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The Journal of International Medical... Jul 2022Myasthenia gravis (MG) is an acquired autoimmune disease. Its clinical manifestations comprise ptosis, diplopia, dysarthria, dysphagia, limb weakness, and in severe... (Review)
Review
Myasthenia gravis (MG) is an acquired autoimmune disease. Its clinical manifestations comprise ptosis, diplopia, dysarthria, dysphagia, limb weakness, and in severe cases, respiratory muscle involvement. Dysarthria as an exclusive initial and primary complaint in MG is rare and seldom reported. In this paper, we report a case of type IIIb MG with isolated dysarthria as the only clinical manifestation and we review the relevant literature. The patient was a 62-year-old man who presented with episodes of slurred speech for 20 days that had worsened in the previous 9 days. His medical history comprised hypertension, diabetes mellitus, and coronary heart disease. The initial diagnosis on admission was transient ischemic attack. Careful re-examination of the patient's history revealed that his symptoms mainly involved increasingly worse slurred speech episodes without drinking or swallowing difficulties, and no significant improvement with rest was observed. Electromyography and autoantibody profiling led to a diagnosis of type IIIb MG. His symptoms improved after the oral administration of pyridostigmine bromide 60 mg. Laryngeal MG is important to differentiate from stroke. It is necessary to perform a computerized voice analysis when encountering patients with atypical symptoms of MG.
Topics: Blepharoptosis; Deglutition Disorders; Dysarthria; Humans; Male; Middle Aged; Myasthenia Gravis; Pyridostigmine Bromide
PubMed: 35915860
DOI: 10.1177/03000605221109395 -
Biochimica Et Biophysica Acta.... Apr 2018Obesity, a major contributor to the development of cardiovascular diseases, is associated with an autonomic imbalance characterized by sympathetic hyperactivity and...
Obesity, a major contributor to the development of cardiovascular diseases, is associated with an autonomic imbalance characterized by sympathetic hyperactivity and diminished vagal activity. Vagal activation plays important roles in weight loss and improvement of cardiac function. Pyridostigmine is a reversible acetylcholinesterase inhibitor, but whether it ameliorates cardiac lipid accumulation and cardiac remodeling in rats fed a high-fat diet has not been determined. This study investigated the effects of pyridostigmine on high-fat diet-induced cardiac dysfunction and explored the potential mechanisms. Rats were fed a normal or high-fat diet and treated with pyridostigmine. Vagal discharge was evaluated using the BL-420S system, and cardiac function by echocardiograms. Lipid deposition and cardiac remodeling were determined histologically. Lipid utility was assessed by qPCR. A high-fat diet led to a significant reduction in vagal discharge and lipid utility and a marked increase in lipid accumulation, cardiac remodeling, and cardiac dysfunction. Pyridostigmine improved vagal activity and lipid metabolism disorder and cardiac remodeling, accompanied by an improvement of cardiac function in high-fat diet-fed rats. An increase in the browning of white adipose tissue in pyridostigmine-treated rats was also observed and linked to the expression of UCP-1 and CIDEA. Additionally, pyridostigmine facilitated activation of brown adipose tissue via activation of the SIRT-1/AMPK/PGC-1α pathway. In conclusion, a high-fat diet resulted in cardiac lipid accumulation, cardiac remodeling, and a significant decrease in vagal discharge. Pyridostigmine ameliorated cardiomyopathy, an effect related to reduced cardiac lipid accumulation, and facilitated the browning of white adipose tissue while activating brown adipose tissue.
Topics: Adipose Tissue; Animals; Cardiomyopathies; Dietary Fats; Lipid Metabolism; Male; Muscle Proteins; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Signal Transduction; Vagus Nerve
PubMed: 29309922
DOI: 10.1016/j.bbadis.2018.01.006 -
Anesthesiology Nov 1984The authors sought to determine whether the metabolites of neostigmine and pyridostigmine contribute to antagonism of neuromuscular blockade. Accordingly, the...
The authors sought to determine whether the metabolites of neostigmine and pyridostigmine contribute to antagonism of neuromuscular blockade. Accordingly, the dose-response relationship, onset and duration of action (n = 60), and pharmacokinetics (n = 22) of neostigmine, pyridostigmine, their metabolites 3-hydroxyphenyltrimethylammonium (PTMA) and 3-hydroxy-N-methylpyridinium (MP), and edrophonium were determined in dogs anesthetized with sodium pentobarbital. The force of contraction of the anterior tibialis muscle was maintained at constant 90% depression by infusing pancuronium. Then, a single iv bolus dose of one of the drugs under study was injected while the pancuronium infusion was continued. Venous blood, urine, and bile were sampled for four hours. Concentrations were determined by liquid chromatographic techniques; a three-compartment pharmacokinetic model was fitted to the serum concentration data. The doses producing 50% antagonism were 6.5, 52, 69, and 40 micrograms/kg for neostigmine, pyridostigmine, edrophonium, and PTMA, respectively. MP was inactive as an antagonist. By comparing approximately equipotent doses, time to peak antagonism (onset) and until 30% of peak antagonism remained (duration) were shorter for both edrophonium and PTMA than for neostigmine and pyridostigmine. Slow distribution and elimination half-lives, volume of distribution at steady state (VDss), and total plasma clearance (Cl) were similar for the drugs except for a smaller Vdss and lower Cl for MP. More than 60% of the dose of each drug was recovered unchanged from urine; less than 1% was recovered from bile. Less than 10% of the dose of neostigmine was recovered as PTMA.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Dogs; Dose-Response Relationship, Drug; Edrophonium; Kinetics; Neostigmine; Neuromuscular Blocking Agents; Pyridinium Compounds; Pyridostigmine Bromide; Quaternary Ammonium Compounds
PubMed: 6149707
DOI: 10.1097/00000542-198411000-00010 -
Cardiovascular Therapeutics Oct 2017Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease.
AIM
This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease.
METHOD
Following a double-blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50±2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA).
RESULTS
Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940-3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033).
CONCLUSION
Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted.
Topics: Administration, Oral; Anti-Arrhythmia Agents; Asymptomatic Diseases; Brazil; Chagas Cardiomyopathy; Cholinesterase Inhibitors; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Male; Middle Aged; Pyridostigmine Bromide; Tachycardia, Ventricular; Time Factors; Treatment Outcome; Ventricular Premature Complexes
PubMed: 28715142
DOI: 10.1111/1755-5922.12288 -
Molecular Medicine (Cambridge, Mass.) Nov 2022Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19.
METHODS
We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described.
RESULTS
We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively).
CONCLUSION
Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.
Topics: Adult; Male; Humans; Middle Aged; Female; Pyridostigmine Bromide; SARS-CoV-2; Respiration, Artificial; Inflammation; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 36348276
DOI: 10.1186/s10020-022-00553-x -
Clinical and Experimental Pharmacology... Aug 2017Heart rate recovery (HRR) describes the rapid deceleration of heart rate after strenuous exercise and is an indicator of parasympathetic tone. A reduction in...
Heart rate recovery (HRR) describes the rapid deceleration of heart rate after strenuous exercise and is an indicator of parasympathetic tone. A reduction in parasympathetic tone occurs in patients with congestive heart failure, resulting in prolonged HRR. Acetylcholinesterase inhibitors, such as pyridostigmine, can enhance parasympathetic tone by increasing cholinergic input to the heart. The objective of this study was to develop a rodent model of HRR to test the hypothesis that subacute pyridostigmine administration decreases cholinesterase activity and accelerates HRR in rats. Ten days after implantation of radiotelemetry transmitters, male Sprague Dawley rats were randomized to control (CTL) or treated (PYR; 0.14 mg/mL pyridostigmine in the drinking water, 29 days) groups. Rats were exercised on a treadmill to record HRR, and blood samples were collected on days 0, 7, 14, and 28 of pyridostigmine administration. Total cholinesterase and acetylcholinesterase (AChE) activity in plasma was decreased by 32%-43% and 57%-80%, respectively, in PYR rats on days 7-28, while plasma butyrylcholinesterase activity did not significantly change. AChE activity in red blood cells was markedly reduced by 64%-66%. HRR recorded 1 minute after exercise was higher in the PYR group on days 7, 14 and 28, and on day 7 when HRR was estimated at 3 and 5 minutes. Autonomic tone was evaluated pharmacologically using sequential administration of muscarinic (atropine) and adrenergic (propranolol) blockers. Parasympathetic tone was increased in PYR rats as compared with the CTL group. These data support the study hypothesis that subacute pyridostigmine administration enhances HRR by increasing cardiac parasympathetic tone.
Topics: Animals; Cholinesterase Inhibitors; Heart; Heart Rate; Male; Parasympathetic Nervous System; Physical Conditioning, Animal; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 28440910
DOI: 10.1111/1440-1681.12773 -
Child's Nervous System : ChNS :... Oct 2022Achondroplasia is the commonest skeletal dysplasia of autosomal dominant inheritance caused by "gain of function" mutations in the fibroblast growth factor receptor 3... (Review)
Review
BACKGROUND
Achondroplasia is the commonest skeletal dysplasia of autosomal dominant inheritance caused by "gain of function" mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum compression due to accelerated ossification and spinal canal stenosis secondary to reduced interpedicular distance is a hallmark of achondroplasia, driven by G380R nucleotide pair substitution. In severe cases, limb weakness and neurogenic claudication will require surgical decompression. Rarely, a neurological condition may mimic the compressive spinal dysfunction and therefore, non-surgical causes must also be considered in cases of acute neurological deterioration in children with achondroplasia. Myasthenia gravis (MG) is an autoimmune condition resulting in fatigable muscle weakness. There are no reported cases of myasthenia gravis in achondroplasia in the literature.
RESULTS
We report a child with achondroplasia scheduled for decompressive surgery for severe lumbar canal stenosis presenting with neurological claudication and knee weakness. While waiting for surgery during the COVID-19 pandemic, she developed generalized fatigability and severe weakness raising concerns of acute worsening of cord compression. Urgent investigations ruled out spinal cord compression but identified an unexpected concurrent myasthenia gravis with positive antibodies to acetylcholine receptors. The surgical intervention was postponed averting the potential risk of life-threatening anaesthetic complications. She was successfully managed with a combination of pyridostigmine, steroids, azathioprine, and plasma exchange.
CONCLUSION
We report the first case of myasthenia gravis in achondroplasia and review implications in the management.
Topics: Achondroplasia; Anesthetics; Azathioprine; COVID-19; Child; Constriction, Pathologic; Female; Humans; Myasthenia Gravis; Nucleotides; Pandemics; Pyridostigmine Bromide; Receptor, Fibroblast Growth Factor, Type 3; Receptors, Cholinergic; Spinal Cord Compression
PubMed: 35908138
DOI: 10.1007/s00381-022-05617-1 -
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 -
Neurotoxicology Mar 2020Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans...
Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6 J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethyl-methylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-HT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.
Topics: Amino Sugars; Animals; Biogenic Monoamines; Brain; Brain Chemistry; DEET; Disease Models, Animal; Encephalitis; Humans; Immunotherapy; Male; Mice, Inbred C57BL; Permethrin; Persian Gulf Syndrome; Pesticides; Polysaccharides; Pyridostigmine Bromide; Spleen
PubMed: 31866310
DOI: 10.1016/j.neuro.2019.12.012 -
Proceedings of the National Academy of... Sep 2006
Topics: Acetylcholine; Acetylcholinesterase; Animals; Atropine; Benzodiazepines; Blood-Brain Barrier; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Drug Therapy, Combination; Galantamine; Guinea Pigs; Insecticides; Neurons; Neurotransmitter Agents; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Paraoxon; Pralidoxime Compounds; Pyridostigmine Bromide; Receptors, Cholinergic; Receptors, Muscarinic; Sarin; Seizures; Soman; Time Factors
PubMed: 16938861
DOI: 10.1073/pnas.0606052103