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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 -
Medicina (Kaunas, Lithuania) Apr 2022: As the use of sugammadex for reversing neuromuscular blockade during general anesthesia increases, additional effects of sugammadex have been reported compared to...
: As the use of sugammadex for reversing neuromuscular blockade during general anesthesia increases, additional effects of sugammadex have been reported compared to cholinesterase inhibitors. Here, we compare the incidence of postoperative catheter-related bladder discomfort (CRBD) between sugammadex and pyridostigmine/glycopyrrolate treatments for reversing neuromuscular blockade. : We retrospectively analyzed patients aged ≥ 18 years who underwent surgery under general anesthesia, received sugammadex or pyridostigmine with glycopyrrolate to reverse neuromuscular blockade, and had a urinary catheter in the post-anesthesia care unit between March 2019 and February 2021. After applying the exclusion criteria, 1179 patients were included in the final analysis. The incidence and severity of CRBD were collected from post-anesthesia recovery records. : The incidence was 13.7% in the sugammadex group ( = 211) and 24.7% in the pyridostigmine group ( = 968). Following propensity score matching, 211 patients each were included in the pyridostigmine and sugammadex matched group (absolute standardized difference (ASD), 0.01-0.05). Compared to the pyridostigmine group, the odds ratio for CRBD occurring in the sugammadex group was 0.568 (95% confidential interval, 0.316-1.021, = 0.059). : Sugammadex has a similar effect on the occurrence of postoperative CRBD compared with pyridostigmine.
Topics: Glycopyrrolate; Humans; Pyridostigmine Bromide; Retrospective Studies; Sugammadex; Urinary Bladder; Urinary Catheters
PubMed: 35630007
DOI: 10.3390/medicina58050590 -
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 -
Scientific Reports May 2021The mechanisms regulating immune cells recruitment into the heart during healing after an acute myocardial infarction (AMI) have major clinical implications. We...
The mechanisms regulating immune cells recruitment into the heart during healing after an acute myocardial infarction (AMI) have major clinical implications. We investigated whether cholinergic stimulation with pyridostigmine, a cholinesterase inhibitor, modulates heart and spleen immune responses and cardiac remodeling after AMI in spontaneous hypertensive rats (SHRs). Male adult SHRs underwent sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated or to pyridostigmine treatment (40 mg/kg once a day by gavage). Blood pressure and heart rate variability were determined, and echocardiography was performed at day six after MI. The heart and spleen were processed for immunohistochemistry cellular analyses (CD3 and CD4 lymphocytes, and CD68 and CD206 macrophages), and TNF levels were determined at day seven after MI. Pyridostigmine treatment increased the parasympathetic tone and T CD4 lymphocytes in the myocardium, but lowered M1/M2 macrophage ratio towards an anti-inflammatory profile that was associated with decreased TNF levels in the heart and spleen. Treatment with this cholinergic agent improved heart remodeling manifested by lower ventricular diameters and better functional parameters. In summary, cholinergic stimulation by pyridostigmine enhances the parasympathetic tone and induces anti-inflammatory responses in the heart and spleen fostering cardiac recovery after AMI in SHRs.
Topics: Animals; Autonomic Nervous System; Blood Pressure; Cholinesterase Inhibitors; Heart; Heart Rate; Hemodynamics; Male; Myocardial Infarction; Pyridostigmine Bromide; Rats; Rats, Inbred SHR; Spleen
PubMed: 33953291
DOI: 10.1038/s41598-021-89104-8 -
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 -
Neurobiology of Stress May 2020Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to...
Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to nerve agents. Although originally thought to pose minimal risk to soldiers, epidemiological studies have since correlated PB administration with the development of a variety of symptoms, including cognitive dysfunction, termed Gulf War Illness (GWI). We previously demonstrated in a rodent model of GWI that central cholinergic responses were altered to various stimuli. In the current study we used microdialysis to examine how combinations of PB and repeated restraint stress (RRS) altered extracellular glutamate levels in response to an innate immune challenge (lipopolysaccharide; LPS) and an immobilization stress challenge in the prefrontal cortex (PFC) and hippocampus. There were four groups in this study: vehicle non-stressed control (Veh-NSC), vehicle-stressed (Veh-RRS), PB-NSC, and PB-RRS. While LPS decreased glutamate levels in PB-treated rats relative to vehicle-treated rats in the PFC, PB and stress interacted to attenuate LPS-induced decreases in hippocampal glutamate levels. Although immobilization stress increased glutamate in the PFC, glutamate levels in PB-NSC rats failed to recover in the post-stress period relative to vehicle-treated rats. In the hippocampus, PB-stressed rats failed to exhibit habituation of the glutamate response to immobilization stress relative to vehicle-stressed rats. Collectively, these results indicate that PB and stress interacted to produce brain-region specific effects on glutamate neurochemistry, providing insight into the potential mechanisms underlying interactions between the immune system and persistent cognitive dysfunction in veterans with GWI.
PubMed: 32258255
DOI: 10.1016/j.ynstr.2019.100210 -
BMJ Case Reports Apr 2021We report a case of a 55-year-old man presenting with diplopia, masticatory weakness and dysarthria several weeks post multitrauma. The clinical suspicion of myasthenia...
We report a case of a 55-year-old man presenting with diplopia, masticatory weakness and dysarthria several weeks post multitrauma. The clinical suspicion of myasthenia gravis (MG) was supported with positive acetylcholine receptor antibodies and abnormal repetitive stimulation study. He responded well to pyridostigmine, intravenous immunoglobulin and oral prednisolone. In this report, we describe the timing and progression of MG in our patient, and review the literature pertaining to the relationship between trauma and MG. The search for definitive evidence of causation may be impractical, but should not delay the recognition and management of a treatable condition.
Topics: Blepharoptosis; Diplopia; Humans; Male; Middle Aged; Myasthenia Gravis; Prednisolone; Pyridostigmine Bromide; Wounds and Injuries
PubMed: 33811091
DOI: 10.1136/bcr-2020-238415 -
International Journal of Environmental... Nov 2020Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and...
Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts.
Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl--toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium.
Topics: Astrocytes; Brain; Cells, Cultured; DEET; Endothelial Cells; Humans; Metals, Heavy; Permethrin; Persian Gulf Syndrome; Pyridostigmine Bromide; Salts
PubMed: 33187257
DOI: 10.3390/ijerph17228336 -
FASEB Journal : Official Publication of... May 2019Gulf War illness (GWI) is a chronic multisymptom disorder that is prominent in Gulf War veterans. Major unexplained symptoms of GWI include functional gastrointestinal...
Gulf War illness (GWI) is a chronic multisymptom disorder that is prominent in Gulf War veterans. Major unexplained symptoms of GWI include functional gastrointestinal disorders and undiagnosed illnesses, including neurologic disorders. Exposure to the antinerve gas drug pyridostigmine bromide (PB) is linked to the development of GWI, but the exact mechanisms remain unclear. Here, we tested the hypothesis that PB alters gut function by disrupting the neural and immune systems of the intestine. We exposed male and female mice to physiologically comparable amounts of PB that match the dose, route, and time frame of exposure experienced by Gulf War veterans and assessed the acute and chronic impacts on gastrointestinal functions, the functional architecture of the enteric nervous system, and immune responses in the gut and brain. Exposure to PB drove acute alterations to colonic motility and structure in both male and female mice that transitioned to chronic changes in gut functions. PB drove acute alterations to enteric neural and glial activity, glial reactivity, and neuron survival with glial reactivity persisting into the chronic phase in male mice. Despite having no effect on colonic permeability, exposure to PB caused major shifts in the expression of proinflammatory cytokines and chemokines in the colon and brain that suggest immunosuppressive effects. Interestingly, immune disruption was still evident in the colon and brain in female animals at 1 mo following exposure to PB. Together, our results show that the paradigm of PB exposure experienced by veterans of the Persian Gulf War contributes to long-lasting pathophysiology by driving enteric neuroinflammation, promoting immunosuppression, and altering functional anatomy of the colon in a sex-dependent manner.-Hernandez, S., Fried, D. E., Grubišić, V., McClain, J. L., Gulbransen, B. D. Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness.
Topics: Animals; Brain; Cholinesterase Inhibitors; Colon; Cytokines; Enteric Nervous System; Female; Gastrointestinal Motility; Male; Mice; Mice, Inbred C57BL; Neuroglia; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 30789759
DOI: 10.1096/fj.201802572R -
Cortex; a Journal Devoted To the Study... Jan 2016Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and... (Review)
Review
Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.
Topics: Brain Neoplasms; Cognition Disorders; Fatigue; Gulf War; Humans; Neurotoxins; Occupational Exposure; Persian Gulf Syndrome; Veterans
PubMed: 26493934
DOI: 10.1016/j.cortex.2015.08.022