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Aviation, Space, and Environmental... Dec 2001Pretreatment with pyridostigmine bromide (PB) has become part of standard military procedures for protection against the effects of possible chemical warfare attack. The... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Pretreatment with pyridostigmine bromide (PB) has become part of standard military procedures for protection against the effects of possible chemical warfare attack. The purpose of the work reported here was to quantify the type, intensity and frequency of side effects of low-dose PB, and to examine factors that predict the intensity and frequency of side effects.
METHOD
A double-blind, cross-over, placebo (PL)-controlled design was used. Of the 67 subjects, 33 received 30 mg PB every 8 h for 13 doses, and 34 received 60 mg on the same schedule. Order of PB and PL administration was counterbalanced.
RESULTS
Overall, side effects were mild, even at the 60-mg dose level. More side effects were reported when volunteers were taking PB than when they were taking placebo. Women reported more symptoms than men. Neither cholinesterase inhibition nor plasma levels of PB predicted side effect scores during the PB week; the best predictor of side effect scores during the PB week was side effect scores during the PL week.
CONCLUSION
PB is well tolerated by healthy young people, even when twice the recommended military dose is administered.
Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Pyridostigmine Bromide
PubMed: 11763111
DOI: No ID Found -
Pharmacology, Biochemistry, and Behavior Mar 1991Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a...
Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3-40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (less than or equal to 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (greater than 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED50 was calculated as 23.3 (17.9-28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (less than or equal to 12 mg/kg) had an onset latency within 40-80 min and a duration of 20-80 min, whereas high doses (greater than or equal to 24 mg/kg) had an onset latency of 20-40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30-120.mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.
Topics: Administration, Oral; Alzheimer Disease; Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Pyridostigmine Bromide; Rats; Rats, Inbred Strains; Reinforcement Schedule
PubMed: 2068191
DOI: 10.1016/0091-3057(91)90012-q -
Anesthesiology Aug 2013The acetylcholinesterase inhibitor, pyridostigmine, is prophylactically administered to mitigate the toxic effects of nerve gas poisoning. The authors tested the...
BACKGROUND
The acetylcholinesterase inhibitor, pyridostigmine, is prophylactically administered to mitigate the toxic effects of nerve gas poisoning. The authors tested the hypothesis that prolonged pyridostigmine administration can lead to neuromuscular dysfunction and even down-regulation of acetylcholine receptors.
METHODS
Pyridostigmine (5 or 25 mg·kg·day) or saline was continuously administered via osmotic pumps to rats, and infused for either 14 or 28 days until the day of neuromuscular assessment (at day 14 or 28), or discontinued 24 h before neuromuscular assessment. Neurotransmission and muscle function were examined by single-twitch, train-of-four stimulation and 100-Hz tetanic stimulation. Sensitivity to atracurium and acetylcholine receptor number (quantitated by I-α-bungarotoxin) provided additional measures of neuromuscular integrity.
RESULTS
Specific tetanic tensions (Newton [N]/muscle weight [g]) were significantly (P < 0.05) decreased at 14 (10.3 N/g) and 28 (11.1 N/g) days of 25 mg·kg·day pyridostigmine compared with controls (13.1-13.6 N/g). Decreased effective dose (0.81-1.05 vs. 0.16-0.45 mg/kg; P < 0.05) and decreased plasma concentration (3.02-3.27 vs. 0.45-1.37 μg/ml; P < 0.05) of atracurium for 50% paralysis (controls vs. 25 mg·kg·day pyridostigmine, respectively), irrespective of discontinuation of pyridostigmine, confirmed the pyridostigmine-induced altered neurotransmission. Pyridostigmine (25 mg·kg·day) down-regulated acetylcholine receptors at 28 days.
CONCLUSIONS
Prolonged administration of pyridostigmine (25 mg·kg·day) leads to neuromuscular impairment, which can persist even when pyridostigmine is discontinued 24 h before assessment of neuromuscular function. Pyridostigmine has the potential to down-regulate acetylcholine receptors, but induces neuromuscular dysfunction even in the absence of receptor changes.
Topics: Animals; Cholinesterase Inhibitors; Down-Regulation; Drug Administration Schedule; Male; Neuromuscular Diseases; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic; Sodium Chloride; Time Factors
PubMed: 23563362
DOI: 10.1097/ALN.0b013e318291c02e -
Xenobiotica; the Fate of Foreign... Nov 19931. To assess the contribution of tubular secretion to the renal excretion of pyridostigmine, and its modification by other cationic drugs, six volunteers were given...
1. To assess the contribution of tubular secretion to the renal excretion of pyridostigmine, and its modification by other cationic drugs, six volunteers were given single oral doses of 60-mg pyridostigmine bromide with and without co-administration of ranitidine or pirenzepine. Renal clearances were determined by h.p.l.c. analysis of pyridostigmine and enzymic measurement of endogenous creatinine in plasma and urine. 2. In patients with myasthenia receiving continuous pyridostigmine therapy, renal clearance values were obtained in the same manner with and without ranitidine (10 patients) or pirenzepine (nine patients) co-medication. 3. Pyridostigmine was not bound to plasma proteins. Its renal clearance averaged 6.65 ml/min per kg (350% of the creatinine clearance) in all subjects, 74% being due to net tubular secretion. 4. Mean values for pyridostigmine renal clearance and for clearance by secretion were decreased in the presence of pirenzepine, but plasma concentrations were not affected significantly. Ranitidine caused a small non-significant decrease of the pyridostigmine clearance in patients. 5. Pyridostigmine had a higher elimination (2 h-1) than the absorption rate constant (0.23 h-1) when administered orally as a non-retarded preparation. 6. The renal clearance of creatinine was slightly increased by pyridostigmine in volunteers and slightly decreased by pirenzepine in the total group of subjects.
Topics: Adolescent; Adult; Aged; Drug Interactions; Female; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Myasthenia Gravis; Pirenzepine; Pyridostigmine Bromide; Ranitidine
PubMed: 8310710
DOI: 10.3109/00498259309059437 -
JAMA Aug 1991To determine the adverse effects of pretreatment with pyridostigmine bromide for nerve agent exposure during wartime.
OBJECTIVE
To determine the adverse effects of pretreatment with pyridostigmine bromide for nerve agent exposure during wartime.
DESIGN
A retrospective study.
SETTING
Southwest Asia.
PARTICIPANTS
Personnel who provided medical support to the XVIII Airborne Corps. These medical officers supplied information pertaining to symptoms and disposition of 41,650 soldiers who received pyridostigmine at the onset of hostilities of Operation Desert Storm.
INTERVENTION
Pyridostigmine bromide, 30 mg orally, was self-administered every 8 hours while under the threat of nerve agent attack (for 1 to 7 days).
MAIN OUTCOME MEASURE
Physiologic changes attributable to pyridostigmine that resulted in need for medical attention, discontinuation of the drug, hospitalization, and/or evacuation from Southwest Asia.
RESULTS
About half of the population noted physiologic changes that were not incapacitating, such as increased flatus, abdominal cramps, soft stools, and urinary urgency. Approximately 1% of the soldiers believed they had effects that warranted medical attention, but fewer than 0.1% had effects sufficient to discontinue the drug. Nonincapacitating symptoms often occurred; however, military mission performance was not impaired.
CONCLUSION
While under the threat of nerve agent attack, pyridostigmine can be administered to virtually all soldiers.
Topics: Chemical Warfare Agents; Cholinesterase Inhibitors; Female; Gastrointestinal Diseases; Humans; Hypertension; Male; Nervous System Diseases; Premedication; Pyridostigmine Bromide; Receptors, Muscarinic; Retrospective Studies
PubMed: 2072481
DOI: No ID Found -
British Journal of Pharmacology Nov 19751 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at...
1 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 mumol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose-dependent process is involved in the urinary excretion of 3-OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3-OH NMP at different dose levels. After 4 h, approximately85% of the lowest dose was eliminated unchanged in ug this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.
Topics: Animals; Cytomegalovirus; Injections, Intravenous; Jugular Veins; Kinetics; Male; Portal Vein; Pyridinium Compounds; Pyridostigmine Bromide; Rats; Time Factors
PubMed: 173444
DOI: 10.1111/j.1476-5381.1975.tb06936.x -
Neurology Mar 1977Four patients with myasthenia gravis were under unsatisfactory control while receiving oral pyridostigmine. In each of these patients, the serum levels of this drug were...
Four patients with myasthenia gravis were under unsatisfactory control while receiving oral pyridostigmine. In each of these patients, the serum levels of this drug were below those observed in patients with myasthenia gravis who are well controlled. The strength of each of these patients improved when the serum pyridostigmine level was increased by intravenous administration of this agent. Furthermore, the rate of disappearance of pyridostigmine from the serum following intravenous administration was the same as that for control subjects and patients under good control. This demonstrates that failure to achieve adequate serum pyridostigmine levels following oral administration is due to malabsorption rather than to increased rates of tissue uptake, degradation, or excretion of the drug.
Topics: Administration, Oral; Adult; Aged; Atropine; Biological Availability; Female; Gastrointestinal Motility; Humans; Injections, Intravenous; Intestinal Absorption; Male; Middle Aged; Myasthenia Gravis; Pyridostigmine Bromide
PubMed: 557769
DOI: 10.1212/wnl.27.3.299 -
Life Sciences Jan 2010The purpose of the present work was to investigate the ability of pyridostigmine encapsulated in long-circulating liposomes, to protect against ECG (electrocardiogram)...
AIMS
The purpose of the present work was to investigate the ability of pyridostigmine encapsulated in long-circulating liposomes, to protect against ECG (electrocardiogram) alterations induced by sympathetic stimulation in rats.
MAIN METHODS
The encapsulation of pyridostigmine was carried out by freeze-thaw and extrusion. Blood pressure and ECG (limb lead II) were monitored in anaesthetized male Wistar rats. The formulation containing pyridostigmine was intravenously administrated in 0.1, 0.3 and 1.0mg/kg doses, and sympathetic stimulation was conducted by administration of 1 or 3 microg of noradrenaline (NA) after 1, 2, 4 or 6h. The obtained cardiovascular parameters were compared to animals that received intravenous injection of pyridostigmine in free form or saline.
KEY FINDINGS
After saline, NA induced a significant increase in QT interval (22.3% after 3.0 microg). Previous administration of free pyridostigmine significantly prevented the increase of QT interval after sympathetic stimulation and the most prominent effect was observed after 1h for the dose of 0.3mg/kg (6.8% after 3.0 microg of NA) and was no longer observed after 2h of the treatment. On the other hand, the maximum effect of pyridostigmine in liposomal formulation preventing QT interval increase was observed 2h after treatment (9.7% after 3.0 microg of NA) and was still present until 6h when 1mg/kg was previous administrated.
SIGNIFICANCE
The results of the present study, beyond to confirm the cardioprotective action of pyridostigmine, suggest that liposomal pyridostigmine may be a potential therapeutic alternative to prevent cardiovascular disturbances resulting from sympathetic hyperactivity.
Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiotonic Agents; Electrocardiography; Heart Rate; Injections, Intravenous; Liposomes; Male; Norepinephrine; Particle Size; Pyridostigmine Bromide; Rats; Rats, Wistar; Sympathomimetics; Time Factors
PubMed: 19896489
DOI: 10.1016/j.lfs.2009.10.011 -
Aviation, Space, and Environmental... Jan 1992Five men underwent eight heat stress tests (HSTs) at 35 degrees C, each consisting of four 25-min treadmill walks (35% Vo2max), separated by 5-min rests, in four... (Comparative Study)
Comparative Study
Five men underwent eight heat stress tests (HSTs) at 35 degrees C, each consisting of four 25-min treadmill walks (35% Vo2max), separated by 5-min rests, in four conditions: 1) 20% relative humidity (rh), subjects euhydrated and drinking ad libitum; 2) 20% rh, euhydrated; 3) 75% rh, euhydrated; and 4) 20% rh, hypohydrated 3% of body weight. In Conditions 2-4 subjects drank during the walks to maintain their pre-HST weight. In each condition we tested subjects once after 30 mg pyridostigmine bromide (PB) by mouth and once after placebo. PB lowered heart rate a mean of 3 beats/min overall, most with hypohydration. PB did not significantly affect rectal temperature (Tre), but reduced the rise in Tre during hypohydrated exercise. In Condition 2, chest skin temperature decreased more during exercise with PB. PB had no significant effect on other skin temperatures, sweating, hematocrit, hemoglobin, total plasma protein, osmolality, ad libitum drinking, rate of O2 uptake, or subject ratings of temperature, discomfort, or exertion. PB thus had little effect on physiological responses to moderate exercise-heat stress.
Topics: Adult; Blood Circulation; Body Temperature Regulation; Cholinesterases; Exercise; Heart Rate; Hot Temperature; Humans; Male; Placebos; Pyridostigmine Bromide; Stress, Physiological; Sweating
PubMed: 1550532
DOI: No ID Found -
Toxicology 1991These studies were performed to evaluate the reproductive and developmental toxicity of pyridostigmine bromide (PB) in rats. Separate male and female...
These studies were performed to evaluate the reproductive and developmental toxicity of pyridostigmine bromide (PB) in rats. Separate male and female fertility/reproductive performance studies, a perinatal/postnatal study and a teratology study were conducted. Dose levels were sufficient to result in overt cholinergic tremors at the high dose in each study. PB did not affect male or female fertility/reproductive performance. Pups born to treated dams did show slight, transient decreases in body weight gain, apparently secondary to the nursing behavior of dams demonstrating overt tremors. PB did not result in an increase in visceral or skeletal malformations. A slight increase in delayed ossification and early resorption were seen at the highest dose tested and were considered secondary to maternal stress/toxicity.
Topics: Analysis of Variance; Animals; Female; Fertility; Growth; Male; Pyridostigmine Bromide; Rats; Rats, Inbred Strains; Reproduction; Teratogens; Tremor
PubMed: 1949052
DOI: 10.1016/0300-483x(91)90188-7