Oral Pyridostigmine Bromide Research Articles

A RARE CASE OF JUVENILE MYASTHENIA GRAVIS

Juvenile Myasthenia Gravis is arare auto immune disorder affecting children and adolescents, characterized by ptosis, muscle weakness and fatigability, untreated patients may progress to paralysis of the respiratory muscles and the risk of aspiration, particularly at times when they have an upper respiratory tract infection. Early recognition of this disease helps avoid unnecessary testing, prevent undue parental anxiety and stop the progression of symptoms. An 18 months old girl admitted with progressive dropping of eyelids, swallowing difficulty, loss of head control and generalized fatigability. She had positive acetyl cholinesterase test. Investigation releavedelectro decrementalresponsonse in electromyography. Patient treated with oral pyridostigmine bromide and steroid resulted in improvement in muscle strength and functional ability with regularly followed in OPD.JMG requires prompt recognition and management to prevent complications. This case highlights the importance of considering JMG in children with persistent weakness and fatigue.

Kennedy’s disease presented with mastication fatigue combined with positive titin antibody: a case report

BackgroundSpinal 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 presentationThe 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.ConclusionThis 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.

Acupuncture combined with western medication for ocular myasthenia gravis: a randomized controlled trial

To compare the clinical efficacy between acupuncture combined with western medication and simple western medication for ocular myasthenia gravis (OMG), and to explore its possible mechanism. A total of 60 patients of ocular myasthenia gravis were randomized into an acupuncture combined with western medication group (30 cases, 1 case dropped off) and a western medication group (30 cases, 2 cases dropped off). Oral pyridostigmine bromide tablet and prednisone acetate tablet were given in the western medication group. On the basis of the treatment in the western medication group, Tongdu Tiaoqi acupuncture (acupuncture for unblocking the governor vessel and regulating qi ) was applied at Baihui (GV 20), Fengfu (GV 16), Hegu (LI 4), Zusanli (ST 36), etc. in the acupuncture combined with western medication group, once a day, 6 days a week. The treatment was given 8 weeks in both groups. Before and after treatment, the OMG clinical absolute score was observed, electrophysiological indexes of orbicularis oculi (value of mean jitter, percentage of jitter >55 μs and percentage of blocks) were measured by single-fiber electromyography (SFEMG), serum levels of acetylcholine receptor antibody (AChR-Ab), interferon-gamma (IFN-γ) and interleukin-4 (IL-4) were detected by ELISA method. After treatment, the OMG clinical absolute scores, values of mean jitter, percentages of jitter >55 μs, percentages of blocks and serum levels of AChR-Ab, IFN-γ and IL-4 were decreased compared before treatment in both groups (P<0.05), and those in the acupuncture combined with western medication group were lower than the western medication group (P<0.05). Acupuncture combined with western medication can effectively improve ptosis, palpebra superior fatigability, eye movement disorder and neuromuscular junction dysfunction in patients with ocular myasthenia gravis, the therapeutic effect is superior to simple western medication. Its mechanism may be related to down-regulating serum levels of AChR-Ab, IFN-γ and IL-4 and promoting the recovery of orbicularis oculi function.

Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors.

Background and PurposeAcetylcholinesterase inhibitors (AChEIs) are widely used to treat myasthenia gravis (MG). Although AChEIs are usually tolerated well, some MG patients suffer from side effects. Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate AChEIs. Because repetitive compound muscle action potentials (R-CMAPs) are an electrophysiologic feature of cholinergic neuromuscular hyperactivity, we investigated the clinical characteristics of MG patients with R-CMAPs to identify their clinical usefulness in therapeutic decision-making.MethodsWe retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT).ResultsAmong 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups.ConclusionsSide effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance.

Concurrent Chronic Motor Axonal Polyneuropathy and Synaptic Impairment of Neuromuscular Junction

Polyneuropathies may exhibits clinical, electrophysiologic signs of neuromuscular junction impairment. Distal motor nerve terminals and neuromuscular junction contain pre or postsynaptically specific targets for circulating autoantibodies, if present in neuropathies. Motor nerve terminal blockade either reversible or permanent is a putative factor of muscle weakness. A 59-year-old patient exhibited oropharyngeal, facial, extremity weakness, fluctuating fatigability, and areflexia. Elecectrophysiologic studies showed purely motor axonal polyneuropathy. Thenar, facial slow rate repetitive stimulation revealed up to 47% decrement of compound muscle action potential size. Single fiber electromyography on voluntary activation confirmed increased jitter and impulse blocking in all muscles examined in one third of the fibers. Repeated testings for antibodies to gangliosides, acetylcholine, muscle tyrosine kinase receptors, voltage-gated calcium channels were negative. Oral pyridostigmine bromide improved bulbar symptoms. Pulse intravenous immunoglobulin, oral steroids, and azathioprine had steady benefit. Impairment of neuromuscular transmission if occurring in chronic axonal neuropathies highlights mechanisms and significance of neuromuscular chronic "synaptopathies."

Electrophysiological signs and the prevalence of adverse effects of acetylcholinesterase inhibitors in patients with myasthenia gravis

The aim of this prospective study was to assess whether extra discharges (EDs), sometimes following the compound muscle action potential, could be used as a neurophysiological indicator of overdose of acetylcholinesterase inhibitors (AChEIs) in patients with myasthenia gravis (MG). The characteristics and frequency of EDs were explored and the correlation of EDs with cholinergic side effects was also determined. Twenty-two MG patients (14 women, 8 men; 61 +/- 16 years of age) with daily AChEI treatment were examined. The mean disease duration was 10 years (range 2-62 years) and all patients had been treated with AChEI since MG onset. Both single and repetitive stimulation of the ulnar and accessory nerves were performed before and 60 min after oral pyridostigmine bromide (PB) administration and after additional edrophonium injection. Fatigue, side effects, and AChE activity in blood were assessed before and 60 min after PB intake. The daily dose of PB ranged from 150 to 900 mg/day. Fourteen patients (64%) experienced daily cholinergic adverse effects, and muscarinic side effects correlated with AChE activity. Eleven patients (50%) developed EDs after oral PB. Among the eight patients with daily nicotinic side effects, EDs were significantly (P < 0.05) more common. Additionally, older patients were more prone to develop cholinergic side effects and EDs. Thus, when EDs are found, patients should be asked about daily muscular symptoms, which may be related to AChEI treatment and not solely to MG.

Non-small-cell lung cancer associated with non-thymomatous myasthenia gravis

A non-small-cell lung cancer without distant metastases was incidentally found in a 77-year-old man who had suffered from myasthenia gravis (MG) without thymoma. The patient's condition was stabilized by oral pyridostigmine bromide which he had taken during the past 6 years. He simultaneously underwent thymectomy and left lower lobectomy with regional lymph node dissection. Although postoperative myasthenic crisis occurred, mechanical ventilation and intravenous steroid pulse relieved the patient and the symptoms improved thereafter. Cases of operable lung cancer with non-thymomatous MG have rarely been reported and the appropriate therapeutic strategy for such cases remains to be debated. Their causal association remains to be identified, whereas some studies have implied that immune disorder due to the abnormal thymus might possibly enhance the oncogenesis of extrathymic malignancies. Myasthenic crisis should also be taken into account in postoperative management of MG patients who simultaneously undergo thymectomy and lobectomy for synchronous lung cancer.

The effect of oral pyridostigmine bromide on the recovery of whole blood cholinesterase activity following ex vivo exposure to soman

Background RBC acetylcholinesterase (AChE) and serum butyrylcholinesterase (BChE) inhibition are considered good biomarkers for protection against exposure to nerve agents. These enzymes may be sequestered (reversibly bound) by pyridostigmine bromide (PB) to protect against the lethal, irreversible binding to organophosphates such as soman (GD). Methods Twenty-four human subjects were given either 30 mg PB orally (n=19) or nothing (n=5). Blood samples were obtained pre- and 2.5, 5, 8, and 24 hours post-dosing. The samples were analyzed for AChE and BChE activity and for PB concentration, using validated spectrophotometric and HPLC/MS methods, respectively. Additionally, the recovery of AChE activity over time following ex vivo exposure of the samples to GD was quantified. Results Maximal inhibition of AChE (29.9%) and concentration of PB (17.1 ng/mL) was noted at 2.5h. AChE activity returned to 95% of pre-dose values at 24h. A linear correlation was found between the amount of PB measured in the blood and the inhibition of AChE. Following GD exposure, recovered AChE activity was similar to levels that were reversibly protected by the PB administration. Conclusion Preliminary data analysis confirms previous findings that PB is an effective pre-treatment drug against soman nerve agent exposure, and that RBC-AChEI is a marker of protection. Complete data and analysis will be presented. Clinical Pharmacology & Therapeutics (2004) 75, P87–P87; doi: 10.1016/j.clpt.2003.11.332

The Effect of Oral Pyridostigmine Bromide Nerve Agent Prophylaxis on Return of Twitch Height in Persons Receiving Succinylcholine

Prophylactic pyridostigmine is used for troops under threat of organophosphate exposure and can affect the neuromuscular blocking agent succinylcholine. The purpose of this study was to determine what effect pyridostigmine would have on neuromuscular blockade from succinylcholine. Thirty-nine subjects were enrolled in this double-blind, placebo-controlled investigation and assigned to either the pyridostigmine or the placebo group. All subjects were evaluated for pyridostigmine or placebo side effects and given an anesthesia induction that included the neuromuscular blocking agent succinylcholine. Neuromuscular blockade was measured by twitch height with a nerve stimulator. Interval data were analyzed using the chi 2 test and Student's t test. The pyridostigmine group demonstrated a prolonged recovery time to return of 25% (p = 0.003) and 75% (p = 0.028) of twitch height compared with the placebo group. No differences were noted for any other parameter measured. We conclude that the recovery from neuromuscular blockade after succinylcholine is prolonged while the intubating conditions remain unaffected.

Suspected congenital myasthenia gravis in Brahman calves

Four, three- to four-week-old Brahman calves, with a common sire and a common maternal grandsire, developed progressive muscular weakness which was exacerbated by exercise and improved with rest. Although the...

Cholinolytic antagonism to the disruptive effects of oral low doses of pyridostigmine on simple discrimination performance in rats

We have previously reported that acute oral administration of low doses (less than or equal to 12 mg/kg) of pyridostigmine bromide (PYR) to rats resulted in a dose-dependent decrement in reinforcement rate under two different multiple schedules of response-produced water presentation, which involved motivational dysfunction rather than motor impairment and alterations in visual perception. The purpose of the present investigation was to examine further if the anticipated operant behavioral deficits of PYR are mediated by central and/or peripheral cholinergic mechanisms. Lever-press responses of male Sprague-Dawley rats were maintained under a multiple fixed-ratio GO/differential-reinforcement-of-low-rate NO GO, brightness discrimination, schedule of water reinforcement. The effects of the muscarinic antagonists atropine (ATR) and methylatropine (MAT), both at doses of 0.25, 0.5 and 1.0 mg/kg (SC), against a single oral low dose of PYR (12 mg/kg)-induced behavioral disruption were compared. ATR partially antagonized the reinforcement loss of PYR with concomitant dose-related increases in nonreinforced responses, whereas MAT completely antagonized the reinforcement loss without affecting the frequency of nonreinforced responses. These results suggest that in rats, the debilitating effects of oral PYR on operant behavior are primarily due to the stimulation of peripheral muscarinic receptors via its anticholinesterase activity. The increments of nonreinforced responses observed after coadministration of PYR with ATR may reflect a central, excitatory action of ATR which could affect the discrimination performance. The present results have practical implications for the clinical utilization of PYR in combination with the peripherally active muscarinic antagonist in situations where optimal performance is required.

Acute effects of oral pyridostigmine bromide on conditioned operant performance in rats

Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3–40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (≤ 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (> 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED 50 was calculated as 23.3 (17.9–28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (≤ 12 mg/kg) had an onset latency within 40–80 min and a duration of 20–80 min, whereas high doses (≥ 24 mg/kg) had an onset latency of 20–40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30–120 mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.

Plasma pyridostigmine levels in patients with myasthenia gravis.

Plasma concentrations of pyridostigmine were measured in 7 patients with myasthenia gravis. Six subjects on oral pyridostigmine bromide were stabilized on widely different doses of the drug (60 to 660 mg/day). Nevertheless, the concentration of the quaternary amine in plasma was maintained within a relatively narrow range (usually between 20 and 60 ng/ml). In 3 myasthenic patients, the area under the plasma concentration-time curve was relatively constant for 4 hr after the same oral dose of pyridostigmine (60 mg). Despite this similarity, there were in general considerable interindividual differences in the bioavailability of pyridostigmine in myasthenic patients. In 1 subject, the bioavailability of the quaternary amine was increased sixfold by doubling the oral dose from 30 mg to 60 mg. After oral administration of pyridostigmine, the half-life of the drug in one subject (4.25 hr) was almost three times as great as after intramuscular administration in a different patient (1.49 hr).