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AIMS Biological rationale suggests that parasympathomimetics (cholinergic receptor stimulating agents) could be beneficial for patients with underactive bladder. However, no systematic review with meta-analysis addressing potential benefits or adverse effects exists. The aim of this review was to assess the effectiveness, both benefits and harms, of using parasympathomimetics for the treatment of underactive bladder. METHODS The protocol was registered in PROSPERO, and searches undertaken in PubMed, Embase, and CENTRAL, including randomized and non-randomized controlled trials of patients with underactive bladder, comparing parasympathomimetic to placebo, no treatment, or other pharmaceuticals. Risk ratios, odds ratios, and mean differences were calculated. RESULTS Twelve trials with 3024 participants were included. There was a significant difference between parasympathomimetics and comparators (favoring parasympathomimetics) in the number of patients with urinary retention (risk ratio 0.55, 95% confidence interval [CI] 0.3-0.98, p = 0.04, low quality of evidence). There was no difference in mean postvoid volume overall (MD -41.4 ml, 95% CI -92.0 to 9.1, p = 0.11, low quality of evidence). There was a significant difference at up to 1 week post-intervention, favoring parasympathomimetics (MD -77.5 ml, 95% CI -90.9 to -64.1, p

At the neuromuscular junction (NMJ), the binding of the excitatory neurotransmitter acetylcholine (ACh) to postsynaptic receptors leads to muscle contraction. As in vertebrate skeletal muscle, cholinergic signaling in the body wall muscles of the model organism Caenorhabditis elegans is required for locomotion. Exposure to levamisole, a pharmacological agonist of one class of ACh receptors on the body wall muscles, causes time-dependent paralysis of wild-type animals. Altered sensitivity to levamisole suggests defects in signaling at the NMJ or muscle function. Here, a protocol for a liquid levamisole assay performed on C. elegans grown in 24-well plates is presented. Vigorous swimming of the animals in liquid allows for the assessment and quantitation of levamisole-induced paralysis in hundreds of worms over a one-hour time period without requiring physical manipulation. This procedure can be used with both wild-type and mutants that have altered sensitivity to levamisole to demonstrate the functional consequences of altered signaling at the NMJ.

Objective : To report on postoperative outcomes related to the administration of neostigmine for reversal of nondepolarizing neuromuscular blocking agents in cardiovascular surgery patients, with a specific focus on the duration of postoperative mechanical ventilation as the primary endpoint. Design : A retrospective cohort study design was followed to achieve the study objectives. Setting : This was a single center chart review study conducted at a large academic medical center of adult patients post cardiovascular surgery. Participants : Patients were included if they had received a bolus dose of perioperative nondepolarizing neuromuscular blocking agent and underwent one of the targeted cardiovascular surgeries. Interventions : Final analysis consisted of 175 patients: 95 received neostigmine and 80 did not receive neostigmine. Measurements and Main Results : The primary endpoint was the duration of post-operative mechanical ventilation. When controlling for all covariates, neostigmine use was associated with a 0.34-hour reduction (∼20.4 minutes) in duration of mechanical ventilation (parameter estimate: 0.66, 95% CI 0.49-0.89, p=0.0071). More patients who received neostigmine met the early extubation benchmark of less than six hours (55 vs 34 patients, p=0.04). Finally, neostigmine use was also not found to be associated with increased risk of respiratory complications or postoperative nausea and/or vomiting. Conclusions : The use of neostigmine was found to have a protective effect on the duration of postoperative mechanical ventilation without increasing the risk for adverse complications.

Background Calcium increases the probability of transmitter release at the neuromuscular junction. It is not known whether there is a dose-dependent relationship between the dosage of calcium gluconate and the probability of transmitter release for non-depolarizing neuromuscular blockade (NMB) recovery by acetylcholinesterase inhibitors (AchEIs). This study compared the neuromuscular recovery time and the incidence of postoperative residual curarization (PORC) according to the dosage of calcium gluconate co-administered with neostigmine in three patient groups. Methods Patients were randomly allocated to a control group, a 5 mg/kg calcium gluconate group (calcium 5 group), or a 10 mg/kg calcium gluconate group (calcium 10 group). In patients with a TOF ratio (TOFr) between 0.2–0.7, 0.04 mg/kg of neostigmine was administered and both 0.2 mg of glycopyrrolate and 0.4 mg of atropine per 1 mg of neostigmine were administered. And additional 5 or 10 mg/kg of calcium gluconate were administrated to the calcium 5 and 10 groups. The primary endpoint was neuromuscular recovery time (the time between reversal and TOFr≥0.9). The secondary endpoints were the incidence of PORC at 5, 10, and 20 min after reversal administration and the train-of-four ratio (TOFr) at each time point. Results The neuromuscular recovery time was 5.3 min in the control group, 3.9 min in the calcium 5 group, and 4.1 min in the calcium 10 group, respectively (P = 0.004). The incidence of PORC at 5 min after neostigmine administration was 12 in the control group, 4 in the calcium 5 group, and 4 in the calcium 10 group, respectively, with statistical significance (P = 0.014). Conclusions The co-administration of calcium gluconate with neostigmine safely promoted early NMB recovery, and the neuromuscular recovery time of the calcium 10 group tended to be more evenly distributed than that of the calcium 5 group. Trial registration https://cris.nih.go.kr/cris/index.jsp(KCT0004182). Date of registration: August 122,019.

Background Bladder dysfunction is a common complication following radical hysterectomy, caused by the damage to pelvic autonomic nerves that innervate the muscles of the bladder, urethral sphincter, and pelvic floor fasciae. Bladder dysfunction increases the rates of urinary tract infection, hospital visits or admission, and patient dissatisfaction. In addition, bladder dysfunction can also negatively impact patient quality of life (QoL). Several postoperative interventions have been proposed to prevent bladder dysfunction following radical hysterectomy. To our knowledge, there has been no systematic review evaluating the effectiveness and safety of these interventions for preventing bladder dysfunction following radical hysterectomy in women with cervical cancer. Objectives To evaluate the effectiveness and safety of postoperative interventions for preventing bladder dysfunction following radical hysterectomy in women with early-stage cervical cancer (stage IA2 to IIA2). Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library, MEDLINE via Ovid (1946 to April week 2, 2020), and Embase via Ovid (1980 to 2020, week 16). We also checked registers of clinical trials, grey literature, conference reports, and citation lists of included studies. Selection criteria We included randomised controlled trials (RCTs) evaluating the effectiveness and safety of any type of postoperative interventions for preventing bladder dysfunction following a radical hysterectomy in women with stage IA2 to IIA2 cervical cancer. Data collection and analysis Two review authors independently selected potentially relevant RCTs, extracted data, assessed risk of bias, compared results, and made judgments on the quality and certainty of the evidence. We resolved any disagreements through discussion or consultation with a third review author. Outcomes of interest consisted of spontaneous voiding recovery one week after the operation, quality of life (QoL), adverse events, post-void residual urine volume one month after the operation, urinary tract infection over the one month following the operation, and subjective urinary symptoms. Main results We identified 1464 records as a result of the search (excluding duplicates). Of the 20 records that potentially met the review criteria, we included five reports of four studies. Most of the studies had unclear risks of selection and reporting biases. Of the four studies, one compared bethanechol versus placebo and three studies compared suprapubic catheterisation with intermittent self-catheterisation. We identified two ongoing studies. Bethanechol versus placebo The study reported no information on the rate of spontaneous voiding recovery at one week following the operation, QoL, adverse events, urinary tract infection in the first month after surgery, and subjective urinary symptoms for this comparison. The volume of post-void residual urine, assessed at one month after surgery, among women receiving bethanechol was lower than those in the placebo group (mean difference (MD) -37.4 mL, 95% confidence interval (CI) -60.35 to -14.45; one study, 39 participants; very-low certainty evidence). Suprapubic catheterisation versus intermittent self-catheterisation The studies reported no information on the rate of spontaneous voiding recovery at one week and post-void residual urine volume at one month following the operation for this comparison. There was no difference in risks of acute complication (risk ratio (RR) 0.77, 95% CI 0.24 to 2.49; one study, 71 participants; very low certainty evidence) and urinary tract infections during the first month after surgery (RR 0.77, 95% CI 0.53 to 1.13; two studies, 95 participants; very- low certainty evidence) between participants who underwent suprapubic catheterisation and those who underwent intermittent self-catheterisation. Available data were insufficient to calculate the relative measures of the effect of interventions on QoL and subjective urinary symptoms. Authors' conclusions None of the included studies reported rate of spontaneous voiding recovery one week after surgery, time to a post-void residual volume of urine of 50 mL or less, or post-void residual urine volume at 6 and 12 months after surgery, all of which are important outcomes for assessing postoperative bladder dysfunction. Limited evidence suggested that bethanechol may minimise the risk of bladder dysfunction after radical hysterectomy by lowering post-void residual urine volume. The certainty of this evidence, however, was very low. The effectiveness of different types of postoperative urinary catheterisation (suprapubic and intermittent self-catheterisation) remain unproven.

Introduction. The gastric residual volume (GRV) monitoring in patients with mechanical ventilation (MV) is a common and important challenge. The purpose of this study was to compare the effect of neostigmine and metoclopramide on GRV among MV patients in the intensive care unit (ICU). Methods. In a double-blind randomized clinical trial, a total of 200 mechanically ventilated ICU patients with GRV > 120 ml (6 hours after the last gavage) were randomly assigned into two groups (A and B) with 100 patients in each group. Patients in groups A and B received intravenous infusion of neostigmine at a dose of 2.5 mg/100 ml normal saline and metoclopramide at a dose of 10 mg/100 ml normal saline, within 30 minutes, respectively. GRV was evaluated 5 times for each patient, once before the intervention and 4 times (at 3, 6, 9, and 12 hours) after the intervention. In addition, demographic characteristics including age and gender, as well as severity illness based on the sequential organ failure assessment score (SOFA), were initially recorded for all patients. Results. After adjusting of demographic and clinical characteristics (age, gender, and SOFA score), the generalized estimating equation (GEE) model revealed that neostigmine treatment increased odds of GRV improvement compared to the metoclopramide group ( OR = 2.45 , 95% CI: 1.60-3.76, P < 0.001 ). However, there is a statistically significant time trend (within-subject differences or time effect) regardless of treatment groups ( P < 0.001 ). Conclusion. According to the results, although neostigmine treatment significantly improved GRV in more patients in less time, within 12 hours of treatment, all patients in both groups had complete recovery. Considering that there was no significant difference between the two groups in terms of side effects, it seems that both drugs are effective in improving the GRV of ICU patients.

Background: After colorectal surgery, anastomotic leakage is a major cause of mortality and morbidity. There are many factors affecting anastomotic leakage. It is known that agents such as neostigmine that is used to reverse neuromuscular blockade have certain effects on anastomosis. In our study, in which we planned to test this hypothesis, we aimed to compare the possible effects of different doses of sugammadex and neostigmine on colon anastomosis strength in a colonic resection anastomosis model in rats. Materials and methods: Forty adult Wistar albino male rats were divided into five groups as control (group C), Sugammadex 16 mg/kg (group SL), sugammadex 96 mg/kg (group SH), neostigmine 0.3 ?mol/kg (group NL), and neostigmine 1.5 ?mol/kg (group NH). The transverse colons of all rats were resected, and colonic anastomosis was performed. Appropriate drug doses according to the groups were given on the postoperative seventh day, and tissue hydroxyproline (TH) level and anastomotic bursting pressure were measured. Results: Anastomotic bursting pressure values were statistically significantly different between the groups (P = 0.001). The bursting pressure in group SH was significantly higher compared with group C, group NL, and group NH. The hydroxyproline values were statistically significantly different between the groups (P = 0.015). According to the post hoc test results, the difference was between group SH and group C (P = 0.007). There were no significant differences between the other groups (P > 0.05). There was no significant difference in terms of intra-abdominal adhesion rates between the groups. Conclusions: In our study, we found that low and high doses of neostigmine had no variable effect on anastomosis, but high dose of sugammadex (96 mg/kg) had an increasing effect on intestinal anastomosis strength. © 2019 Elsevier Inc. 2-s2.0-85077025251 PubMed: 31896497

Background Neuromuscular blocking drugs (NMBD) are administered intra-operatively to facilitate intubation and to achieve muscle relaxation for surgical procedures. Incomplete reversal of NMBD can lead to adverse events in the postoperative period. Patients with obstructive sleep apnea (OSA) may be at higher risk of complications related to the use of NMBD. The objectives of this systematic review were to determine whether: 1) OSA patients are at higher risk of postoperative complications from the use of NMBD than non-OSA patients, and 2) the choice of NMBD reversal agent affects the risk of postoperative complications in OSA patients. Methods A literature search of multiple databases was conducted up to April 2017. The inclusion criteria were: (1) adult surgical patients (≥18 years old) with OSA diagnosed by polysomnography, or history, or suspected by screening questionnaire; (2) patients who were given NMBD and/or NMBD reversal agents intraoperatively; (3) reports on postoperative adverse events, particularly respiratory events were available; (4) published studies were in English; and (5) RCTs or observational cohort studies. The quality of evidence was determined by the Oxford Center for Evidence Based Medicine levels of evidence. Results Out of 4123 studies, five studies (2 RCTs and 3 observational studies) including 1126 patients were deemed eligible. These studies were heterogeneous precluding a meta-analysis of the results. Two of three studies (1 RCT, 2 observational studies) reported that OSA patients given NMBD may be at higher risk of developing postoperative pulmonary complications (PPCs) like hypoxemia, residual neuromuscular blockade or respiratory failure compared to non-OSA patients. Two studies (1 RCT, 1 observational study) reported that OSA patients who were reversed with sugammadex vs. neostigmine had less PPCs and chest radiographic changes, but the quality of the included studies was Oxford level of evidence: low to moderate. Conclusions OSA patients who receive intraoperative NMBD may be at higher risk for postoperative hypoxemia, respiratory failure and residual neuromuscular blockade compared to non-OSA patients. There is some, albeit very limited evidence that NMBD reversal with sugammadex may be associated with less PPCs than neostigmine in patients with OSA. More high-quality studies are needed.

The superior salivatory nucleus (SSN) contains parasympathetic preganglionic neurons innervating the submandibular and sublingual salivary glands. Cevimeline, a muscarinic acetylcholine receptor (mAChR) agonist, is a sialogogue that possibly stimulates SSN neurons in addition to the salivary glands themselves because it can cross the blood-brain barrier (BBB). In the present study, we examined immunoreactivities for mAChR subtypes in SSN neurons retrogradely labeled with a fluorescent tracer in neonatal rats. Additionally, we examined the effects of cevimeline in labeled SSN neurons of brainstem slices using a whole-cell patch-clamp technique. Mainly M1 and M3 receptors were detected by immunohistochemical staining, with low-level detection of M4 and M5 receptors and absence of M2 receptors. Most (110 of 129) SSN neurons exhibited excitatory responses to application of cevimeline. In responding neurons, voltage-clamp recordings showed that 84% (101/120) of the neurons exhibited inward currents. In the neurons displaying inward currents, the effects of the mAChR antagonists were examined. A mixture of M1 and M3 receptor antagonists most effectively reduced the peak amplitude of inward currents, suggesting that the excitatory effects of cevimeline on SSN neurons were mainly mediated by M1 and M3 receptors. Current-clamp recordings showed that application of cevimeline induced membrane depolarization (9/9 neurons). These results suggest that most SSN neurons are excited by cevimeline via M1 and M3 muscarinic receptors.

This study aimed to assess the effects of sugammadex and neostigmine/atropine on postoperative cognitive dysfunction (POCD) in adult patients after elective surgery. A randomised, double-blind controlled trial was carried out on 160 American Society of Anesthesiologists physical status I to III patients who were >40 years of age. The Mini–Mental State Evaluation, clock-drawing test and the Isaacs Set test were used to assess cognitive function at three timepoints: 1) preoperatively, 2) one hour postoperatively, and 3) at discharge. The anaesthetic protocol was the same for all patients, except for the neuromuscular block reversal, which was administered by random allocation using either sugammadex or neostigmine/ atropine after the reappearance of T2 in the train-of-four sequence. POCD was defined as a decline ≥1 standard deviation in ≥2 cognitive tests. The incidence of POCD was similar in both groups at one hour postoperatively and at discharge (28% and 10%, in the neostigmine group, 23% and 5.4% in the sugammadex group, P=0.55 and 0.27 respectively). In relation to individual tests, a significant decline of clock-drawing test in the neostigmine group was observed at one hour postoperatively and at discharge. For the Isaacs Set test, a greater decline was found in the sugammadex group. These findings suggest that there are no clinically important differences in the incidence of POCD after neostigmine or sugammadex administration.

Combination of prokinetic drugs with different mechanisms of action is frequently used when feeding intolerance is not improved with a single agent. In this study, we evaluated the effect of combined infusion of neostigmine and metoclopramide on gastric passage in critically ill patients in the intensive care unit (ICU).This study is a randomized double-blind controlled trial in 90 patients between 20 and 60years of age who were under mechanical ventilation and had gastric residual volumes (GRVs)120mL 3h after the last lavage. Patients were randomly assigned to one of the following three groups: intravenous neostigmine 2.5mg, intravenous metoclopramide 20mg, and combination of both agents at the mentioned doses. Gastric volume aspiration was first performed before starting the study and then at 3, 6, 9, and 12h after the infusion of study drugs was finished. Increase in gastric lavage was defined as an aspiration volume of120mL.In total, 86 cases in the three groups completed the treatment (all 90 patients included in the study were analysed according to an intention-to-treat approach). There was no significant difference detected at baseline in age, intubation duration, albumin, haemoglobin, haematocrit, total leucocytic count (WBC), Na, K, Mg, and sequential organ failure assessment score between the study groups. In the combination group, 96.7% of patients showed GRV improvement (GRV120cc), whereas in the metoclopramide and neostigmine groups, 50% and 43.3% of the patients, respectively, showed improvement (p0.001). The frequency of overall adverse effects in the metoclopramide, neostigmine, and combination groups were 3.3%, 16.7%, and 10%, respectively (p=0.28).The present results suggested that combination therapy with metoclopramide and neostigmine decreases GRV in critically ill patients with a higher efficacy than monotherapies.

Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2 ) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity. Significance High-risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

Asthma is a chronic inflammatory lung disease of the airway; the incidence and prevalence of asthma remain high worldwide. Astragaloside IV (AS-IV) is the main active constituent of Astragalus membranaceus. Accumulating evidence suggests that AS-IV possesses anti-inflammatory and anti-asthmatic ability, but the potential molecular mechanism is required to further clarify. In this study, the anti-asthmatic effects of AS-IV on mice with ovalbumin (OVA)-induced allergic inflammation were analysed. We analysed airway hyperresponsiveness (AHR), numbers of inflammatory cells, inflammation situation in lung tissue and cytokines level in bronchoalveolar lavage fluid (BALF) between OVA-induced mice with and without AS-IV treatment. Moreover, we explored the possible signalling pathway behind the anti-asthmatic effects. Our results revealed that AS-IV treatment ameliorates airway inflammation and AHR in an OVA-induced asthma model. Besides, AS-IV treatment inhibits the interleukin (IL)-4, -5 and -13 production, and further study indicated that AS-IV treatment downregulates the expression level of p-JAK2/p-STAT6 proteins. Taken together, the present study suggested that the inhibitory effects of AS-IV on asthma therapy are at least partially involved in inhibiting the JAK2/STAT6 signalling pathway.

Glaucoma is a group of diseases that exhibit a characteristic optic neuropathy which, untreated, initially causes loss of peripheral and ultimately central vision. It is a leading cause of blindness worldwide and is estimated to affect over three million people in the United States. Although vision loss due to glaucoma is irreversible, blindness can typically be prevented when it is detected and treated in its earlier stages. A number of different medication classes are currently in use to treat glaucoma, including prostaglandin analogues, B-adrenergic antagonists, adrenergic agonists, carbonic anhydrase inhibitors, parasympathomimetics, and hyperosmotic agents. In general, these medications reduce IOP either by reducing aqueous humor secretion from the ciliary body or by increasing aqueous outflow from the eye.