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The Turkish Journal of Pediatrics 2023Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. Allergic...
BACKGROUND
Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. Allergic reaction to pyridostigmine bromide is rare. In the literature, no allergic reaction to pyridostigmine bromide has been reported in the pediatric population.
CASE
A 12-year-old female patient diagnosed with myasthenia gravis consulted our clinic with the complaint of urticaria due to pyridostigmine bromide. The oral challenge test performed with pyridostigmine bromide was positive. As the patient was required to be continue pyridostigmine bromide with no suitable alternatives, it was decided that the patient had to be desensitized to pyridostigmine. During and after the desensitization protocol, no reaction was observed.
CONCLUSIONS
In this report, a successful desensitization protocol for pyridostigmine bromide in a child with myasthenia gravis is discussed.
Topics: Child; Female; Humans; Pyridostigmine Bromide; Acetylcholinesterase; Myasthenia Gravis; Cholinesterase Inhibitors; Muscle Weakness; Hypersensitivity
PubMed: 37114698
DOI: 10.24953/turkjped.2022.386 -
Brain, Behavior, and Immunity Jul 2020Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of...
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HC, n = 8), were examined using integrated [C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HC subgroup, veterans with GWI demonstrated widespread cortical elevations in [C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.
Topics: Astrocytes; Gulf War; Humans; Persian Gulf Syndrome; Pyridostigmine Bromide; Receptors, GABA; Veterans
PubMed: 32027960
DOI: 10.1016/j.bbi.2020.01.020 -
European Journal of Neurology Apr 2017Evidence for effective treatment options for orthostatic hypotension (OH) in Parkinson's disease (PD) is scarce. Elevation of cholinergic tone with pyridostigmine... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND PURPOSE
Evidence for effective treatment options for orthostatic hypotension (OH) in Parkinson's disease (PD) is scarce. Elevation of cholinergic tone with pyridostigmine bromide has been reported as a way to improve blood pressure (bp) regulation in neurogenic hypotension without causing supine hypertension.
METHODS
This was a double-centre, double-blind, randomized, active-control, crossover, phase II non-inferiority trial of pyridostigmine bromide for OH in PD (clinicaltrials.gov NCT01993680). Patients with confirmed OH were randomized to 14 days 3 × 60 mg/day pyridostigmine bromide or 1 × 0.2 mg/day fludrocortisone before crossover. Outcome was measured by peripheral and central bp monitoring during the Schellong manoeuvre and questionnaires.
RESULTS
Thirteen participants were enrolled between April 2013 and April 2015 with nine participants completing each trial arm. Repeated measures comparison showed a significant 37% improvement with fludrocortisone for the primary outcome diastolic bp drop on orthostatic challenge (baseline 22.9 ± 13.6 vs. pyridostigmine bromide 22.1 ± 17.0 vs. fludrocortisone 14.0 ± 12.6 mmHg; P = 0.04), whilst pyridostigmine bromide had no effect. Fludrocortisone caused an 11% peripheral systolic supine bp rise (baseline 128.4 ± 12.8 vs. pyridostigmine bromide 130.4 ± 18.3 vs. fludrocortisone 143.2 ± 10.1 mmHg; P = 0.01) but no central mean arterial supine bp rise (baseline 107.2 ± 7.8 vs. pyridostigmine bromide 97.0 ± 12.0 vs. fludrocortisone 107.3 ± 6.3 mmHg; P = 0.047). Subjective OH severity, motor score and quality of life remained unchanged by both study interventions.
CONCLUSIONS
Pyridostigmine bromide is inferior to fludrocortisone in the treatment of OH in PD. This trial provides first objective evidence of the efficacy of 0.2 mg/day fludrocortisone for OH in PD, causing minor peripheral but no central supine hypertension. In addition to peripheral bp, future trials should include central bp measurements, known to correlate more closely with cardiovascular risk.
Topics: Aged; Blood Pressure; Cholinesterase Inhibitors; Cross-Over Studies; Double-Blind Method; Female; Fludrocortisone; Humans; Hypotension, Orthostatic; Male; Middle Aged; Parkinson Disease; Pyridostigmine Bromide; Quality of Life; Risk Factors; Treatment Outcome
PubMed: 28224720
DOI: 10.1111/ene.13260 -
Journal of Integrative Neuroscience Jun 2020Tolosa-Hunt syndrome is an uncommon disease that exhibits unilateral periorbital pain or headache, accompanied by cranial nerve palsies. Myasthenia gravis is an acquired...
Tolosa-Hunt syndrome is an uncommon disease that exhibits unilateral periorbital pain or headache, accompanied by cranial nerve palsies. Myasthenia gravis is an acquired immune system disease involving the neuromuscular junction. One rare case of Tolosa-Hunt syndrome combined with ocular myasthenia gravis had been reported in the literature, but not general myasthenia gravis. We present a patient with a probable coincidence of Tolosa-Hunt syndrome and general myasthenia gravis. A 63-year-old male exhibited episodes of unilateral headache with double vision, bilateral ptosis, vision decrease in the left eye and left facial hypoesthesia, muscle weakness in limbs and neck. The muscle weakness was fluctuating and could be relieved by rest. Blood analysis, cranial magnetic resonance imaging, magnetic resonance angiography/venogram) and orbit/mediastinum computed tomography demonstrated no abnormalities. Serum myasthenia gravis related antibodies detection showed positive titin- antibodies and ryanodine receptor antibodies. Corticosteroid and pyridostigmine bromide treatments were effective. Each of the patient's symptoms had almost disappeared at the third-month follow-up. We speculate on the etiology of Tolosa-Hunt syndrome with general myasthenia.
Topics: Adrenal Cortex Hormones; Cholinesterase Inhibitors; Humans; Male; Middle Aged; Myasthenia Gravis; Neuroimaging; Tolosa-Hunt Syndrome
PubMed: 32706200
DOI: 10.31083/j.jin.2020.02.1254 -
Scientific Reports Aug 2021We investigated hemodynamic, cardiac morphofunctional, and cardiovascular autonomic adaptations in spontaneously hypertensive rats (SHRs) after aerobic physical training...
Effects of chronic cholinergic stimulation associated with aerobic physical training on cardiac morphofunctional and autonomic parameters in spontaneously hypertensive rats.
We investigated hemodynamic, cardiac morphofunctional, and cardiovascular autonomic adaptations in spontaneously hypertensive rats (SHRs) after aerobic physical training associated with chronic cholinergic stimulation. Fifty-four SHRs were divided into two groups: trained and untrained. Each group was further subdivided into three smaller groups: vehicle, treated with pyridostigmine bromide at 5 mg/kg/day, and treated with pyridostigmine bromide at 15 mg/kg/day. The following protocols were assessed: echocardiography, autonomic double pharmacological blockade, heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS). Physical training and pyridostigmine bromide reduced BP and HR and increased vagal participation in cardiac autonomic tonic balance. The associated responses were then potentialized. Treatment with pyridostigmine bromide increased HRV oscillation of both low frequency (LF: 0.2-0.75 Hz) and high frequency (HF: 0.75-3 Hz). However, the association with physical training attenuated HF oscillations. Additionally, treatment with pyridostigmine bromide also increased LF oscillations of BPV. Both treatment groups promoted morphofunctional adaptations, and associated increased ejection volume, ejection fraction, cardiac output, and cardiac index. In conclusion, the association of pyridostigmine bromide and physical training promoted greater benefits in hemodynamic parameters and increased vagal influence on cardiac autonomic tonic balance. Nonetheless, treatment with pyridostigmine bromide alone seems to negatively affect BPV and the association of treatment negatively influences HRV.
Topics: Animals; Blood Pressure; Cardiac Output; Cholinesterase Inhibitors; Heart; Hypertension; Physical Conditioning, Animal; Pyridostigmine Bromide; Rats; Rats, Inbred SHR; Vagus Nerve
PubMed: 34433865
DOI: 10.1038/s41598-021-96505-2 -
Environmental Health : a Global Access... Jul 2023Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War...
INTRODUCTION
Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI.
METHODS
Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria.
RESULTS
Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria.
CONCLUSION
These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.
Topics: Persian Gulf Syndrome; Humans; Apolipoproteins E; Veterans; Pyridostigmine Bromide; Pesticides; Hazardous Substances; Male; Female; Middle Aged; Smoke
PubMed: 37415220
DOI: 10.1186/s12940-023-01002-w -
Biological & Pharmaceutical Bulletin 2017To elucidate the mechanism whereby distigmine, an underactive bladder remedy, potentiates urinary bladder contractions long-lastingly, the inhibition of recombinant...
To elucidate the mechanism whereby distigmine, an underactive bladder remedy, potentiates urinary bladder contractions long-lastingly, the inhibition of recombinant human acetylcholinesterase (rhAChE) by distigmine was investigated. A centrifugal ultrafiltration device, Nanosep 10K, was used to separate rhAChE and a bound inhibitor from an unbound inhibitor, reaction substrate, and reaction product. This allowed the same aliquot of rhAChE to be repeatedly assayed for up to 48 h to confirm the long-lasting binding of an inhibitor. Cholinesterase (ChE) inhibitors, distigmine, pyridostigmine, neostigmine, and ambenonium, were tested. The dissociation rate constant (k) and dissociation half-life (t) of each inhibitor were determined based on the changes in rhAChE activity. Within 2-4 h after removing pyridostigmine, neostigmine, or ambenonium, the rhAChE activity was restored to the control levels. The k values for pyridostigmine, neostigmine, and ambenonium were calculated to be 0.51±0.05, 0.66±0.03, and 1.41±0.08 h, and the t values were calculated to be 1.36, 1.05, and 0.49 h, respectively. With distigmine, the rhAChE activity initially dropped to 17% of that in the control and then slowly recovered to only 50% by 48 h after drug removal. The k and t values of distigmine were calculated to be 0.012±0.001 h and 57.8 h, respectively. Based on the t values, distigmine was judged to dissociate from acetylcholinesterase (AChE) 40-120-fold slower than the other ChE inhibitors did. This may explain the long-lasting potentiation of urinary bladder contractions and motility by distigmine as a treatment for an underactive bladder.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Humans; Pyridinium Compounds; Recombinant Proteins
PubMed: 28966245
DOI: 10.1248/bpb.b17-00351 -
Medicine Jun 2021To investigate clinical features and diagnosis process of ocular myasthenia gravis (OMG) in ophthalmology department.A total of 36 patients with ptosis or diplopia who... (Observational Study)
Observational Study
To investigate clinical features and diagnosis process of ocular myasthenia gravis (OMG) in ophthalmology department.A total of 36 patients with ptosis or diplopia who had follow-up for at least 3 months between March 2016 and December 2019 were included in this study. Clinical symptoms of patients and the test results were analyzed. According to the positivity of serologic test, these patients were divided into 2 groups (confirmed OMG and possible OMG with relief of symptoms after antimyasthenic treatment) for comparison.Ptosis was present in 12 (33.33%) patients, diplopia was present in 14 (38.89%) patients, and both ptosis and diplopia were present in 10 (27.78%) patients. Acetylcholine receptor auto-antibody (AchR Ab) was positive in 14 (38.89%) of 36 patients and ice test was positive in 15 (71.43%) of 21 patients with ptosis. Unequivocal response to pyridostigmine was observed in 31 (86.11%) patients. For seropositive cases, AchR Ab titer was significantly higher in the group with 2 clinical symptoms than that in the 1 clinical symptom (P = .011).This study presents the usefulness and diagnostic validity of antimyasthenic treatment for OMG, especially seronegative OMG, with detailed symptom analysis.
Topics: Adult; Aged; Autoantibodies; Blepharoptosis; Cholinesterase Inhibitors; Diagnosis, Differential; Diplopia; Feasibility Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myasthenia Gravis; Oculomotor Muscles; Pyridostigmine Bromide; Receptors, Cholinergic; Treatment Outcome; Young Adult
PubMed: 34160444
DOI: 10.1097/MD.0000000000026457 -
PloS One 2021Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and...
Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and cardiovascular disease. Since cholinergic deficiency is closely linked with Alzheimer's disease (AD) progression, acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with AD. However, there is a heterogenous response to these drugs and mostly the subjects do not respond to the treatment. Gene polymorphism, the simultaneous occurrence of two or more discontinuous alleles in a population, could be one of the important factors for this. Hence, we hypothesized that PON2 and its polymorphic forms may be hydrolyzing the AChEIs differently, and thus, different patients respond differently. To investigate this, two AChEIs, donepezil hydrochloride (DHC) and pyridostigmine bromide (PB), were selected. Human PON2 wildtype gene and four mutants, two catalytic sites, and two polymorphic sites were cloned, recombinantly expressed, and purified for in vitro analysis. Enzyme activity and AChE activity were measured to quantitate the amount of DHC and PB hydrolyzed by the wildtype and the mutant proteins. Herein, PON2 esterase activity and AChE inhibitor efficiency were found to be inversely related. A significant difference in enzyme activity of the catalytic site mutants was observed as compared to the wildtype, and subsequent AChE activity showed that esterase activity of PON2 is responsible for the hydrolysis of DHC and PB. Interestingly, PON2 polymorphic site mutants showed increased esterase activity; therefore, this could be the reason for the ineffectiveness of the drugs. Thus, our data suggested that the esterase activity of PON2 was mainly responsible for the hydrolysis of AChEI, DHC, and PB, and that might be responsible for the variation in individual response to AChEI therapy.
Topics: Alzheimer Disease; Aryldialkylphosphatase; Cholinesterase Inhibitors; Donepezil; Humans; Mutation; Protein Binding; Pyridostigmine Bromide
PubMed: 34714861
DOI: 10.1371/journal.pone.0258879 -
Life Sciences Nov 2021Approximately 30% of the nearly 700,000 Veterans who were deployed to the Gulf War from 1990 to 1991 have reported experiencing a variety of symptoms including...
AIMS
Approximately 30% of the nearly 700,000 Veterans who were deployed to the Gulf War from 1990 to 1991 have reported experiencing a variety of symptoms including difficulties with learning and memory, depression and anxiety, and increased incidence of neurodegenerative diseases. Combined toxicant exposure to acetylcholinesterase (AChE) inhibitors has been studied extensively as a likely risk factor. In this study, we modeled Gulf War exposure in male C57Bl/6J mice with simultaneous administration of three chemicals implicated as exposure hazards for Gulf War Veterans: pyridostigmine bromide, the anti-sarin prophylactic; chlorpyrifos, an organophosphate insecticide; and the repellant N,N-diethyl-m-toluamide (DEET).
MAIN METHODS
Following two weeks of daily exposure, we examined changes in gene expression by whole transcriptome sequencing (RNA-Seq) with hippocampal isolates. Hippocampal-associated spatial memory was assessed with a Y-maze task. We hypothesized that genes important for neuronal health become dysregulated by toxicant-induced damage and that these detrimental inflammatory gene expression profiles could lead to chronic neurodegeneration.
KEY FINDINGS
We found dysregulation of genes indicating a pro-inflammatory response and downregulation of genes associated with neuronal health and several important immediate early genes (IEGs), including Arc and Egr1, which were both reduced approximately 1.5-fold. Mice exposed to PB + CPF + DEET displayed a 1.6-fold reduction in preference for the novel arm, indicating impaired spatial memory.
SIGNIFICANCE
Differentially expressed genes observed at an acute timepoint may provide insight into the pathophysiology of Gulf War Illness and further explanations for chronic neurodegeneration after toxicant exposure.
Topics: Animals; Down-Regulation; Environmental Pollutants; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Gulf War; Hippocampus; Male; Maze Learning; Mice, Inbred C57BL; Spatial Memory; Up-Regulation; Mice
PubMed: 34293396
DOI: 10.1016/j.lfs.2021.119845