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Brain, Behavior, and Immunity Aug 2019Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of...
Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI. Accordingly, the goal of this study was to determine how responses to an immune challenge (lipopolysaccharide; LPS) or stress impacts inflammation, acetylcholine (ACh) neurochemistry and behavior in an experimental model of GWI. Rats with a history of PB treatment exhibited potentiated increases in C-reactive protein levels in response to a submaximal LPS challenge compared to control rats, indicating that prior treatment with this cholinesterase inhibitor leads to exacerbated inflammatory responses to a subsequent immune challenge. ACh responses to LPS administration were decreased in the hippocampus, but not prefrontal cortex (PFC), in rats with a prior history of PB treatment or stress exposure. Additionally, ACh release in response to acute immobilization stress was attenuated in the PFC and hippocampus in these groups. These attenuated cholinergic responses were accompanied by impairments in contextual and cue-based fear learning. The results of this study suggest that stress and LPS challenges adversely affect central ACh neurochemistry in a rodent model of GWI and support the hypothesis that dysregulated immune responses are mechanistically linked to the neurological complications of GWI.
Topics: Acetylcholine; Animals; Behavior, Animal; C-Reactive Protein; Cholinesterase Inhibitors; Conditioning, Classical; Disease Models, Animal; Fear; Hippocampus; Inflammation; Lipopolysaccharides; Male; Persian Gulf Syndrome; Prefrontal Cortex; Pyridostigmine Bromide; Rats, Sprague-Dawley; Stress, Psychological
PubMed: 30953774
DOI: 10.1016/j.bbi.2019.04.015 -
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 -
PloS One 2023Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial... (Observational Study)
Observational Study
Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.
Topics: Humans; Adenosine Triphosphate; Biological Warfare Agents; DNA, Mitochondrial; Energy Metabolism; Gulf War; Leukocytes, Mononuclear; Persian Gulf Syndrome; Pesticides; Pyridostigmine Bromide; Veterans; Case-Control Studies
PubMed: 37910447
DOI: 10.1371/journal.pone.0287412 -
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 -
Neurotoxicology May 2022Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the...
Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the exposure to neurological chemicals, including the anti-nerve gas drug pyridostigmine bromide (PB) and the insecticide permethrin (PER), among others. Mouse models utilizing these chemicals have reported symptomology analogous to human GWI. These changes include behavioral and cognitive impairment, neuroinflammation and hippocampal pathogenesis. Disease modifying interventions that target these pathological components are desperately needed. Vagus nerve stimulation (VNS) is FDA approved for drug-resistant epilepsy and depression. VNS has also been used off-label to target a myriad of symptoms, some of which are encompassed within the Kansas and CDC definitions of clinical GWI symptomology. A GWI animal model in which mice are exposed to a daily injection of PB and PER for 10 consecutive days has been shown to exhibit cognitive impairment and hippocampal pathology. The purpose of this study was to determine if 2-4 weeks of continuous vagus nerve stimulation initiated at 32 weeks after exposure to PB and PER would improve cognitive performance and hippocampal pathology. The results of the study revealed that exposure to PB and PER produces long-term cognitive deficits and reduced hippocampal neurogenesis. The results also showed that the VNS treatment was anxiolytic, improved some aspects of pattern separation deficits, and mitigated the reduced hippocampal neurogenesis. Thus, VNS improves outcomes in a mouse model of GWI and should be examined as a potential therapeutic strategy for mitigating some symptomology associated with GWI.
Topics: Animals; Disease Models, Animal; Gulf War; Mice; Neurogenesis; Permethrin; Persian Gulf Syndrome; Pyridostigmine Bromide; Vagus Nerve Stimulation
PubMed: 35421512
DOI: 10.1016/j.neuro.2022.04.001 -
International Journal of Pharmaceutics Nov 2021Changes of weight and axial expansion of tablets of the deliquescent drug pyridostigmine bromide with Kollidon SR were followed with relative humidity (RH) using dynamic...
Monitoring the weight and dimensional expansion of pyridostigmine bromide tablets under dynamic vapor sorption and impact of deliquescence on tablet strength and drug release.
Changes of weight and axial expansion of tablets of the deliquescent drug pyridostigmine bromide with Kollidon SR were followed with relative humidity (RH) using dynamic vapor sorption and displacement transducer. The effects of RH on placebo and drug containing (API) tablets prepared at low and high compression were related to tablet strength and molecular changes. Tablet weight and expansion increased with RH, especially above RH 40%. Tablet rigidity and strength decreased linearly with moisture for placebo tablets whereas for API tablets there was decrease up to 50% followed by large drop at 60%. Raman spectra of tablets did not show chemical interactions due to moisture, but decreased intensity of drug peak at 2370 cm indicating solid state changes. Decrease of polymer peak intensities at 805 and 1740 cm occurred only in API tablets implicating drug deliquescence in polymer moisture sorption. X-ray diffraction and thermal analysis of tablets indicated complete drug liquefaction after exposure at 60% RH, which impacted great loss of strength but did not affect the sustained release profile. In conclusion, monitoring of the physical properties of tablets during production of deliquescent drugs is necessary to avoid pitfalls during downstream processes such as coating, packaging and storage.
Topics: Drug Liberation; Humidity; Pyridostigmine Bromide; Tablets; X-Ray Diffraction
PubMed: 34600060
DOI: 10.1016/j.ijpharm.2021.121150 -
Biomedical Chromatography : BMC Jun 2023Recently, the main interest of analytical chemistry researchers has been the development of green analytical methods to minimize harmful effects on the environment and...
Recently, the main interest of analytical chemistry researchers has been the development of green analytical methods to minimize harmful effects on the environment and natural life. Therefore, an RP-HPLC method was developed and assessed regarding its greenness criteria using three greenness assessment tools: an analytical eco-scale, an analytical greenness metric approach and a green analytical procedure index. This method aims to separate and quantitatively determine three co-administered drugs, namely pyridostigmine bromide (PYR), 6-mercaptopurine (MRC) and prednisolone (PRD), in their tertiary mixture and spiked human plasma. These drugs are co-administered to manage myasthenia gravis autoimmune disease. The separation was done using a C column and a gradient elution of a mixture of 0.1% H PO aqueous solution (pH 2.3) and methanol. The flow rate was adjusted to 1 ml/min and detection was done at 254 (for PYR and PRD) and at 330 nm (for MRC). The lower limits of quantitation were 15, 2, and 5 μg/ml for PYR, MER and PRD, respectively. Linear correlations were obtained and found to be near 1. In addition, the proposed method was validated according to the US Food and Drug Administration's instructions, and the results proved its success to determine the three studied drugs in their tertiary mixture and spiked human plasma.
Topics: United States; Humans; Chromatography; Myasthenia Gravis; Chromatography, High Pressure Liquid
PubMed: 36882891
DOI: 10.1002/bmc.5615 -
American Journal of Physiology.... Aug 2019Diabetic patients are more susceptible to myocardial ischemia damage than nondiabetic patients, with worse clinical outcomes and greater mortality. The mechanism may be...
Diabetic patients are more susceptible to myocardial ischemia damage than nondiabetic patients, with worse clinical outcomes and greater mortality. The mechanism may be related to glucose metabolism, mitochondrial homeostasis, and oxidative stress. Pyridostigmine may improve vagal activity to protect cardiac function in cardiovascular diseases. Researchers have not determined whether pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice. In the present study, autonomic imbalance, myocardial damage, mitochondrial dysfunction, and oxidative stress were exacerbated in isoproterenol-stimulated diabetic mice, revealing the myocardial vulnerability of diabetic mice to injury compared with mice with diabetes or exposed to isoproterenol alone. Compared with normal mice, the expression of glucose transporters (GLUT)1/4 phosphofructokinase (PFK) FB3, and pyruvate kinase isoform (PKM) was decreased in diabetic mice, but increased in isoproterenol-stimulated normal mice. Following exposure to isoproterenol, the expression of (GLUT)1/4 phosphofructokinase (PFK) FB3, and PKM decreased in diabetic mice compared with normal mice. The downregulation of SIRT3/AMPK and IRS-1/Akt in isoproterenol-stimulated diabetic mice was exacerbated compared with that in diabetic mice or isoproterenol-stimulated normal mice. Pyridostigmine improved vagus activity, increased GLUT1/4, PFKFB3, and PKM expression, and ameliorated mitochondrial dysfunction and oxidative stress to reduce myocardial damage in isoproterenol-stimulated diabetic mice. Based on these results, it was found that pyridostigmine may reduce myocardial vulnerability to injury via the SIRT3/AMPK and IRS-1/Akt pathways in diabetic mice with isoproterenol-induced myocardial damage. This study may provide a potential therapeutic target for myocardial damage in diabetic patients.
Topics: Animals; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Glucose; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Ischemia; Myocytes, Cardiac; Oxidative Stress; Pyridostigmine Bromide
PubMed: 31211620
DOI: 10.1152/ajpendo.00569.2018 -
Photodiagnosis and Photodynamic Therapy Mar 2023Although the mechanism is not clear, the inability of the orbicularis oculi muscle, especially the deeper segment (Horner muscle), is thought to be responsible in...
BACKGROUND
Although the mechanism is not clear, the inability of the orbicularis oculi muscle, especially the deeper segment (Horner muscle), is thought to be responsible in epiphora. This study evaluates the effect of the anticholinergic drug pyridostigmine (Mestinon) in patients with patent but dysfunctional lacrimal drainage system.
MATERIAL AND METHODS
Twenty patients with bilateral epiphora (mean age:60.78 ± 6.49 yrs) were included in this study. Patients with a patent lacrimal irrigation test based on persistent and symptomatic epiphora, wiping >10 times daily or continuous tearing and grade 4-5 epiphora according to Munk scale, showing neuropathic involvement in the orbicularis oculi muscle by the quantitative motor unit potential (MUP) analysis method were evaluated prospectively. Fluorescein dye disappearance test (a semi-quantitative assessment of delayed tear outflow) together with a Schirmer test reading were performed in order to detect dry eye. The patients were evaluated for tear meniscus measurements by anterior segment optical coherence topography (OCT) and non-invasive tear break-up time (NI-BUT) was measured by Oculus Keratograph 5 M. Those with a NI-BUT value above 10 s, without eyelid laxity, previous ocular surgery or ocular surface disease, or nasolacrimal duct obstruction, and who agreed to use the drug were included in the study. Each subject underwent OCT measurements of the lower tear meniscus of both eyes before and 15 mins after taking Mestinon (1 × 60 mg tablet). Upon measurement of the positive effect of the drug on tear meniscus height (TMH), the patients were asked to continue this regime daily for 1 month and then evaluated for relief in their epiphora complaints and any systemic drug side effects.
RESULTS
A total of 20 patients (40 eyes) with bilateral epiphora were included in the study. All eyes had grade 4 Munk-score epiphora, Schirmer's test was within the normal range in all eyes (mean, 14 ± 4 mm), and patent lacrimal irrigation test. The lower mean TMH reductions 15 min after Mestinon in the right and left eyes were 135.41 ± 85.47 and 55.44 ± 61.56 mm, respectively, a statistically significant decrease in both eyes (p = 0.001, p < 0.01). The mean tear meniscus area (TMA) in the right and left eyes was 131.83 ± 68.27 mm and 62.72 ± 50.57 mm, respectively; 15 mins after administration of Mestinon, the mean TMA in the right and left eyes was 77.27 ± 48.34 and 59.18 ± 44.74 mm, respectively (p = 0.001, p < 0.01). The mean decreases of 54.56 ± 39.34 mm in the right eye area and 3.53 ± 42.32 mm in the left eye area were statistically significant (p = 0.041, p < 0.05).
CONCLUSION
Symptomatic relief for epiphora cannot be achieved with known treatment options due to lacrimal pump dysfunction. We found that pyridostigmine (Mestinon) provided relief in patients' complaints of epiphora consistent with a significant reduction in TMH levels.
Topics: Humans; Middle Aged; Aged; Pyridostigmine Bromide; Lacrimal Duct Obstruction; Nasolacrimal Duct; Tomography, Optical Coherence; Photochemotherapy; Photosensitizing Agents
PubMed: 36592783
DOI: 10.1016/j.pdpdt.2022.103240 -
Integrative Medicine Research Jun 2022Myasthenia Gravis (MG) is a disorder of neuromuscular transmission bringing mild ocular weakness to severe generalized muscle weakness and disability. The conventional... (Review)
Review
BACKGROUND
Myasthenia Gravis (MG) is a disorder of neuromuscular transmission bringing mild ocular weakness to severe generalized muscle weakness and disability. The conventional treatments have long-term side effects, and Chinese herbal medicines (CHM) have shown possible effect and safety for MG patients, but the existing evidence was not robust enough and the results were out of date.
METHODS
Searching for randomized controlled trials (RCTs) was conducted in 7 databases and clinical trial registries until July 2021. The ROB 2 tool was used to assess the study quality and GRADE was used to assess the quality of whole evidence. Meta-analyses were conducted and the results were presented as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI).
RESULTS
Nineteen RCTs (1283 participants) testing 13 kinds of CHM with adequate randomization were included and six RCTs investigating Compound Huangqi were included in the meta-analyses. In addition to conventional treatment, nine CHMs reduced symptom scores of MG. Compound Huangqi plus conventional treatment (pyridostigmine bromide or prednisone or both) reduced the symptom scores compared with conventional treatment (MD = -3.56, 95%CI -4.86 to -2.26). Less adverse events happened in the CHM groups (3/247 in the CHM groups, 52/245 in the control groups, RR = 0.13, 95%CI 0.06 to 0.30, 9 RCTs, a total of 492 participants). The effect on quality of life was inconsistent.
CONCLUSION
Nine CHMs could probably bring benefit for MG symptom improvement. Moderate to low certainty of evidence supported Compound Huangqi added-on conventional treatment probably bring extra benefit of improving MG symptoms. Adding CHMs could be safer than giving only conventional treatment.
STUDY REGISTRATION
The protocol was registered in PROSPERO (ID: 32718).
PubMed: 35024335
DOI: 10.1016/j.imr.2021.100806