomic tests. However, the drug had no