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Dysphagia Feb 2022Weak or absent peristalsis of the esophageal musculature is a common finding in ambulatory patients suffering from dysphagia and frequently associated with...
Weak or absent peristalsis of the esophageal musculature is a common finding in ambulatory patients suffering from dysphagia and frequently associated with gastroesophageal reflux. There is currently no pharmacologic intervention that reliably improves esophageal contractility in patients suffering from various esophageal motility disorders. Our objective was to evaluate the acute effects of pyridostigmine on high-resolution manometry parameters in patients suffering from dysphagia with evidence of esophageal dysmotility. Pyridostigmine is an acetylcholinesterase inhibitor which increases effective concentrations of acetylcholine at the neuromuscular junction of both striated and smooth muscle cells. We conducted a prospective crossover study of five patients with dysphagia and proven esophageal dysmotility. Three patients had baseline ineffective esophageal motility and two had achalasia. Patients underwent pharyngeal and esophageal manometry before and after pyridostigmine administration. The median distal contractile integral (DCI), a marker of esophageal contractile vigor, was significantly higher post pyridostigmine administration 3001 (1950.3-3703.2) mmHg × s × cm compared to pre-pyridostigmine DCI of 1229.9 (956.2-2100) mmHg × s × cm; P < 0.001. Pre-pyridostigmine 18/25 (72%) of the patient's swallows was peristaltic compared to 25/25 (100%) post-pyridostigmine; P < 0.005. No other pharyngeal or esophageal high-resolution manometry parameter differed significantly after pyridostigmine administration. The results of this pilot study demonstrate that pyridostigmine acutely improves esophageal contractile vigor in patients suffering from dysphagia with esophageal dysmotility. Further investigation with larger sample size, longer follow-up, side effect profile, and patient-reported outcome measures is still needed to determine the clinical usefulness of pyridostigmine in specific disorders of esophageal motility.
Topics: Acetylcholinesterase; Cross-Over Studies; Esophageal Motility Disorders; Humans; Manometry; Peristalsis; Pilot Projects; Prospective Studies; Pyridostigmine Bromide
PubMed: 33452552
DOI: 10.1007/s00455-020-10243-7 -
Journal of Environment and Health... 2017Several studies have implicated immune system disruption in the pathophysiology of GWI. In addition, alterations in brain structure and functioning have been associated...
Several studies have implicated immune system disruption in the pathophysiology of GWI. In addition, alterations in brain structure and functioning have been associated with specific exposures in theater, including pyridostigmine bromide and nerve gas agents. Recent studies conducted up to 25 years after the 1991 conflict have examined factors associated with the continuation or worsening of GWI. Drawing upon published studies of neural and immune system abnormalities in veterans with GWI, this paper proposes a model of GWI that takes into account neurologic and immunologic pathways, neuroimmune mechanisms of disease pathophysiology, individual predisposition due to sex and genetic background, and comorbid factors including neurological conditions such as neuritis/neuralgia and epilepsy that may occur along a continuum with GWI. The proposed neuroimmune model of GWI is likely to be useful for designing new research studies, clarifying factors involved in the continuation or worsening of GWI, and identifying biomarker screening algorithms for the illness. The proposed model goes beyond previously proposed frameworks for GWI by taking into account potential differences in risk based upon female male sex, time elapsed since exposure to neurotoxicants, duration and severity of illness, comorbid conditions, and genotype.
PubMed: 29862319
DOI: 10.15436/2378-6841.17.1665 -
Biomedical Chromatography : BMC Mar 2024The present study focuses on the development of a simple, rapid, specific, and stability-indicating HPLC method for the simultaneous analysis of pyridostigmine bromide...
Stability indicating reversed-phase-high-performance liquid chromatography method development and validation for pyridostigmine bromide and sodium benzoate in oral solution.
The present study focuses on the development of a simple, rapid, specific, and stability-indicating HPLC method for the simultaneous analysis of pyridostigmine bromide (PGB) and sodium benzoate (SBN) in oral liquid dosage forms. Analytical techniques should enhance sensitivity and specificity for the estimation of pharmaceutical drug products. Stress studies were conducted under various International Conference on Harmonization (ICH) conditions for evaluation. The further optimized HPLC method was validated in accordance with the current ICH guidelines. Chromatographic separation was accomplished using a mobile phase consisting of a 950:50 v/v ratio of perchloric acid buffer and acetonitrile as mobile phase-A, and 100% acetonitrile as mobile phase-B. The flow rate is 1.0 mL/min, and the injection volume is 20 μL. Detection of components was carried out at 220 nm for PGB and 228 nm for SBN. The validated HPLC method demonstrated high specificity, with linearity ranging between 24 and 72 μg/mL for PGB and 5.2-15.6 μg/mL for SBN. The correlation coefficient for both drugs exceeded 0.999. The method demonstrated high accuracy, exceeding 97%. In stress studies, PGB was found to be sensitive to alkaline stress conditions. The results reveal the successful applicability of the current method for the estimation of PGB and SBN in its marketed formulation, which can be reasonably inferred to assess other formulation systems.
Topics: Sodium Benzoate; Chromatography, High Pressure Liquid; Pyridostigmine Bromide; Acetonitriles; Chromatography, Reverse-Phase; Drug Stability
PubMed: 38081595
DOI: 10.1002/bmc.5800 -
Life Sciences Jan 2022To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War...
Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.
AIMS
To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI).
METHODS
Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin.
KEY FINDINGS
Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces.
SIGNIFICANCE
Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.
Topics: Animals; Biomarkers; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Dysbiosis; Endotoxemia; Fatigue; Gastrointestinal Microbiome; Gene Expression Profiling; Gene Expression Regulation; Gliosis; Male; Mice; Mice, Inbred C57BL; Neuralgia; Neuroinflammatory Diseases; Persian Gulf Syndrome; Physical Conditioning, Animal; Pyridostigmine Bromide
PubMed: 34801513
DOI: 10.1016/j.lfs.2021.120153 -
Minerva Ginecologica Feb 2020Myasthaenia gravis (MG) is the most common disease of the neuromuscular junction; clinical presentation of the disease includes a variety of symptoms, the most frequent...
INTRODUCTION
Myasthaenia gravis (MG) is the most common disease of the neuromuscular junction; clinical presentation of the disease includes a variety of symptoms, the most frequent beign the only ocular muscles involvement, to the generalized myasthenic crisis with diaphragmatic impairment and respiratory insufficiency. It is most common in women between 20 ad 40 years.
EVIDENCE ACQUISITION
We performed a comprehensive search of relevant studies from January1990 to Dicember 2019 to ensure all possible studies were captured. A systematic search of Pubmed databases was conducted.
EVIDENCE SYNTHESIS
Pregnancy has an unpredictable and variable effect on the clinical course of MG; however, a stable disease before is likely not to relapse during pregnancy. exacerbations can still occur more often during the first trimester and the post partum period. The transplacental passage of antibodies results in a neonatal transient disease, whereas the major concern is related to foetal malformations such as fetal arthrogryposis and polyhydramnios. The overall neonatal outcome described in literature is variable, perinatal mortality in women with MG is generally the same as non affected patients, although in one study the risk of premature rupture of the membranes was higher. Treatment of MG in pregnangncy includes pyridostigmine and corticosteroids, although the latter have been associated with higher risk of cleft palate, premature rupture of the membranes and preterm delivery. These drugs appear also to be safe in breastfeeding. In MG patients spontaneous vaginal delivery should be encouraged, for surgery could cause acute worsening of myasthenic symptoms; also an accurate anesthesiological evaluation must be performed prior to both general and local anesthesia due to increased risk of complications.
CONCLUSIONS
Most of the myasthenic women could have uneventful pregnancy with good obstetrical outcomes, both for mother and neonate. However, a careful planning of pregnancy and multidisciplinary team approach, composed by neurologists, obstetricians, neonatologists and anesthesiologists, is required to manage these pregnancies.
Topics: Adrenal Cortex Hormones; Arthrogryposis; Breast Feeding; Cholinesterase Inhibitors; Cleft Palate; Congenital Abnormalities; Delivery, Obstetric; Disease Progression; Female; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Myasthenia Gravis; Patient Care Team; Perinatal Mortality; Polyhydramnios; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Pyridostigmine Bromide; Recurrence
PubMed: 32153161
DOI: 10.23736/S0026-4784.20.04505-0 -
Hypertension (Dallas, Tex. : 1979) Jan 2019Patients with autonomic failure are characterized by disabling orthostatic hypotension because of impaired sympathetic activity, but even severely affected patients have... (Clinical Trial)
Clinical Trial
Patients with autonomic failure are characterized by disabling orthostatic hypotension because of impaired sympathetic activity, but even severely affected patients have residual sympathetic tone which can be harnessed for their treatment. For example, norepinephrine transporter blockade with atomoxetine raises blood pressure (BP) in autonomic failure patients by increasing synaptic norepinephrine concentrations; acetylcholinesterase inhibition with pyridostigmine increases BP by facilitating ganglionic cholinergic neurotransmission to increase sympathetic outflow. We tested the hypothesis that pyridostigmine will potentiate the pressor effect of atomoxetine and improve orthostatic tolerance and symptoms in patients with severe autonomic failure. Twelve patients received a single oral dose of either placebo, pyridostigmine 60 mg, atomoxetine 18 mg or the combination on separate days in a single blind, crossover study. BP was assessed seated and standing before and 1-hour postdrug. In these severely affected patients, neither pyridostigmine nor atomoxetine improved BP or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated BP in a synergistic manner (133±9/80±4 versus 107±6/66±4 mm Hg for placebo, 105±5/67±3 mm Hg for atomoxetine, and 99±6/64±4 mm Hg for pyridostigmine; P<0.001); the maximal increase in seated BP with the combination was 33±8/18±3 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement of orthostatic tolerance and symptoms. In conclusion, the combination pyridostigmine and atomoxetine had a synergistic effect on seated BP which was associated with improvement in orthostatic tolerance and symptoms. This pharmacological approach could be useful in patients with severe autonomic failure but further safety and long-term efficacy studies are needed.
Topics: Adult; Atomoxetine Hydrochloride; Autonomic Nervous System Diseases; Blood Pressure; Blood Pressure Determination; Cross-Over Studies; Drug Monitoring; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypotension, Orthostatic; Male; Pyridostigmine Bromide; Single-Blind Method; Treatment Outcome; Vasoconstrictor Agents
PubMed: 30571543
DOI: 10.1161/HYPERTENSIONAHA.118.11790 -
Neurotoxicology Sep 2020Shortly after the Gulf War in 1990-1991, service men and women began reporting multiple symptoms ranging from persistent headaches, widespread pain, chronic fatigue,... (Review)
Review
Shortly after the Gulf War in 1990-1991, service men and women began reporting multiple symptoms ranging from persistent headaches, widespread pain, chronic fatigue, cognitive dysfunction, mood dysregulation, gastrointestinal issues, skin abnormalities, and respiratory problems. This prompted the Centers for Disease Control and Prevention (CDC) to initially classify the disorder as chronic multi-symptom illness (CMI), where it later became known as Gulf War Illness (GWI). Researchers and healthcare professionals since the early 1990s have been working extensively on alleviating the symptoms expressed in GWI as well as attempting to understand the mechanisms behind this illness. Scientific literature as well as reports from GWI veterans indicate that the toxic exposures during deployment may be responsible for the symptoms. These toxic exposures potentially include nerve agents, pyridostigmine bromide pills, pesticides, munitions with depleted uranium, and burning oil well fires. GWI currently affects 25-32 % of the 697,000 American troops who were stationed overseas during the short conflict. The purpose of this paper is to review the literature on neurotoxic exposures in Gulf War Illness, to explain how these exposures may lead to glutamate excitotoxicity, which has been implicated in the majority of the symptoms characterizing the illness, and to propose a novel treatment option for GWI.
Topics: Animals; Brain; Glutamic Acid; Humans; Neurotoxicity Syndromes; Oxidative Stress; Persian Gulf Syndrome; Risk Factors; Up-Regulation; Veterans Health
PubMed: 32585289
DOI: 10.1016/j.neuro.2020.06.008 -
Clinical Neurophysiology : Official... Oct 2023To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA).
METHODS
We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively.
RESULTS
In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes.
CONCLUSIONS
sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance.
SIGNIFICANCE
Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.
Topics: Humans; Pyridostigmine Bromide; Muscular Atrophy, Spinal; Electromyography; Muscles; Muscle Fatigue; Muscle, Skeletal
PubMed: 37595479
DOI: 10.1016/j.clinph.2023.06.024 -
Neurology Sep 2017To evaluate the long-term (for up to 3 months) efficacy and safety of single or combined therapy with midodrine and pyridostigmine for neurogenic orthostatic hypotension... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To evaluate the long-term (for up to 3 months) efficacy and safety of single or combined therapy with midodrine and pyridostigmine for neurogenic orthostatic hypotension (OH).
METHODS
This was a randomized, open-label clinical trial. In total, 87 patients with symptomatic neurogenic OH were enrolled and randomized to receive 1 of 3 treatments: midodrine only, pyridostigmine only, or midodrine + pyridostigmine. The patients were followed up at 1 and 3 months after treatment. The primary outcome measures were improvement in orthostatic blood pressure (BP) drop at 3 months. Secondary endpoints were improvement of the orthostatic BP drop at 1 month and amelioration of the questionnaire score evaluating OH-associated symptoms.
RESULTS
Orthostatic systolic and diastolic BP drops improved significantly at 3 months after treatment in all treatment groups. Orthostatic symptoms were significantly ameliorated during the 3-month treatment, and the symptom severity was as follows: midodrine only < midodrine + pyridostigmine < pyridostigmine only group. Mild to moderate adverse events were reported by 11.5% of the patients.
CONCLUSIONS
Single or combination treatment with midodrine and pyridostigmine was effective and safe in patients with OH for up to 3 months. Midodrine was better than pyridostigmine at improving OH-related symptoms.
CLINICALTRIALSGOV IDENTIFIER
NCT02308124.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that for patients with neurogenic OH, long-term treatment with midodrine alone, pyridostigmine alone, or both midodrine and pyridostigmine is safe and has similar effects in improving orthostatic BP drop up to 3 months.
Topics: Adrenergic alpha-1 Receptor Agonists; Blood Pressure; Cholinesterase Inhibitors; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypotension, Orthostatic; Male; Middle Aged; Midodrine; Pyridostigmine Bromide; Self Report; Time Factors; Treatment Outcome; Vasoconstrictor Agents
PubMed: 28794253
DOI: 10.1212/WNL.0000000000004340 -
Journal of the American Animal Hospital... Sep 2023Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine...
Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine receptor. Megaesophagus is the most common focal form of MG. Although exacerbation of MG has been associated with the use of fluoroquinolones in humans, it has not been previously described in dogs. The medical records of 46 dogs diagnosed with MG based on acetylcholine receptor antibody testing from 1997 to 2021 were retrospectively evaluated to identify any dogs who demonstrated exacerbation of MG after the administration of a fluoroquinolone. Exacerbation of MG, from focal to generalized, occurred in a median of 4.5 days after initiation of fluoroquinolone therapy in six dogs. In addition, one dog with generalized MG and megaesophagus developed pyridostigmine resistance subsequent to fluoroquinolone therapy. Marked improvement in generalized weakness was reported 36 hr after discontinuation of fluoroquinolone therapy alone in one dog and in combination with pyridostigmine in two dogs. Fluoroquinolone therapy was never stopped in three dogs who were euthanized because of severe weakness and one dog who died of respiratory arrest.
Topics: Humans; Dogs; Animals; Pyridostigmine Bromide; Esophageal Achalasia; Retrospective Studies; Dog Diseases; Myasthenia Gravis; Fluoroquinolones; Receptors, Cholinergic
PubMed: 37708471
DOI: 10.5326/JAAHA-MS-7353