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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 -
European Journal of Medicinal Chemistry Jan 2023A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and...
Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning.
A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (τ = 1/k = 18.6 ± 7.5 min). Moreover, compound 2h ameliorated muscle weakness in myasthenia gravis rat model with a lower effective dose and longer lasting effect than pyridostigmine bromide. Besides, it was shown that compound 2h has an effect of increasing efficiency of antidotal therapy as a pretreatment for poisoning by organophosphates.
Topics: Rats; Animals; Cholinesterase Inhibitors; Butyrylcholinesterase; Acetylcholinesterase; Organophosphate Poisoning; Uracil; Kinetics; Myasthenia Gravis
PubMed: 36462442
DOI: 10.1016/j.ejmech.2022.114949 -
Computational and Structural... 2022Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging...
Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging across cognitive deficits, fatigue, gastrointestinal problems, and musculoskeletal pain. Research indicates that chemical warfare agents play a key role in the onset and progression of GWI. The Khamisiyah ammunition storage that housed chemical warfare agents such as sarin, an acetylcholinesterase (AChE) inhibitor, was demolished during the GW, releasing toxicants into the atmosphere affecting deployed troops. Exposure to other chemical agents such as pyridostigmine bromide, N,N-diethyl-m-toluamide, permethrin and chlorpyrifos, were also prevalent during the war. These additional chemical agents have also been shown to inhibit AChE. AChE inhibition induces an acetylcholine build-up, disrupting signals between nerves and muscles, which in high doses leads to asphyxiation. Little is known about low dose exposure. As bioactive compounds tend to interact with multiple proteins with various physiological effect, we aimed to identify other potential shared targets to understand the extent in which these chemicals could lead to GWI. We followed a reverse screening approach where each chemical is computationally docked to a library of protein targets. The programs PharmMapper and TargetNet were used for this purpose, and further analyses were conducted to mark significant changes in participants with GWI. Previously published work on DNA methylation status in GWI was reanalyzed focusing specifically on the predicted shared targets indicating significant changes in DNA methylation of the associated genes. Our findings thus suggest that exposure to GWI-related agents may converge on similar targets with roles in inflammation, neurotransmitter and lipid metabolism, and detoxification which may have impacts on neurodegenerative-like disease and oxidative stress in Veterans with GWI.
PubMed: 36420170
DOI: 10.1016/j.csbj.2022.11.006 -
Brain, Behavior, & Immunity - Health Dec 2022Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to...
Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI.
PubMed: 36405424
DOI: 10.1016/j.bbih.2022.100553 -
BMC Neurology Nov 2022Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive hereditary neuromuscular disorder caused by the expanded trinucleotide repeat in the androgen...
BACKGROUND
Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive hereditary neuromuscular disorder caused by the expanded trinucleotide repeat in the androgen receptors gene. The major clinical manifestations of SBMA consist of weakness in the bulbar and limb muscles, fasciculations, tremors, cramps, sensory impairment, and gynecomastia. However, atypical SBMA cases may lead to misdiagnosis. Muscular fatigue and decremental responses to repetitive nerve stimulation (RNS), despite being observed in some SBMA patients, are usually occurred in MG patients, and patient with the symptom of mastication fatigue was rarely reported. In addition, cardiological investigations have been performed in SBMA patients and several ECG alterations were identified. Here we report an SBMA patient presenting with a rare onset symptom of mastication fatigue, who has been detected with a positive titin antibody in the serum and showed a WPW pattern electrocardiogram.
CASE PRESENTATION
The patient showed mildly progressive fatigue in the muscles of mastication over 3 years. Neurological examination showed facial muscle weakness and a wasting tongue with fasciculations, but the weakness, wasting, or fasciculations were not obvious in the limbs. 3-Hz RNS showed a decremental response in bilateral orbicularis oculi. The test of titin antibody was positive in the serum, and the electrocardiogram showed a WPW pattern ECG. Genetic analysis revealed an increased number (39 repeats) of tandem CAG repeats in the AR gene, which confirmed the diagnosis of SBMA. The fatigue symptom was significantly improved after oral pyridostigmine bromide treatment.
CONCLUSION
This case calls for more attention to muscular fatigue as the onset symptoms of Kennedy's disease. ECG screening is of importance in SBMA patients and further studies are needed to investigate the titin antibody in SBMA patients as well as other neurogenic disorders.
Topics: Humans; Male; Bulbo-Spinal Atrophy, X-Linked; Connectin; Mastication; Fasciculation; Muscular Atrophy, Spinal; Fatigue
PubMed: 36376797
DOI: 10.1186/s12883-022-02971-0 -
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 -
Journal of AOAC International May 2023Prednisolone, 6-mercaptopurine, and pyridostigmine bromide are co-administered together to treat a neuromuscular autoimmune disease called myasthenia gravis....
BACKGROUND
Prednisolone, 6-mercaptopurine, and pyridostigmine bromide are co-administered together to treat a neuromuscular autoimmune disease called myasthenia gravis. Prednisolone and 6-mercaptopurine are immunosuppressant drugs. 6-Mercaptopurine is the active form of the pro-drug azathioprine. Pyridostigmine bromide is a cholinesterase enzyme inhibitor. Curently, green characteristics are taken into account by analysts when they develop new methods.
OBJECTIVE
The spectra of the three compounds and plasma are highly overlapped, so this study aims to remove this overlap and determine the three components quantitatively in raw powders and spiked human plasma using green methods.
METHODS
Two multivariate updated chemometric models called principle component analysis and partial least-squares were developed. Three greenness assessment tools: the eco-scale, the analytical greenness metric approach, and the green analytical method index, were used to evaluate the greenness behavior of the generated models.
RESULTS
The two models were verified in accordance with Food and Drug Administration requirements, and the results were within acceptable limits. In addition they are relatively green in accordance with the abovementioned greenness evaluation tools.
CONCLUSION
The developed models succeeded in determining the proposed drugs in their tertiary combinations and spiked human plasma with satisfactory precision, accuracy, and good greenness behavior.
HIGHLIGHTS
Two ecologically evaluated, multivariate spectrophotometric methods were developed for the determination of pyridostigmine bromide, 6-mercaptopurine, and prednisolone in spiked human plasma.
Topics: United States; Humans; Pyridostigmine Bromide; Mercaptopurine; Chemometrics; Myasthenia Gravis; Prednisolone
PubMed: 36322814
DOI: 10.1093/jaoacint/qsac139 -
Brain and Behavior Dec 2022This review highlights the potential mechanisms of neuromuscular manifestation of COVID-19, especially myasthenia gravis (MG). (Review)
Review
INTRODUCTION
This review highlights the potential mechanisms of neuromuscular manifestation of COVID-19, especially myasthenia gravis (MG).
METHODS
An extensive literature search was conducted by two independent investigators using PubMed/MEDLINE and Google Scholar from its inception to December 2020.
RESULTS
Exacerbations of clinical symptoms in patients of MG who were treated with some commonly used COVID-19 drugs has been reported, with updated recommendations of management of symptoms of neuromuscular disorders. Severe acute respiratory syndrome coronavirus 2 can induce the immune response to trigger autoimmune neurological disorders.
CONCLUSIONS
Further clinical studies are warranted to indicate and rather confirm if MG in the setting of COVID-19 can pre-existent subclinically or develop as a new-onset disease.
Topics: Humans; SARS-CoV-2; COVID-19; Myasthenia Gravis
PubMed: 36306401
DOI: 10.1002/brb3.2789 -
Acta Neuropathologica Communications Oct 2022Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of...
Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.
Topics: Mice; Animals; Gulf War; Brain Concussion; Pyridostigmine Bromide; Permethrin; Disease Models, Animal; Brain Injuries, Traumatic; Pesticides; Pharmaceutical Preparations
PubMed: 36258255
DOI: 10.1186/s40478-022-01449-x