Pyridostigmine in Pediatric Intestinal Pseudo-obstruction: Case Report of a 2-year Old Girl and Literature Review

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, long-acting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility.

Comparison of sugammadex and pyridostigmine bromide for reversal of rocuronium-induced neuromuscular blockade in short-term pediatric surgery: a prospective randomized study

BACKGROUND: Sugammadex reverses rocuronium-induced neuromuscular blockade quickly and effectively. Herein, we compared the efficacy of sugammadex and pyridostigmine in the reversal of rocuronium-induced light block or minimal block in pediatric patients scheduled for elective entropion surgery. METHODS: A prospective randomized study was conducted in 60 pediatric patients aged 2–11 years who were scheduled for entropion surgery under sevoflurane anesthesia. Neuromuscular blockade was achieved by administration of 0.6 mg/kg rocuronium and assessed using the train-of-four (TOF) technique. Patients were randomly assigned to 2 groups receiving either sugammadex 2 mg/kg or pyridostigmine 0.2 mg/kg and glycopyrrolate 0.01 mg/kg at the end of surgery. Primary outcomes were time from administration of reversal agents to TOF ratio 0.9 and TOF ratio 1.0. Time from the administration of reversal agents to extubation and postoperative adverse events were also recorded. RESULTS: There were no significant differences in the demographic variables. Time from the administration of reversal agents to TOF ratio 0.9 and TOF ratio 1.0 were significantly shorter in the sugammadex group than in the pyridostigmine plus glycopyrrolate group: 1.30 ± 0.84 vs. 3.53 ± 2.73 min (P < 0.001) and 2.75 ± 1.00 vs. 5.73 ± 2.83 min (P < 0.001), respectively. Extubation time was shorter in the sugammadex group. Adverse events, such as skin rash, nausea, vomiting, and postoperative residual neuromuscular blockade (airway obstruction), were not statistically different between the two groups. CONCLUSIONS: Sugammadex provided more rapid reversal of rocuronium-induced neuromuscular blockade in pediatric patients undergoing surgery than did pyridostigmine plus glycopyrrolate.

Current use of neuromuscular blocking agents and antagonists in Korea: a 2018 survey

BACKGROUND: Neuromuscular blocking agents (NMBAs) and neuromuscular monitoring in anesthetic management are integral for endotracheal intubation, better visualization of the surgical field, and prevention of residual neuromuscular blockade and pulmonary complications. Sugammadex is a drug that reduces risk of residual neuromuscular blockade, with more rapid recovery compared to anticholinesterase. The purpose of this study was to investigate current usage status of NMBAs and antagonist with neuromuscular monitoring, among anesthesiologists in Korea.METHODS: Anesthesiologists working in Korea were invited to participate in an online survey via email January 2–February 28, 2018. The questionnaire consisted of 45 items, including preferred NMBAs, antagonists, neuromuscular monitoring, and complications related to the use sugammadex. A total of 174 responses were analyzed.RESULTS: Rocuronium was a commonly used NMBA for endotracheal intubation (98%) of hospitals, and maintenance of anesthesia (83.3%) in of hospitals. Sugammadex, pyridostigmine, and neostigmine were used in 89.1%, 87.9%, and 45.4% of hospitals. Neuromuscular monitoring was employed in 79.3% of hospitals; however only 39.7% of hospitals used neuromuscular monitoring before antagonist administration. Usual dosage range of sugammadex was 2.1–4 mg/kg in 35.1% of hospitals, within 2 mg/kg in 34.5% of hospitals, and 1 vial regardless of body weight in 22.4% of hospitals. Sugammadex-related complications were encountered by 14.9% of respondents.CONCLUSIONS: This survey indicates several minor problems associated with the use of antagonists and neuromuscular monitoring. However, most anesthesiologists appear to have appropriate information regarding the usage of NMBAs and sugammadex.

Response to neuromuscular blockade with rocuronium during general anesthesia in a patient with dermatomyositis: A case report

Dermatomyositis is an idiopathic inflammatory myopathy characterized by skin changes and muscle weakness. Depending on the involvement of various muscles, dermatomyositis can cause aspiration pneumonia, ventilatory impairment, and heart failure. Several reports have documented normal or prolonged neuromuscular blockade following administration of different non-depolarizing neuromuscular blockers in patients with dermatomyositis. We observed delayed onset of blockade and prolonged recovery following administration of 0.6 mg/kg rocuronium in a patient with dermatomyositis. However, when the train-of-four ratio reached 0.3, the patient was administered pyridostigmine and glycopyrrolate, which led to normal response to reversal of rocuronium. The patient was extubated without respiratory complications. The outcomes of this case indicate that response to the usual dosage of muscle relaxants in patients with dermatomyositis might be different from that in patients without this condition. Anesthesiologists should pay attention to preoperative cardiorespiratory evaluation and intraoperative neuromuscular monitoring.

In vitro release and gastrointestinal absorption of novel pyridostigmine bromide nanoemulsion / 中国药理学通报

Aim To prepare the novel pyridostigmine bromide nanoemusion(PPNE)and study its release in vitro, and to investigate the intestinal absorption. Methods Pyridostigmine bromide (PB)and PPNE were tested by HPLC in pH 1 .2 HCl,pH 6.8,pH 7.4,pH 7.8 PBS.Rat single pass intestinal perfusion method was employed to investigate the absorption mechanism of PB and PPNE.Results PB release rate was faster than PB in the four release media;the intes-tinal absorption rate constant(Ka )and apparent perme-ability coefficient(Papp)of PPNE were increased in the duodenum,jejunum,ileum and colon segments.PB and PPNE had significant difference in the duodenum, jejunum,ileum and colon segments by t test (P <0.05).Conclusions PPNE can improve the bioavail-ability of drugs,increase the drugs permeability,sig-nificantly improve the absorption of the drugs in the in-testinal segments. PPNE has obviously sustained effects.

Preparation, in Vitro and in Vivo evaluation of pyridostigmine bromide-phospholipids complex nanoemulsion / 中国药学杂志

OBJECTIVE: To prepare pyridostigmine bromide-phospholipids complex nanoemulsion (PPNE) and carry out in vitro and in vivo evaluation. METHODS: The pyridostigmine bromide-phospholipids and PPNE were prepared by solvent evaporation method and pseudo-ternary phase diagram method, respectively. The morphology, particle size, Zeta potential, in vitro release and oral bioavailability of PPNE were evaluated. RESULTS: The PPNE was approximately circular. The particle size and Zeta potential were 26.16 nm and -3.88 mV, respectively. The in vitro release behavior of PPNE was similar to pyridostigmine bromide. The relative oral bioavailability of PPNE was 208.1% to pyridostigmine bromide. CONCLUSION: PPNE was successfully prepared with a simple and repeatable method, which may be a fundamental formulation for further research of pyridostigmine bromide.

Pyridostigmine bromide phospholipid complex nanoemulsion: Correlation between dissolution in vitro and absorption in vivo / 第二军医大学学报

Objective To investigate the correlation between in vitro release and in vivo absorption of pyridostigmine bromide phospholipid complex nanoemulsion (PPNE) by Loo-Reieglman method. Methods PPNE was prepared and dynamic penetration system was used to analyze its in vitro release. The plasma concentration of pyridostigmine bromide was determined by HPLC after oral administration in rats. Loo-Riegelman method was employed to calculate the in vivo absorption percentage (Fa). Then the regression equation was established between absorption percentage and cumulative release. Results The regression equation was set up as follows: Y=1.376 9X-47.543 2,r=0.9411 (P<0.001). Y represented in vivo absorption percentage and X represented in vitro cumulative release rate. Conclusion There is a significant correlation between in vitro release and in vivo absorption of PPNE.

Effect of neuromuscular blockade reversal by pyridostigmine on spectral entropy values during recovery from desflurane anesthesia: a prospective, randomized, double-blind, controlled trial / 대한마취과학회지

BACKGROUND: According to several studies investigating the relationship between muscle activity and electroencephalogram results, reversal of neuromuscular blockade (NMB) may affect depth of anesthesia indices. Therefore, we investigated the effect of pyridostigmine on these indices via spectral entropy. METHODS: Fifty-six patients scheduled for thyroidectomy or parotidectomy were included in this study and randomized into two groups. At the start of skin suturing, the desflurane concentration was adjusted to 4.2 vol% in both groups. Following this, the pyridostigmine group (group P, n = 28) was administered pyridostigmine 0.2 mg/kg mixed with glycopyrrolate 0.04 mg/kg, while the control group (group C, n = 28) received normal saline. Entropy values (response entropy [RE] and state entropy [SE]), train of four (TOF) ratio, and end-tidal desflurane concentration were recorded from point of drug administration to 15 minutes post-drug administration. RESULTS: Mean RE values at 15 minutes, when the maximum effect of pyridostigmine was anticipated, showed a statistically significant difference between groups (53.8 ± 10.5 in group P and 48.0 ± 8.8 in group C; P = 0.030). However, mean SE at 15 minutes showed no significant difference between the two groups (P = 0.066). At 15 minutes, there were significant differences in the TOF ratio between the two groups (P < 0.001). CONCLUSIONS: NMB reversal by pyridostigmine significantly increased RE values but not SE values. This finding suggests that spectral entropy may be a useful alternative tool for monitoring anesthetic depth during recovery from anesthesia in the presence of electromyogram activity.

Pharmacokinetics and relative bioavailability study of multiple oral doses of pyridostigmine bromide sustained-release tablets in rabbits / 第二军医大学学报

Objective To evaluate the pharmacokinetics and the relative bioavailability of pyridostigmine bromide sustained-release tablets (PBSTs) by comparing with the conventional tablets using a multiple-dose design. Methods Six rabbits were randomly divided into 2 groups and were assigned to a self crossover design. The plasma pyridostigmine bromide concentration was determined by high-performance liquid chromatography as multiple oral dose of PBSTs (90 mg each time, and twice a day) or conventional tablets (60 mg each time, three times a day). The pharmacokinetic parameters and relative bioavailability were calculated. Results A two-compartment model was used to describe the in 'vivo behavior of PBSTs after oral administration. The main pharmacokinetic parameters for conventional tablets and multiple oral dose of PBSTs were calculated as the follows: tmax(2. 00 + 0) and (4. 00 ± 0) h; Cmax(25. 48 ± 0.18) mg/Land(19.24±0.45) mg/L; AUC0-α (321. 42 ± 5. 00) mg • h • L-1 and (370.08 ±12.23) mg • h •L-1. The relative bioavailability of the sustained-release tablets was 119. 15% compared with the conventional tablets. Conclusion PBSTs has the property of sustained-relsease and is bioequivalent to the conventional tablets.

Treatment of Dysphagia with Pyridostigmine Bromide in a Patient with the Pharyngeal-Cervical-Brachial Variant of Guillain-Barre Syndrome

A 24-year-old male developed bulbar palsy, ophthalmoplegia, ptosis, and shoulder weakness bilaterally 2 weeks after he had experienced an upper respiratory infection. The electrodiagnostic study demonstrated axonal polyradiculoneuropathy. The repetitive nerve stimulation study (RNS) showed no significant decrement of the compound muscle action potentials (CMAPs). The videofluoroscopic swallowing study (VFSS) showed severe impairment of the pharyngeal phase of swallowing. He was diagnosed as having the pharyngeal-cervical-brachial variant of Guillain-Barre syndrome. The patient's dysphagia was not improved for 3 months. A follow up RNS showed a significant decrement of the CMAPs. Pyridostigmine bromide was tried to improve the dysphagia. The patient showed immediate improvement of his dysphagia on the VFSS after the trial with pyridostigmine bromide. Pyridostigmine bromide was given before each meal for 8 days and he showed continuous improvement of his dysphagia. The follow up VFSS after 3 months showed complete recovery of dysphagia.

Postintervention status in ocular myasthenia gravis: effects of treatment / 中华神经科杂志

ObjectiveTo assess the differences of short- and long-term postintervention status on ocular and systemic symptoms for patients with ocular myasthenia gravis (OMG) after pyridostigmine bromide, corticosteroid, thymectomy, or thymectomy-corticosteroid combination therapy ( combination ).MethodsThis retrospective plus prospective study included 180 OMG patients, whose age of onset ≥ 15 years, treated non-randomly with above therapies separately: thymectomy group (60 cases ), corticosteroid group (39 cases), combination group ( 31 cases ), symptomatic group ( 50 cases ). Postintervention status complying with Myasthenia Gravis Foundation of America (MGFA)complete stable remission ,pharmacologic remission, or minimal manifestations was considered as desirable response, which was used as statistical indicator. Results ①Corticosteroid group showed higher desirable response rates on ptosis, ophthalmoplegia and general weakness at 3-6 months after treatment than other groups, and 42. 1％( 16/38 ) of them at 3 months achieved the desired state of ptosis, higher than the symptomatic group (7/48,14. 6％, ×2 = 8. 200, P = 0. 004 ). ② Ascending ideal rates had been presented in both combination and thymectomy groups since 1 year after treatments, while a little bit higher rate was presented in the former. At the end of observation, 21.7％ ( 13/60 )of patients in thymectomy group achieved complete stable remission.By paired longitudinal comparisons,thymectomy group showed higher ideal rates on ptosis (22/40,55.0％ ), ophthalmoplegia ( 16/27,59. 3％ ) and general weakness (20/40,50. 0％ ) at 2 years than that at 3 months( 11/59,18.6％ ;11/44,25.0％ ;9/60,15.0％ ;P =0. 002, 0. 031,0.000). ③For those patients by symptomatic treatment, the average age of onset was (51.9 ± 18.0) years, higher than that by other 3 therapies (F = 10. 563 ,P =0. 000). ④OMG patients with ophthalmoplegia more likely select corticosteroid or combined therapy. Ophthalmoplegia in combination group was higher than that in symptomatic and surgery groups( ×2 = 12. 939,14. 380, P =0. 000 in both). Ophthalmoplegia in corticosteroid group was higher than that in surgery group ( ×2 = 8. 017, P = 0. 005 ).Conclusions Corticosteroid appears to early overcome ptosis, ocular motor dysfunction and general weakness for patient with OMG in early-to-middle adulthood.Thymectomy andsurgery-corticosteroid combinationtherapies bothshowlong-term effectonthem.

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.