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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 -
Military Medicine May 1992The side effects of chronic pyridostigmine bromide administration were studied in seven male soldiers performing moderate-intensity exercise in a desert environment. A... (Clinical Trial)
Clinical Trial
The side effects of chronic pyridostigmine bromide administration were studied in seven male soldiers performing moderate-intensity exercise in a desert environment. A 2-week, double-blind, placebo-controlled crossover design was employed in which pyridostigmine was administered for 7 consecutive days (30 mg orally, t.i.d.). Four hours each day were spent in the heat (42 degrees C, 20% relative humidity); 2 hours rest followed by 2 hours moderate exercise (40% maximal aerobic power). Each day, subjects completed four symptom questionnaires and received three focused physical examinations. Symptoms reported did not differ between treatment groups except for fewer headaches during pyridostigmine treatment. Soldiers were unable to distinguish the effects of pyridostigmine from placebo. Pyridostigmine was associated with lower resting diastolic blood pressure (approximately 4 mmHg, p less than 0.05), smaller pupil diameter (approximately 0.5 mm, p less than 0.01), decreased handgrip strength (approximately 3%, p less than 0.05), and higher final rectal temperature (approximately 0.1 degree C, p less than 0.01). Effects of this magnitude are not likely to appreciably limit performance. We conclude that chronic pyridostigmine administration does not negatively impact on soldiers' ability to perform physical work over repeated days in a desert environment.
Topics: Adolescent; Adult; Desert Climate; Double-Blind Method; Headache; Humans; Male; Military Personnel; Pyridostigmine Bromide
PubMed: 1630657
DOI: No ID Found -
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 -
Archives of Pharmacal Research Mar 2012A novel pyridostigmine bromide (PB)-phospholipid nanocomplex (PBPLC) was prepared to increase the bioavailability of PB. A central composite design approach was employed...
A novel pyridostigmine bromide (PB)-phospholipid nanocomplex (PBPLC) was prepared to increase the bioavailability of PB. A central composite design approach was employed for process optimization. The physicochemical properties of PBPLC were investigated by means of differential scanning calorimetry, ultraviolet spectroscopy, Fourier transformed infrared spectroscopy and the n-octano/water partition coefficient. The intestinal permeability of PBPLC was observed via a single pass intestinal perfusion in rats. After oral administration of PBPLC, the concentrations of PB at predetermined time points were determined by HPLC, and the pharmacokinetic parameters were computed by DAS 2.1.1 software. Multiple linear regression analysis for process optimization revealed that the optimal PBPLC was obtained when the values of X(1), X(2), and X(3) were 8, 40°C, and 4 mg/mL, respectively. The average particle size and zeta potential of PBPLC with the optimized formulation were 204.60 nm and -25.12 mV, respectively. Non-covalent interactions between PB and phospholipids were found in the PBPLC. The n-octanol/water partition coefficient of PBPLC was substantially increased. PBPLC had better intestinal permeability in comparison with free PB. Mean plasma drug concentration-time curves of PBPLC and free PB after oral administration were both in accordance with the two-compartment open model. The values of pharmacokinetic parameters of PBPLC and free PB were the peak time (T(max)) 2 h vs 2 h, the maximum concentration (C(max)) 22.79 μg/mL vs 6.00 μg/mL, and the value of the area under the concentration vs time curve (AUC(0-∞)) 7128.21 μg·min/mL vs 1772.36 μg·min/mL, respectively. In conclusion, compared with free PB, PBPLC remarkably improves the oral bioavailability of PB, which is likely due to its higher lipophilicity and permeability.
Topics: 1-Octanol; Administration, Oral; Animals; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Drug Compounding; Intestinal Absorption; Intestinal Mucosa; Linear Models; Male; Models, Biological; Nanoparticles; Nanotechnology; Permeability; Phospholipids; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Solubility; Solvents; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Water
PubMed: 22477197
DOI: 10.1007/s12272-012-0313-6 -
Clinical Neurology and Neurosurgery Nov 2010For more than 50 years the acetylcholinesterase inhibitor pyridostigmine bromide has been the drug of choice in the symptomatic therapy for myasthenia gravis. The... (Clinical Trial)
Clinical Trial
INTRODUCTION
For more than 50 years the acetylcholinesterase inhibitor pyridostigmine bromide has been the drug of choice in the symptomatic therapy for myasthenia gravis. The sustained-release dosage form of pyridostigmine (SR-Pyr) is only available in a limited number of countries (e.g. in the United States and Germany). Astonishingly, the therapeutic usefulness of SR-Pyr has not yet been evaluated.
METHODS
In this non-interventional prospective open-label trial, 72 patients with stable myasthenia gravis were switched from instant-release dosage forms of pyridostigmine bromide to SR-Pyr. The results from the 37 patients younger than 60 years were separately analyzed.
RESULTS
The initial daily dose of SR-Pyr was 288.1 ± 171.0mg. The drug switch was unproblematic in all patients. The number of daily doses was significantly reduced from 4.3 to 3.6 (p=0.011). The switch to SR-Pyr ameliorated the total quantified myasthenia gravis (QMG) score from 0.9 ± 0.5 to 0.6 ± 0.4 (p<0.001) in all patients and in the younger subgroup. This was accompanied by a significant improvement in the quality of life parameters. The health status valued by EuroQoL questionnaire improved from 0.626 ± 0.286 to 0.782 ± 0.186 (p<0.001). After switching to SR-Pyr, 28 adverse reactions disappeared and 24 adverse reactions occurred less frequent or weaker, however, 17 new adverse reactions were documented.
CONCLUSIONS
Our results support the usefulness of SR-Pyr in an individualized therapeutic regimen to improve quality of life regardless of the patient's age in myasthenia gravis.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Delayed-Action Preparations; Demography; Female; Germany; Humans; Male; Middle Aged; Myasthenia Gravis; Neurologic Examination; Prospective Studies; Pyridostigmine Bromide; Quality of Life; Young Adult
PubMed: 20663605
DOI: 10.1016/j.clineuro.2010.06.018 -
The American Journal of Physiology Apr 1990Five subjects exercised on a cycle ergometer for 30 min at 55% peak oxygen consumption on two occasions in an environmental test chamber (ambient temperature = 29...
Five subjects exercised on a cycle ergometer for 30 min at 55% peak oxygen consumption on two occasions in an environmental test chamber (ambient temperature = 29 degrees C; dew point temperature = 10 degrees C). Pyridostigmine bromide (PYR), an acetylcholinesterase (AChE) inhibitor, was ingested (30 mg) approximately 150 min before one experiment, and no drug was administered during the other experiment (control). Red blood cell AChE inhibition averaged 40 (+/- 7)% during PYR treatment. Esophageal temperature (Tes), an eight site-derived mean skin temperature, forearm blood flow (FBF; venous occlusion plethysmography), skin blood flow (SkBF; laser-Doppler velocimetry), and metabolic rate (indirect calorimetry) were measured. SkBF decreased 37% after PYR treatment compared with control (P less than or equal to 0.05). The Tes threshold for initiation of cutaneous vasodilation was 36.8 (+/- 0.3) degrees C for the control treatment and 37.0 (+/- 0.3) degrees C for the PYR treatment (P less than or equal to 0.01). FBF was not significantly different between treatments, whereas heart rate was reduced by 7 and 9 beats/min during rest and exercise, respectively (P less than or equal to 0.01). The increased threshold for initiation of cutaneous vasodilation with AChE inhibition by PYR is compatible with nonthermal modulation of the control of thermoregulation through increased acetylcholine (ACh) accumulation. This could potentiate preganglionic transmission to enhance adrenergic vasoconstrictor tone. One suggested mechanism possible at the neuroeffector junction of the sweat gland may be that accumulated ACh diffusion across the adventitia of adjacent arterioles to muscarinic receptors initiates contraction of the smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Body Temperature Regulation; Cholinesterase Inhibitors; Exercise; Female; Forearm; Humans; Male; Pyridostigmine Bromide; Regional Blood Flow; Skin; Sweating; Ultrasonography
PubMed: 2184685
DOI: 10.1152/ajpregu.1990.258.4.R951 -
Journal of Pharmaceutical Sciences Apr 1991The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an...
The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.
Topics: Administration, Oral; Animals; Biological Availability; Delayed-Action Preparations; Dogs; Infusions, Intravenous; Male; Pyridostigmine Bromide
PubMed: 1865335
DOI: 10.1002/jps.2600800414 -
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 -
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 -
Journal of Pharmacy & Pharmaceutical... 2006Pyridostigmine bromide (PB) is a quartenary ammonium compound that inhibits the hydrolysis of acetylcholine by competitive reversible binding to acetylcholinesterase. PB...
Pyridostigmine bromide (PB) is a quartenary ammonium compound that inhibits the hydrolysis of acetylcholine by competitive reversible binding to acetylcholinesterase. PB is used for the symptomatic treatment of myasthenia gravis and has been applied as a prophylaxis against nerve agents. Many studies on PB have involved the reliance on techniques that extract and quantify PB in biological samples. This article presents an overview of the currently applied methodologies for the determination of PB and its metabolites in various biological samples. Articles published from January 1975 to the July 2005 were taken into consideration for the discussion of the metabolism and analytical method of PB. HPLC and GC methods have been used and discussed in most of the references cited in this review. Other methods such as RIA and CE that have been recently reported are also mentioned in this article. Basic information about the type of sample used for analysis, sample preparation, chromatographic column, mobile phase, detection mode and validation data are summarized in a table.
Topics: Animals; Cholinesterase Inhibitors; Chromatography, Gas; Chromatography, High Pressure Liquid; Humans; Myasthenia Gravis; Plasma; Pyridostigmine Bromide; Reproducibility of Results; Urine
PubMed: 16849010
DOI: No ID Found