Gulf War and Health Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines (2000) / Chapter Skim
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Pyridostgmine Bromide
Pyridostgmine Bromide
Pages 207-266
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The drug is poorly absorbed after oral administration iMyasthenia gravis is an autoimmune disorder characterized by antibody blockade of the acetylcholine (ACh) receptor at the neuromuscular junction.
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reported that 5,328,710 doses were fielded and estimated that approximately 250,000 personnel took at least some PB during the Gulf War.3 It was supplied as a 21-tablet blister pack, the dosage prescribed was one 30-mg tablet every 8 hours.4 Variation in use occurred, how2AChE is an enzyme necessary to remove ACh. Acetylcholine transmits nerve signals at the cholinergic neuromuscular junction or synapses in the central nervous system.
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The committee then turns its attention to studies in humans. These include clinical studies, related principally to the use of PB in the treatment of myasthenia gravis and its use as a test of hypothalamic pituitary function or growth hormone response.
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To prevent it from inappropriately reactivating the receptors, ACh is hydrolyzed to inactive products by the enzyme AChE in the synapse, thus ensuring that one action potential leads to a single response. Interference with the ability of AChE to hydrolyze ACh leads to accumulation of the latter in the synapse, and the excess neurotransmitter is then responsible for both the pharmacological and the toxicological manifestations of AChE inhibition.
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The relationship between the degree of ChE inhibition and the facilitation of twitch tension is complex. No twitch potentiation is seen until RBC AChE is at least 85 percent inhibited (Barber et al., 1979~; this threshold is nearly identical to that noted for other ChE inhibitors.
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. In addition to acute toxicity, certain ChE inhibitors, particularly the organophosphorus compounds, produce other neuro- and myopathic effects, which are apparently unrelated to ChE inhibition and are described as intermediate and delayed neurotoxicity (or organo
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, PB has historically been used as a negative control in behavioral studies of other ChE inhibitors or as an agent to selectively produce peripheral nervous system actions of ChE inhibitors. PB is a carbamate possessing a positively charged quaternary group that restricts its penetration of the blood-brain barrier (Xia et al., 1981~.
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Of the doses of PB tested, only the highest dose interfered with performance of the task (Murphy et al., 1989~. Plasma ChE inhibition at this dose was 83 percent.
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Cardiac Dysrhythmias and Cardiomyopathy The autonomic, parasympathetic innervation of the heart is concerned principally with the regulation of heart rate and atrioventricular conduction and exerts this influence via cholinergic synapses much like those found elsewhere in the nervous system. Inhibition of AChE at these synapses results in prolonged residence time of ACh, leading to slowing of the sinoatrial firing rate (bradycardia)
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is correlated with the degree of brain ChE inhibition (and presumably with the extent of penetration of the ChE inhibitor through the blood-brain barrier) and, further, there are no significant effects on temperature regulation when plasma ChE inhibition is less than 30 percent (Francesconi et al.
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It is noteworthy that the pathology and the neurological impairment are hallmarks of OPIDN, but symptoms of this neurotoxic disorder are not consistent with those reported in Gulf War veterans' illnesses. Also, in this study (Abou-Donia et al., 1996a)
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Although data derived from laboratory investigations may have general applicability to humans, there are enough differences in toxic responses to the ChE inhibitors as a class to caution against making direct inferences to humans. For instance, although chickens are reported to be highly sensitive to OPIDN, this disorder is difficult to induce in laboratory rats, except at extremely high doses of organophosphates.
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examined the influence of PB on the CNS uptake of permethrin, at doses and durations relevant to human exposure, and found that oral PB actually reduced the amount of permethrin reaching the central nervous system. Such data, although limited, do not support a role for either decreased metabolism or enhanced penetration into the brain as the basis for enhanced toxicity.
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However, the biologic plausibility of some degree of PB penetration into the CNS is suggested by reports of positive actions on behavioral measurements, as well as hypothalamic actions of PB modifying temperature regulation and release of growth hormone (see later discussion)
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have recently suggested a relationship between polymorphisms and neurological impairment in Gulf War veterans. The authors identif~ed a study population of veterans with symptom complexes (Haley et al., 1997a,b)
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Several of the studies review general health outcomes, whereas others focus on specific organ systems. Clinical Studies There are a large number of clinical studies, principally related to the use of PB as a test of hypothalamic pituitary function or growth hormone response and in the treatment of myasthenia gravis.
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Abdominal symptoms were described as cramps, increased digestive sounds (due to the movement of gas in the intestines) , pain, diarrhea, and nausea, and the principal nicotinic cholinergic symptoms were skeletal muscle and tongue fasciculations (sometimes accompanied by dysarthria)
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Nonetheless it is clear that patients with a variety of disease states—many causing severe stress such as thyrotoxicosis or Cushing's disease had relatively mild acute and transient side effects from PB, and no study reported major clinical problems or obvious acute CNS symptoms after PB administration. Clinical Studies of PB and Myasthenia Gravis Myasthenia gravis is an autoimmune disorder characterized by antibody blockade of the ACh receptor of the neuromuscular junction.
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Despite a short half-life, the pre-dose plasma concentration is relatively stable (Aquilonius et al., 1983~. Blood levels of PB do not correlate with the degree of clinical toxicity observed, although they are somewhat predictive of cholinergic crisis in myasthenia gravis patients (Breyer-Pfaff et al., 19904.
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and 10 controls were studied for response to ChE inhibitors (Trojan et al., 1993~. Patients with PPS suffer generalized weakness as well as signs and symptoms of muscle weakness thought to be due to neuromuscular junction transmitter defects.
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Further, the possible reversal of cognitive dysfunction with anticholinesterases in myasthenics and the lack of evidence that the CNS of myasthenics responds differently to PB than that of the nonmyasthenic population might argue against adverse effects of PB on cognition in normal individuals. Clinical Studies of PB and Cardiovascular-Related Effects Because AChE inhibitors have been used for more than 50 years in the treatment of myasthenia gravis, clinical records may provide evidence of ad
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Based on this review of more than 1,000 patients with myasthenia gravis treated with AChE inhibitors, the estimated frequency of such drug-related syncopal or presyncopal events is approximately 1 percent. The authors advise extreme caution in the use of this class of medications in all patients with pre-existing conduction defects and in the elderly, the groups that seem most prone to medication-precipitated hypotensive episodes.
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In conclusion, studies of PB in patients with underlying medical problems are difficult to generalize to the normal healthy population because the disease state may affect the outcome of the response. The greatest experience with the cardiovascular side effects of PB is drawn from the clinical histories of patients with myasthenia gravis, usually at doses higher than those likely to have been used in the Gulf War.
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230 GULF WAR AND HEALTH Clinical Studies of PB and Respiratory Effects The respiratory effects of PB have been studied in clinical investigations of normal subjects, asthmatics, and individuals with myasthenia gravis.
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In summary, the literature on respiratory effects of PB is sparse and inconsistent. Taken together, the existing studies suggest that mild increases in airflow obstruction may occur within 1-2 hours of PB administration, but the effects are subclinical and rapidly reversible.
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Neuromuscular Studies in Healthy Volunteers In a double-blind, placebo-controlled crossover study, Graham and Cook (1984) evaluated the effects of PB on 24 healthy male volunteers between the ages of 21 and 35, measuring a wide variety of performance measures including neuromuscular strength by grip testing and perceived level of exertion.
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Neurobehavioral arid Cognitive Function in Healthy Volunteers A number of controlled studies have shown subtle neurobehavioral changes in subjects exposed to low doses of PB. Cognitive tests such as visuomotor coordination, dynamic visual acuity, reaction time, digit symbol, critical flicker fusion, and mood have been used to assess the effect of PB on performance.
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Although tests of many psychomotor and cognitive functions are unaffected by PB, there appears to be a trend for decrements in performance of complex tasks involving rapid shifts of attention. The study suggests subtle effects of this drug on cognition, reaction time, and complex performance that are not, however, supported by the prevailing concepts regarding the inability of PB to penetrate the bloodbrain barrier.
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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)
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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)
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In an investigation of heat stress and PB effects on thermoregulatory indices, eight heat-acclimated healthy young men were subjected to repeated bouts of exercise in a hot-humid environment after receiving four oral doses of either PB or placebo in a double-blind crossover fashion (Seidman and Epstein, 1989~. No significant effects of PB could be demonstrated on physiological parameters, including final rectal temperature, amount of heat stored in the body, dry heat exchange, sweat excretion, and sweat efficiency.
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, a slight but statistically significant decrease in heart rate was observed but was asymptomatic. In this study the mean age of volunteers was 23.5 years and the eight subjects were preacclimatized.
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; increased sweating, increased evaporative water loss, and lowered skin temperature with dry heat stress and exertion, with an increased change in exercise-induced sweating and drop in skin temperature and heart rate on later days of treatment (Wenger et al., 1993~; and episodes of self-limited but severe abdominal cramping in coldexposed subjects (Prusaczyk and Sawka, 1991~. These findings are of unknown clinical significance, but because of the rapid return to baseline, these PBassociated changes are not likely to be harbingers of long-term effects.
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as well as visual performance in 24 healthy male volunteers. In a double-blind, placebo-controlled, crossover study comparing 5 days of treatment with 30 mg of oral PB or placebo three times daily, investigators tested a number of visual function parameters, including spatial resolution by contrast sensitivity; neural transit time by steady-state visual evoked response; visual acuity by Snellen eye chart; and depth perception by biopter test.
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noted that visual acuity decreased as the percentage of plasma AChE inhibition increased, while an opposite relationship occurred with depth perception, which improved as AChE inhibition was decreased by PB treatment. Therefore, PB treatment seemed to augment depth perception while having a negative effect on visual acuity.
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Overall Performance in Healthy Volunteers A number of studies have been carried out to assess overall measurements of both physiological and behavioral or cognitive parameters in healthy subjects treated with PB. Izraeli and colleagues (1990)
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, showed no drug-related changes in heart rate, minute respiration, oxygen consumption, tidal volume, handgrip strength, or perceived exertion. Another study of like design measured the effects of standard doses of PB combined with heat-exercise stress and wearing CW protective clothing on eight healthy male volunteers (Arad et al., 1992b)
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, 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.
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They further speculated that anticholinesterase exposure might lead to long-term adverse consequences with symptoms that are not incompatible with those of Gulf War veterans, and that combined exposures to other ChE inhibitors might increase the risk of such outcomes. In summary, individuals within a healthy population differ widely in their rates of absorption, distribution, elimination (PK)
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In an initial survey designed to search for syndromes characteristic of Gulf War veterans, Haley et al.
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Another potential source of bias is the numerous medical examinations and media contacts of study subjects before the survey was conducted and the reliance on self-reports of symptoms and adverse responses to PB that occurred many years earlier (Gray et al., 1998~. The study population was a reserve naval command, whose members were often employed full-time in nonmilitary careers, with occupational exposures and subsequent confounding health risks, and thus may not be representative of the general population of Gulf War veterans.
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This study found impairment in ill Gulf War veterans compared to controls on each of two global measurements of brain dysfunction (the Hallstead Impairment Index, p = .01, and the General Neuropsychological Deficit Scale, p = .05. There were significant differences on 20 of 89 tests with endpoints that did not depend on volitional action by subjects (e.g., evoked potentials)
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. Nevertheless, the authors expressed the view that the neuropsychological abnormalities seen in Gulf War veterans are likely the result of neurotoxic exposures associated with service in the Gulf War.
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Nevertheless, the association of symptoms with self-reported PB use was not different between the three cohorts with elevated odds ratios observed for the three principal health outcome measures in all three cohorts. CONCLUSIONS Acute Effects A large number of clinical studies report acute transient cholinergic effects in normal volunteers and patients with a wide variety of clinical disorders given PB as a diagnostic test of hypothalamic pituitary function and patients with my
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The effects are self-limited and well tolerated by young adults. As noted above, the most extensive information available on the acute effects of PB comes from studies of its use for diagnosis of growth hormone deficiency in adults and children and its therapeutic use in the treatment of myasthenia gravis.
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, is limited by the lack of consistency with results from toxicological and clinical studies; uncertainty about the selection, administration, and interpretation of the neuropsychological tests employed; the highly select nature of the small number of Gulf War veterans studied; and the lack of comparable studies in a nondeployed comparison group. The epidemiologic data do not provide evidence of a link between PB and chronic illness in Gulf War veterans.
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1996b. Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War chemical exposures.
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1990. Neuromuscular function and plasma drug levels in pyridostigmine treatment of myasthenia gravis.
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on pyridostigmine bromide (PB) -induced inhibition of total cholinesterase activity.
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1990. Effects of pyridostigmine bromide on in-flight aircrew performance.
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1990c. A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: Combined administration of pyridostigmine and growth hormone-releasing hormone.
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1985. Neuromuscular toxicity of pyridostigmine bromide in the diaphragm, extensor digitorum longus, and soleus muscles of the rat.
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1991. Subchronic oral toxicity of pyridostigmine bromide in rats.
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1998. Population pharmacokinetics and pharmacodynamics of pyridostigmine bromide for prophylaxis against nerve agents in humans.
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1990. One Hundred Eighty Day Subchronic Oral Toxicity Study of Pyridostigmine Bromide in Rats.
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1998. Pyridostigmine bromide and Gulf War syndrome.
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1991. Acute effects of oral pyridostigmine bromide on conditioned operant performance in rats.
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Fundam Appl Toxicol 1~2~:217-221. Yamamoto K, Shimizu M, Ohtani H
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Such an approach may help elucidate the nature of the illnesses in Gulf War veterans in a way that is not possible by examining single agents. Unfortunately, most of the studies conducted to date focus on single agents.
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268 ANTHRAX VACCINE 272 Toxicology, 275 Human Studies, 280 BOTULINUM TOXOID 287 Toxicology, 289 Human Studies, 291 MULTIPLE VACCINATIONS 294 Toxicology, 296 Human Studies, 299 SQUALENE 307 Dietary Intake, Absorption, Distribution, and Metabolism, 307 Animal Studies, 308 Use of Squalene as a Vaccine Adjuvant, 309 Gulf War Issues, 311 Future Research Directions Regarding Squalene, 312 CONCLUSIONS 312 Anthrax Vaccine, 312 Botulinum Toxoid, 313 Multiple Vaccinations, 314 REFERENCES.
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