Appendix B
EFFECTS OF PB IN HUMANS
291
292
Table B.1
Author
Sample
Size
Wenger,
1993
7
Wenger,
1992;
Wenger,
1992
6
Roberts,
1994
Roach, 1991
7
Utopia
30
Sample/Study Characteristics
Healthy male soldiers age 22±2.8
Placebo controlled partial-doubleblind crossover with 7 d phases after
heat acclimation
Healthy male soldiers, age 25.6±9.6:
test outcomes with heat, exercise,
and hypohydration
Dose
30 mg q8 hr for
19 doses, or
placebo
PB 30 mg tab or
placebo
Findings
PB caused a modest increase in whole-body sweating and reduced
skin temperature on the chest during exercise by 0.5–0.9° C.
Trend toward increased rectal temperature
“Near lack of adverse effects”
“PB had only minor effects on tolerance to moderate exercise-heat
stress and did not aggravate the strain of hypohydration”
Rectal temperature: PB reduced rise in Tre but significant only
during hypohydration
Skin temperature on chest: decreased with exercise at 20% rh, more
with PB, significant only in condition 2
Skin temperature on upper arm: no difference?
Skin temperature on calf: No difference
Heart rate: lowered 3 beats/min (p = .004)
PB decreased expansion of plasma volume that occurred during heat
exposure: significant only at 75% rh
No change in thermoregulation during exercise in cold air
Healthy male
10 nonsmokers, 10 smokers, and 10
mild asthmatics
Double-blind placebo-controlled
crossover with PB or placebo before
bronchoprovocation
Utopia Bold
30 mg q8 hr
No effect of PB on nonspecific bronchial hyperreactivity in normals,
smokers, or asthmatics
Pyridostigmine Bromide
Physiological Findings
Table B.1—continued
Author
Ram, 1991
Sample
Size
25
Sample/Study Characteristics
12 healthy and 13 asthmatic
Dose
Statistically but not physiologically significant decrease in FEV1 at
rest (p < .015) and with exercise (p < .05), strongly correlated to
degree of AChE inhibitor (p < .00001)
30 mg
AChE inhibition: 28% with 60 mg; 23% with 30 mg
Pulse: significantly reduced (p < .005)
Respiratory function: no change
Cannot preclude more vulnerable subpopulation of asthmatics
No clinical adverse effects of PB
No significant effect on heart rate, plasma catecholamine level, or
resting blood pressure
Lower diastolic blood pressure with PB with exercise (average
decrease 5 mm Hg versus placebo, p < .01)
Average 33% whole blood cholinesterase inhibition 4 hr after last
tablet
Higher non-evaporative heat exchange with PB (p < .03)
No difference in heart rate, rectal temperature, heat storage, and
sweat rate with PB versus placebo
8
Hypertensive patients on betablockers
Randomized double-blind crossover
PB or placebo for 2 days
30 mg tid for 2
days
Epstein,
1990
8
Male heat-acclimatized volunteers,
age 23.5±1.1
Randomized double-blind crossover
with subjects exposed to 170 min of
exercise heat stress (relative
humidity 60%, Tdb 33° C)
Healthy male soldiers
Counterbalanced drug and control: 2
days tested with drug, 2 with placebo
Not stated to be blinded
30 mg q8 hr for 4
doses versus
placebo
10
Levine, 1991
7
Utopia Bold
No change in pulmonary function tests with PB: FEV1, FVC,
maximum voluntary ventilation in 15 seconds, carbon dioxide
sensitivity, or maximum inspiratory or expiratory flow rates
No significant change in skeletal muscle strength (peak hand-grip
strength and 60% peak hand-grip endurance time, peak torque for
leg extension), and muscle tissue damage by serum enzymes
293
Utopia
Healthy male soldiers
Counterbalanced drug and control: 2
days tested with drug, 2 with placebo
Not stated to be blinded
PB 30 mg tab
once, or
placebo; test
days separated
by = 48 hr
PB 30 mg tab
once or
placebo; test
days separated
by = 48 hr
Effects of PB in Humans
Arad, 1992
Levine, 1991
Findings
60 mg once
294
Table B.1—continued
Sample
Size
Kolka, 1991
Stephenson,
1989;
Stephenson,
1990;
Kolka, 1990
Utopia
Sample/Study Characteristics
Placebo-controlled crossover
Dose
PB 30 mg po tid
Findings
PB lowers esophageal temperature and HR in hot environment; HR
in warm environment
5
Healthy males age 20±2 tested at rest,
2 hr after PB, and 2 hr p seventh PB
tab in hot environment
Reduced resting esophageal temperature and heart rate with PB
(p < .05) no change in arterial blood pressure, forearm blood flow
and forearm skin blood flow; *74 hr data presented for a mean of
only 3 of the 5 subjects because PB was discontinued in 2 due to
high red blood cell AChE inhibition
4
Healthy males age 19.4±0.5 tested (a)
control at sea level (b) control at
10,000 feet; (c) 2 hr after first PB at
10,000 feet; (d) 26 hr after first and
2 hr after fourth PB tab; (e) sea level
2 hr after tenth tab
Tested in warm environment at sea
level and 10,000 feet
Healthy adult males
Lower esophageal temperature (trend only) at sea level
HR lower at sea level 74 hr after PB
5
4
Utopia Bold
PB 30 mg po or
no drug, 150
min before
40% decrease red blood cell AChE (329%±7)
PB decreased skin blood flow;
PB decreased heart rate at rest and in exercise
Esophageal temperature: increased with exercise only with PB
8-site mean skin temperature
Forearm blood flow (venous occlusion plethysmography): no change
Cutaneous perfusion (laser doppler velocimetry): reduced 37% after
PB (p = .05) with higher temperature threshold for initiation of
cutaneous perfusion of PB (p = .01)
Slope of LDV: esophageal temperature was reduced 35% with PB
(p = 0.22)
Metabolic rate (indirect calorimetry)
Pyridostigmine Bromide
Author
Table B.2
Performance
Author
Sample
Size
Sample/Study Characteristics
Dose
8
Healthy males
30 mg q8 hr for 4
doses
Forster, 1994
5
Healthy male members of human
centrifuge acceleration pattern; age
26±3; weight 80±4 kg
30 mg q8 hr or
placebo
Borland,
1985
4
Healthy male 19-27 years
Crossover; double-blind crossover
PB 30 mg q8 hr for
3 days or placebo
Wiley, 1992
4
Healthy aviators
PB 30 mg q8 hr for
3 days after
baseline
measurements
No significant effect of PB, protective gear, or interactions on
performance of vertical addition, reaction time, or perceptual
speed
PB level range: 6–31 ng/ml
AChE inhibitor range: 12–45%
No significant differences in ratings for fatigue, symptoms, and
work effort; grip strength; tapping task Sternberg memory
search; critical tracking, Dual Sternberg, and tracking
pulmonary function tests; Acceleration tolerance; heart rate,
QT interval, PR interval
“Minimal if any effects”
Increased mean critical flicker fusion; impaired visuomotor
coordination performance; no changes in mood, mean choice
reaction time; grating contrast sensitivity; macular thresholds,
digit symbol substitution, symbol copying; quantitative
kinetic perimetry, EEG during mental arithmetic
Visual ability “not significantly compromised”; refractive error
and pupil diameter significantly different, but no change in
lateral phoria, fusional vergence, accommodative amplitude
with PB
Effects of PB in Humans
Arad, 1992
Findings
295
Utopia
Utopia Bold
296
Pyridostigmine Bromide
Table B.2—continued
Author
Sample
Size
Izraeli, 1990
10
Brooks, 1992
24
Utopia
Sample/Study Characteristics
Pilots experienced in actual and
simulated A-4 flights
Double-blind placebo-controlled
crossover
A-10 pilots
Crossover counterbalanced doubleblind trial of performance with PB
versus placebo
Utopia Bold
Dose
Findings
PB 30 mg q8 hr
No decrement in performance under treatment with PB
PB 30 mg tid
versus placebo
No operationally significant effects of PB. No clear interference
of PB with performance
Table B.3
Side Effects
Author
Sharabi,
Danon, et
al., 1991
“Approximately
30”
Dose
Male Israeli soldiers 18–22, retrospective cohort
30 mg q8 hr
Retrospective survey of proxy
recollection by medical support
personnel involved with 41,650
soldiers in PGW
30 mg q8 hr
Utopia Bold
Findings
No correlation between AChE inhibition and type or severity of
symptoms
Malaise: 53%
Fatigue, numbness: 37%
Headache: 29%
Dizziness, imbalance: 19%
Moodiness: 18%
Restlessness: 18%
Heavy extremities: 10%
Excessive sweating: 9%
Altered mood: 8%
Sense of fear: 6%
GI:
Dry mouth: 71%
Nausea: 22%
Abdominal pain: 20%
Lack of appetite: 14%
Diarrhea: 6%
Other:
Hot flushes: 20%
Rhinorrhea: 10%
Rapid heart beats: 8%
Frequent urination: 11%
GI symptoms: 50%
Urinary: 5–30%
Headache, rhinorrhea, diaphoresis, tingling of extremities: < 5%
Need for medical visit: 1%
Discontinuation on medical advice: < 0.1%
297
Utopia
213
Sample/Study Characteristics
Effects of PB in Humans
Keeler, 1991
Sample
Size
298
Pyridostigmine Bromide
Table B.3—continued
Author
Sample
Size
Sample/Study Characteristics
Dose
Kennedy,
1991
1
Case report of PGW medical officer
(letter to editor)
30 mg q8 hr
Almog, 1991
9
Observational report of 9 cases of PB
overdose
13 to 39 PB
tabs
Utopia
Utopia Bold
Findings
Esophageal spasm with chest pain and trouble swallowing
Reports of others’ abdominal and skeletal muscle cramps, increased
bowel gas, blurred vision, and one claim of a 36-hour erection
Muscarinic: abdominal cramps, diarrhea, nausea, vomiting,
salivation, urinary incontinence (lacrimation and sweating not
prominent)
Nicotinic symptoms: transient fasciculations and muscle weakness
Central symptoms: (not seen: ataxia, confusion, psychosis,
respiratory or cardiovascular depression, seizure, coma)
No relation between symptoms and AChE inhibition; major
symptoms resolved in several hours while cholinesterase returned
to normal in 1–2 days