Botulinum toxin type a blocks aquaporin 5 trafficking by decreasing synaptosomal-associated protein 23 in submandibular acinar cells.

The trafficking of aquaporin 5 (AQP5) is critical for salivary secretion. Synaptosomal-associated protein 23 (SNAP23) is an important regulator in the process of membrane fusion. However, the role of SNAP23 on AQP5 trafficking has not been explored. Botulinum toxin type A (BoNT/A) is a bacterial toxin that effectively treats sialorrhea. We previously reported that BoNT/A induced AQP5 redistribution in cultured acinar cells, but the mechanism remained unclear. In this study, SNAP23 was predominantly localized to the plasma membrane of acinar cells in the rat submandibular gland (SMG) and colocalized with AQP5 at the apical membrane of acinar cells. In stable GFP-AQP5-transfected SMG-C6 cells, the acetylcholine receptor agonist carbachol (CCh) induced trafficking of AQP5 from intracellular vesicles to the apical membrane. Furthermore, SNAP23 knockdown by siRNA significantly inhibited CCh-induced AQP5 trafficking, whereas this inhibitory effect was reversed by SNAP23 re-expression, indicating that SNAP23 was essential in AQP5 trafficking. More importantly, BoNT/A inhibited salivary secretion from SMGs, and the underlying mechanism involved that BoNT/A blocked CCh-triggered AQP5 trafficking by decreasing SNAP23 in acinar cells. Taken together, these results identified a crucial role for SNAP23 in AQP5 trafficking and provided new insights into the mechanism of BoNT/A in treating sialorrhea and thereby a theoretical basis for clinical applications.

Comparative Efficacy and Side Effect Profiles of Interventions for Pediatric Saliva Control: A Cohort Study.

OBJECTIVE: To compare efficacy and side effect profile data on conservative, behavioral, pharmacological, and surgical treatments used for pediatric saliva control. STUDY DESIGN: A cohort study of children (n = 483) referred to a specialty Saliva Control service between May 2014 and November 2019 was performed, using quantitative data from pretreatment and post-treatment questionnaires (the Drooling Impact Scale [DIS], Drooling Rating Scale [DRS]) and recording of side effects. Overall, 483 children were included; treatment choices were based on published international guidelines. RESULTS: The greatest improvement was seen after intraglandular botulinum toxin A (BTX-A) injections (n = 207; 551 courses; mean DIS change, 34.7; 95% CI = 29.2-35.7) or duct transpositional surgery (n = 31; mean change in DIS, 29.0; 95% CI, 22.3-35.7). Oral anticholinergics were associated with good outcomes, with no significant statistical difference between glycopyrronium bromide (n = 150; mean DIS change, 21.5; 95% CI, 19.1-24.0) or trihexyphenidyl (n = 87; mean DIS change, 22.4; 95% CI, 18.9-25.8). Inhaled ipratropium bromide was not as efficacious (n = 80; mean DIS change, 11.1; 95% CI, 8.9-13.3). Oromotor programs were used in a selected group with reliable outcomes (n = 9; mean DIS change, 13.0). Side effects were consistent with previous studies. Overall, in cases of milder severity, enterally administered therapies provided a good first-line option. With more severe problems, BTX-A injections or saliva duct transpositional surgery were more effective and well tolerated. CONCLUSIONS: We describe a large, single-center pediatric saliva control cohort, providing direct comparison of the efficacy and side effect profiles for all available interventions and inform clinical practice for specialists when considering different options. BTX-A injections or saliva duct transpositional surgery seem to be more effective for saliva control that is more severe.

Evaluation and Comparison of the Effectiveness of Atropine Eye Drops, Ipratropium Bromide Nasal Spray, and Amitriptyline Tablet in the Management of Clozapine-Associated Sialorrhea in Patients With Refractory Schizophrenia: A Randomized Clinical Trial.

PURPOSE: Clozapine, a second-generation antipsychotic medication, is mainly indicated for managing treatment-resistant schizophrenia. Among all the nonthreatening adverse effects of clozapine, sialorrhea is a stigmatizing complication occurring in approximately 31.0% to 97.4% of patients. In this study, 2 topical agents (atropine eye drop and ipratropium nasal spray) and a systemic medication (amitriptyline) were compared simultaneously for the management of clozapine-associated sialorrhea. METHODS: We conducted a randomized, single-blinded, non-placebo-controlled clinical trial from June 2022 to January 2023. Eligible patients were randomly allocated into 3 mentioned groups. Patients were monitored for sialorrhea weekly based on scales, including the Toronto Nocturnal Hypersalivation Scale, Clinical Global Impression-Improvement, and Clinical Global Impression-Severity for 1 month. Possible adverse drug reactions and adherence were also recorded. RESULTS: Twenty-four patients, including 6, 10, and 8 individuals in ipratropium bromide nasal spray, atropine eye drop, and amitriptyline groups, completed the study, respectively. The cohort's demographic, baseline clinical, and sociocultural characteristics were comparable among the 3 groups. Within-group comparisons, between times baseline and week 4, demonstrated that significant differences were in groups atropine and amitriptyline based on Toronto Nocturnal Hypersalivation Scale, in 3 groups based on Clinical Global Impression-Improvement, and also in only-atropine group based on Clinical Global Impression-Severity. Likewise, between-group comparisons showed that atropine was significantly more effective in clozapine-associated sialorrhea management than amitriptyline and ipratropium, in the first 2 weeks and second 2 weeks of study, respectively. Regarding safety, the interventions were tolerated relatively well. CONCLUSIONS: Conclusively, atropine is more efficacious than amitriptyline, within the first 2 weeks of study and also relative to ipratropium, overall. As time effect was significant between atropine and amitriptyline, according to analysis of covariance test, further investigation with longer follow-up duration would be prudent. In addition, expanding patient population with larger sample size should be conducted for more precision.

Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Glycopyrronium 320 µg/mL in children and adolescents with severe sialorrhoea and neurodisabilities: A randomized, double-blind, placebo-controlled trial.

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.

Predicting non-response to intraglandular botulinum neurotoxin A injections for drooling in children with neurodevelopmental disabilities.

AIM: To develop robust multivariable prediction models for non-response to (1) submandibular botulinum neurotoxin A (BoNT-A) injections and (2) concurrent submandibular and parotid (four-gland) injections, to guide treatment decisions for drooling in children with neurodevelopmental disabilities, including cerebral palsy. METHOD: This was a retrospective cohort study including 262 children (155 males/107 females, median age 7 years 11 months [IQR 5 years 1 month], range 4 years 0 months - 17 years 11 months) receiving submandibular injections and 74 children (52 males/22 females, median age 7 years 7 months [IQR 4 years 3 months], range 4 years 9 months - 18 years 8 months) receiving four-gland injections. Multivariable logistic regression analyses were used to estimate associations between candidate predictors and non-response 8 weeks after injection. RESULTS: Ninety-six children (37%) were non-responders to submandibular injections, for which developmental age was the strongest predictor (adjusted odds ratio [aOR] 2.13; 95% confidence interval [CI] 1.02-4.45 for developmental age <4 years or 4-6 years with IQ <70). Other characteristics that showed a trend towards an increased risk of non-response were diagnosis, sex, and head position. Thirty-four children (46%) were non-responders to four-gland injections, for which tongue protrusion (aOR 3.10; 95% CI 1.14-8.43) seemed most predictive, whereas multiple preceding submandibular injections (aOR 0.34; 95% CI 0.10-1.16) showed a trend towards being protective. Predictors were, however, unstable across different definitions of non-response and both models (i.e. submandibular and four-gland) had insufficient discriminative ability. INTERPRETATION: Potential predictors of non-response to BoNT-A injections were identified. Nevertheless, the developed prediction models seemed inadequate for guidance of treatment decisions. WHAT THIS PAPER ADDS: Developmental age seemed most predictive of non-response to submandibular botulinum neurotoxin A injections. Non-response to concurrent submandibular and parotid injections was best predicted by tongue protrusion and number of previous injections. Multivariable prediction models including these clinical characteristics were unable to discriminate well. Predictors differed when non-response was defined using alternative outcome measures.

Comparing the evidence for botulinum neurotoxin injections in paediatric anterior drooling: a scoping review.

Paediatric anterior drooling has a major impact on the daily lives of children and caregivers. Intraglandular botulinum neurotoxin type-A (BoNT-A) injections are considered an effective treatment to diminish drooling. However, there is no international consensus on which major salivary glands should be injected to obtain optimal treatment effect while minimizing the risk of side effects. This scoping review aimed to explore the evidence for submandibular BoNT-A injections and concurrent submandibular and parotid (i.e. four-gland) injections, respectively, and assess whether outcomes could be compared across studies to improve decision making regarding the optimal initial BoNT-A treatment approach for paediatric anterior drooling. PubMed, Embase, and Web of Science were searched to identify relevant studies (until October 1, 2023) on submandibular or four-gland BoNT-A injections for the treatment of anterior drooling in children with neurodevelopmental disabilities. Similarities and differences in treatment, patient, outcome, and follow-up characteristics were assessed. Twenty-eight papers were identified; 7 reporting on submandibular injections and 21 on four-gland injections. No major differences in treatment procedures or timing of follow-up were found. However, patient characteristics were poorly reported, there was great variety in outcome measurement, and the assessment of side effects was not clearly described.   Conclusion: This review highlights heterogeneity in outcome measures and patient population descriptors among studies on paediatric BoNT-A injections, limiting the ability to compare treatment effectiveness between submandibular and four-gland injections. These findings emphasize the need for more extensive and uniform reporting of patient characteristics and the implementation of a core outcome measurement set to allow for comparison of results between studies and facilitate the optimization of clinical practice guidelines. What is Known: • There is no international consensus on which salivary glands to initially inject with BoNT-A to treat paediatric drooling. What is New: • Concluding on the optimal initial BoNT-A treatment based on literature is currently infeasible. There is considerable heterogeneity in outcome measures used to quantify anterior drooling.and clinical characteristics of children treated with intraglandular BoNT-A are generally insufficiently reported. • Consensus-based sets of outcome measures and patient characteristics should be developed and implemented.

Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

The role and mechanism of tight junctions in the regulation of salivary gland secretion.

Tight junctions (TJs) are cell-cell interactions that localize at the most apical portion of epithelial/endothelial cells. One of the predominant functions of TJs is to regulate material transport through paracellular pathway, which serves as a selective barrier. In recent years, the expression and function of TJs in salivary glands has attracted great interest. The characteristics of multiple salivary gland TJ proteins have been identified. During salivation, the activation of muscarinic acetylcholine receptor and transient receptor potential vanilloid subtype 1, as well as other stimuli, promote the opening of acinar TJs by inducing internalization of TJs, thereby contributing to increased paracellular permeability. Besides, endothelial TJs are also redistributed with leakage of blood vessels in cholinergic-stimulated submandibular glands. Furthermore, under pathological conditions, such as Sjögren's syndrome, diabetes mellitus, immunoglobulin G4-related sialadenitis, and autotransplantation, the integrity and barrier function of TJ complex are impaired and may contribute to hyposalivation. Moreover, in submandibular glands of Sjögren's syndrome mouse model and patients, the endothelial barrier is disrupted and involved in hyposecretion and lymphocytic infiltration. These findings enrich our understanding of the secretory mechanisms that link the importance of epithelial and endothelial TJ functions to salivation under both physiological and pathophysiological conditions.

Comparing botulinum toxin and 4-duct ligation for Sialorrhea in children - A systematic review.

INTRODUCTION: Sialorrhea or drooling can result in physical and psychosocial complications, such as aspiration and social isolation. Treatment options include botulinum toxin into the salivary glands and 4-duct ligation (i.e., simultaneous ligation of the bilateral parotid and submandibular ducts). This systematic review aimed to compare the efficacy and complication rates of botulinum toxin and 4-duct ligation for the treatment of drooling in children. METHODS: Following PRISMA guidelines, PubMed, Embase, Web of Science, and Cochrane Library were searched from inception through June 17, 2021 for studies examining the efficacy of botulinum toxin or 4-duct ligation for drooling in children. Data were summarized by pooled counts, percentages, and means. Complication rates were compared by a chi-squared test. RESULTS: A total of 22 studies (n = 606) examining botulinum toxin and 5 studies (n = 124) examining 4-duct ligation were included. From 12 botulinum toxin studies (n = 211), mean drooling frequency and severity scores was 7.5 at baseline. Mean difference from baseline was -2.6 (n = 92) at 4 weeks follow-up, -2.1 at 8 weeks (n = 41), -2.1 at 12 weeks (n = 56), and - 2.1 at 16 weeks (n = 58). From 4 4-duct ligation studies (n = 103), mean baseline drooling frequency and severity score was 8.4. Mean difference was -3.7 at mean follow-up of 35.6 months (n = 103). Eighteen botulinum studies (n = 343) recorded 53 (15.5 %) complications, including thickened saliva (n = 9), dysphagia (n = 4), and cheek abscesses (n = 4). Four 4-duct ligation studies (n = 108) recorded 25 (23.1 %) complications, including parotid gland swelling (n = 4), aspiration pneumonia (n = 3), and oxygen desaturation (n = 3). There was no statistically significant difference in complication rates between botulinum toxin and four-duct ligation (p = 0.065). CONCLUSION: Botulinum toxin injection and 4-duct ligation are both effective in improving sialorrhea in children and have comparable complication rates.

Use of botox for sialorrhea and dysphagia in the neonatal population.

INTRODUCTION: Botox is frequently used for sialorrhea in patients with compromised airways and those with etiologies causing difficulty with secretion management (i.e. strokes, neurologic disorders, etc.). There are no published studies regarding the use of botulinum toxin (BoNT) in the neonate population. We aim to discuss our experience and safety of BoNT use in the neonate population in regards to alleviating secretion management and airway protection. METHODS: Retrospective review of neonates admitted to the neonatal intensive care unit (NICU) ≤12 months of age who received BoNT injection to submandibular (SMG) and parotid (PG) glands for sialorrhea/dysphagia. BoNT was administered under ultrasound (u/s) guidance by interventional radiology. RESULTS: 6 children were examined. 2 (33 %) were male. Avg NICU stay was 87.5 ± 33.1 days. 2 underwent surgical airway intervention prior to injection. Mean age at initial BoNT was 1.5 ± 0.7 months. Avg weight at injection was 4 ± 1.1 kg. Each PG and SMG were injected in 5/6 cases. Bilateral SMG were unidentified on u/s in 1 case and thus not injected. Dose range injected per gland was 5-15u. 100 % required tube feeds, 50 % with tubes distal to stomach (NJT/NDT). 83 % were completely NPO prior to injection and there was no noted clinical improvement in oral skills post injection. All had noted desats/apneas prior to injection and 83 % had reported decreased events post injection. 50 % had reported decrease O2 requirements and frequent suctioning 2wks after injection, however 2 (33 %) required surgical airway intervention after injection (trach, SGP/MDO). 4/6 (67 %) trialed medical therapy, anticholinergics being the most common. 50 % underwent 2nd injection (age = 6.5 ± 0.3 months) avg. 4.7 ± 0.7mo after 1st injection, and the same 3pts underwent 3rd injection (age = 12.5 ± 2.4 months) avg. 6.1 ± 2.5mo after 2nd injection. 1 pt. had a total 6 injections. There were no injection related complications. CONCLUSION: BoNT injection is a safe, non-invasive alterative for management of sialorrhea in neonates. Further extensive study needs to be performed to identify the optimal dose per gland in this population.

A systematic review of the perspectives of botulinum toxin use on the quality of life of neurological patients with drooling.

OBJECTIVE: To investigate the effectiveness of botulinum toxin in the salivary glands of patients with neurological impairment and drooling and its impact on the quality of life. MATERIALS AND METHODS: This systematic review was registered with the International Prospective Register of Systematic Reviews (CRD 42,023,435,242) and conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. An electronic search was performed in the PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and clinical trial databases until August 2023, no language restriction. Cohort studies and randomized clinical trials of patients diagnosed with drooling and neurological impairment who used botulinum toxin on the salivary gland were included, which evaluated subjective quality of life parameters. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist and Risk of Bias 2 tools. The certainty of the evidence was analyzed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Eight studies involving 317 patients were included. All studies, through subjective parameters, suggested the effectiveness of botulinum toxin in reducing drooling, resulting in an improvement in the quality of life. Three studies demonstrated improvements in swallowing and four in cases of respiratory diseases. Two clinical trials had a high risk of bias, whereas one had low risk. The five cohort studies that were evaluated had a high risk of bias. The certainty of the evidence was considered low. CONCLUSIONS: Based on the patient/caregivers' perception of improvement in drooling, dysphagia, and respiratory symptoms, it can be inferred that botulinum toxin application reduces subjective drooling in neurologically compromised patients. Its impact contributes to the general well-being and quality of life. CLINICAL RELEVANCE: Injection of botulinum toxin into the salivary glands can be considered an alternative technique to surgical or medicinal approaches in reducing drooling. It is effective, less invasive and without significant side effects. It promotes a positive impact on the well-being and quality of life of neurological patients.

Self-reported oral moistening disorders in obstructive sleep apnoea: A scoping review.

BACKGROUND: Obstructive sleep apnoea (OSA) is a highly prevalent problem with significant consequences. Continuous positive airway pressure (CPAP) and oral mandibular advancement device (MAD) are considered the standard treatments for OSA. Patients may experience self-reported oral moistening disorders (OMDs) (i.e. xerostomia or drooling) at the beginning, throughout and after treatment. This affects oral health, quality of life and treatment effectiveness. The exact nature of the associations between OSA and self-reported OMD is still unknown. We aimed to provide an overview of the associations between self-reported OMD on the one hand and OSA and its treatment (namely CPAP and MAD) on the other hand. In addition, we sought to determine whether OMD affects treatment adherence. MATERIALS AND METHODS: A literature search in PubMed was performed up to 27 September 2022. Two researchers independently assessed studies for eligibility. RESULTS: In total, 48 studies were included. Thirteen papers investigated the association between OSA and self-reported OMD. They all suggested an association between OSA and xerostomia but not between OSA and drooling. The association between CPAP and OMD was addressed in 20 articles. The majority of studies have indicated xerostomia as a CPAP side effect; however, some have observed that xerostomia diminishes with CPAP therapy. In 15 papers, the association between MAD and OMD was investigated. In most publications, both xerostomia and drooling have been described as common side effects of MADs. These side effects are often mild and transient, and they improve as patients continue to use their appliance. Most studies found that these OMDs do not cause or are not a strong predictor of non-compliance. CONCLUSION: Xerostomia is a common side effect of CPAP and MAD, as well as a significant symptom of OSA. It may be regarded as one of the indicators of sleep apnoea. Moreover, MAD therapy can be associated with OMD. However, it seems that OMD may be mitigated by being adherent to the therapy.

Localization of the Submandibular Glands Using High-Frequency Ultrasound.

BACKGROUND: Injecting botulinum toxin (BTX) into the submandibular glands (SMGs) can treat drooling symptoms in neurological diseases and improve the aesthetics of SMG hypertrophy and ptotic SMGs. OBJECTIVES: This study aimed to define the size and position of the SMGs by high-frequency ultrasound, and to perform statistical analysis to improve the safety and accuracy of BTX injection therapy. METHODS: Neck ultrasonography with high-frequency ultrasound was performed on 214 volunteers. The length, height, and thickness of the SMGs, and the distance between the SMGs and the midline, the anterior border of the sternocleidomastoid, the mandible, and the surface were measured. RESULTS: The SMGs were almond-shaped with a mean [standard deviation] length of 33.7 [4.7] mm, a thickness of 13.3 [2.9] mm, and a height of 27.6 [6.0] mm. The length and height were significantly different between underage and youth groups. The size of the SMGs did not show any notable differences with increasing BMI; however, their depth, and the distance from the mandible, midline, and anterior border of the sternocleidomastoid increased. No significant differences were observed between the affected and healthy sides in patients with microtia, hemifacial microsomia, or cleft lip and palate. CONCLUSIONS: Ultrasound provides more comprehensive information regarding the size and position of the SMGs, which can serve as a reference in BTX therapy and in the diagnosis of SMG diseases involving size alterations.

Treatment of Clozapine-Associated Sialorrhea: The Role of Benzamide Derivatives.

PURPOSE: Hypersalivation is one of the most prevalent and distressing adverse effects associated with clozapine treatment. Currently, there is no standard therapeutic approach toward how to overcome it. Clinicians use various medications for managing this adverse effect. However, some of the agents are not effective enough, whereas others can induce other adverse effects. Recently, several reviews have been published on the treatment of clozapine-associated hypersalivation, in which the focus was on drugs from various pharmacological groups, and little attention was paid to drugs from the group of substituted benzamides. The intention of this brief narrative review is to draw the attention of clinicians to the use of the benzamide group for the treatment of this unpleasant adverse effect. METHODS: A MEDLINE search was conducted to identify published treatment studies and case reports in the literature from 2000 to September 2021, concerning a treatment of clozapine-associated hypersalivation, mainly substituted benzamides. RESULTS: Accumulating evidence during the last 2 decades indicates that agents derived from the benzamide group may be effective and safe agents for treatment of clozapine-associated hypersalivation. Whether with a psychotropic effect or without, medications from this group may produce a beneficial response. CONCLUSIONS: Substitute benzamide derivatives have emerged as effective and well-tolerated agents for treatment clozapine-associated hypersalivation.

Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics.

INTRODUCTION: Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. METHODS: A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. RESULTS: The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (p < 0.05, impact = 0.50), pyrimidine metabolism (p < 0.05, impact = 0.08), and ß-alanine metabolism (p < 0.05, impact = 0.06). CONCLUSION: Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS.

Decision-To-Scope Score: A novel tool with excellent accuracy in predicting foreign bodies in the esophagus.

INTRODUCTION: Foreign body (FB) ingestion is a common indication for urgent esophagogastroduodenoscopy (EGD). Nevertheless, most pass spontaneously through the gastrointestinal (GI) tract. Differently from GI bleeding, there is no validated score aiming to identify "low-risk" patients in suspected FB ingestion. We aimed to create a score able to discriminate patients who are candidates to emergent EGD in this scenario. METHODS: Retrospective study of consecutive patients admitted for suspected FB in the upper GI tract between 2016 and 2021. The evaluated outcome was endoscopic confirmation of FB in the esophagus. Variables significantly associated with the outcome on multivariate analysis were computed into a score predicting endoscopic confirmation. RESULTS: We included 228 patients. From these, 97 (42.5%) had a confirmed FB in EGD. Time since ingestion <6 h (OR = 4.0; P = 0.042), absence of any meal after FB ingestion (OR = 7.1; P = 0.005), dysphagia (OR = 11.8; P < 0.001), odynophagia (OR = 4.6; P = 0.004), and drooling (OR = 15.1; P < 0.001) were independent predictors of confirmed FB. These variables were used to compute a FB predicting score-the Decision-To-Scope (DTS) Score: time since ingestion <6 h (+1 point), absence of meals (+2 points), dysphagia (+3 points), odynophagia (+1 point), and drooling (+4 points). DTS-Score had excellent accuracy to predict the outcome (AUC = 0.953; 95%CI = 0.928-0.977; P < 0.001). The optimal cutoff to identify low-risk patients was a score ≤5 (sensitivity 85.0% and specificity 94.7%). CONCLUSIONS: More than half of the suspected FB were not confirmed by EGD. The DTS-Score presented excellent accuracy at stratifying patients' risk and may contribute to the decision to perform emergent EGD in suspected FB ingestion.

Effect of Gushen shetuo decoction in improving motor and non-motor symptoms and the expression of PERK, ATF4 and CHOP in patients with Parkinson's disease.

This study aims to observe the therapeutic effect of Gushen Shetuo decoction on Parkinson's disease (PD), so as to provide reference for clinical practice. In order to demonstrate the clinical value of Gushen Shetuo Decoction, we selected 80 patients with PD for the study. Among them, 38 patients received the Gushen Shetuo decoction (research group), and 42 patients received Levodopa and Benserazide Hydrochloride Tablets (control group). There was no difference in Non-Motor Symptoms Scale (NMSS) scores between the research group and the control group (P>0. 05). However, the scores of motor complications in Movement Disorder Society-sponsored revision of the Parkinson's Disease Rating Scale (MDS-UPDRS) and those of Drooling Severity and Frequency Scale (DSFS) in the research group were lower than those in the control group (P<0. 05). Subsequently, we established PD model rats, and after Gushen Shetuo Decoction gavage treatment, we found that rats in the intervention group had increased mobility (P<0. 05), as well as notably improved pathological damage of substantia nigra and striatum. Also, the expression of PERK, ATF4 and CHOP in the brain tissues of rats in the intervention group was lower than those in the control group (P<0. 05). These results confirm that Gushen Shetuo decoction effectively improved the drooling of patients with PD and showed high safety.

Overview of Cochrane systematic reviews for rehabilitation interventions in individuals with cerebral palsy: A mapping synthesis.

AIM: This overview of Cochrane systematic reviews (CSRs) reports on current evidence on the effectiveness of rehabilitation interventions for individuals with cerebral palsy (CP) and the quality of the evidence. METHOD: Following the inclusion criteria defined by the World Health Organization, all CSRs tagged in the Cochrane Rehabilitation database that were relevant for individuals with CP were included. A mapping synthesis was used to group outcomes and comparisons of included CSRs indicating the effect of rehabilitation interventions and the certainty of evidence. RESULTS: A total of eight CSRs were included in the evidence map. The effect of interventions varied across comparisons and the certainty of evidence was inconsistent, ranging from high to very low. The best evidence was found for botulinum neurotoxin A (BoNT-A) combined with occupational therapy in the management of spasticity. However, the effect of BoNT-A on drooling and salivation remains unclear. A paucity of randomized controlled trials studying treatments for both dystonia and postural deformities was noted. INTERPRETATION: This review emphasizes the need to further investigate the effectiveness and cost-benefit of rehabilitation interventions for individuals with CP. WHAT THIS PAPER ADDS: The quality and quantity of evidence on rehabilitation interventions for cerebral palsy is limited worldwide. Botulinum neurotoxin A plus occupational therapy showed robust efficacy for the management of upper-limb spasticity. Evidence on sleep-positioning systems for hip migration and trihexyphenidyl for dystonia is scarce.

Application Site of Transdermal Scopolamine Influences Efficacy and Drug Concentration in Salivary Glands in Rats.

Transdermal scopolamine applied to the postauricular area is used to treat drooling. We investigated the duration of action of scopolamine ointment and the effect of the application site on drug efficacy and concentration in the salivary glands of rats. Scopolamine ointment was applied to the skin over the salivary glands (SSG) and back (SB). Saliva volume was measured after intraperitoneal administration of pilocarpine. Blood and salivary glands were collected after scopolamine ointment application, and scopolamine concentrations in the plasma and salivary glands were measured. Saliva volume after application in the SSG group was significantly lower at all time points than in the non-treated group, and the change in saliva volume in the SSG group was greater than that in the SB group at all time points. This suggests that applying scopolamine ointment to the SSG strongly suppresses salivary secretion. Scopolamine concentration in the salivary glands of the SSG group was significantly higher at 9 h. The change in the efficacy of scopolamine ointment depending on the application site was due to the difference in transfer to the salivary glands. Transdermal administration of scopolamine to the skin over the salivary glands may have high efficiency in treating drooling.