The state of the art in therapeutic administration of botulinum toxin in children with cerebral palsy: an integrative review.

OBJECTIVE: To describe the current state of the art in the therapeutic administration of botulinum toxin with indications, efficacy, and safety profile for children and adolescents with cerebral palsy. DATA SOURCE: An integrative review was conducted. The MEDLINE/PubMed database was searched twice within the last decade using distinct terms, and only studies written in the English language were included. The study population was limited to those aged 0-18 years. Articles that were duplicates or lacked sufficient methodology information were excluded. DATA SYNTHESIS: We found 256 articles, of which 105 were included. Among the included studies, most were conducted in developed countries. Botulinum toxin demonstrated good safety and efficacy in reducing spasticity, particularly when administered by a multidisciplinary rehabilitation team. It is primarily utilized to improve gait and upper limb function, facilitate hygiene care, reduce pain, prevent musculoskeletal deformities, and even decrease sialorrhea in patients without a functional prognosis for walking. CONCLUSIONS: The administration of botulinum toxin is safe and efficacious, especially when combined with a multi-professional rehabilitation team approach, which increases the probability of functional improvement. It can also be beneficial for patients with significant functional impairments to help with daily care tasks, such as hygiene, dressing, and reducing sialorrhea. Pediatricians must be familiar with this treatment and its indications to attend to and refer patients promptly when necessary, and to exploit their neuroplasticity. Further research on this topic is required in developing countries.

Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers.

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

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.

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.

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.

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.

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.

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.

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.

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.

Botulinum toxin in the treatment of sialorrhea in severe neurological patients with tracheotomy.

OBJECTIVE: To observe the clinical effect of botulinum toxin type A (BTA) injection into the salivary glands of the severe neurological patients with tracheotomy METHODS: Seven patients with severe neurological disorders after tracheotomy and obvious drooling symptoms were enrolled. BTA was injected into bilateral parotid glands and submandibular glands under the guidance of ultrasound. Unstimulated salivary flow rate (uSFR) and Drooling Severity and Frequency Scale (DSFS) were used to evaluate drooling before injection, 1 week, and 4 weeks after injection. We compared the extubation time, time of changing from balloon cannula to metal cannula, hospitalization time and incidence of recurrent pulmonary infection between these patients and other patients accepted conventional curation. RESULTS: (1) The drooling severity scale (DSFS-S), the drooling frequency scale (DSFS-F), the drooling frequency and severity scale total score (DSFS-T) were significantly lower at 4 weeks after BTA injection compared to prior-treatment (p < .001). (2) uSFR of 1 week and 4 weeks were both statistically decreased than the untreated condition (p < .001). (3) Compared with the conventional group, the time of changing from balloon cannula to metal cannula was shortened obviously (p < .05) and incidence of recurrent pulmonary infection was clearly decreased (p < .05) after BTA treatment CONCLUSION: Ultrasound-guided BTA injection into salivary glands can effectively reduce saliva secretion. We also found that the time of changing cannula was shortened obviously and the incidence of recurrent pneumonia infection was reduced. BTA injection of salivary glands to cure drooling could advance to the clinical therapy in severe neurological patients after tracheotomy.

Cirugía de desfuncionalización de glándulas salivales mayores en sialorrea masiva / Major salivary gland defunctionalization surgery in massive sialorrhea

Introducción: La sialorrea es la pérdida involuntaria de saliva de la boca, ya sea debido a la producción excesiva de saliva o disminución de la frecuencia de deglución. Se habla de sialorrea patológica cuando persiste más allá de los 4 años de edad. Además de las implicaciones sociales, cambios de ropa frecuentes, puede provocar neumonías por aspiración y deshidratación. El manejo de la sialorrea requiere una evaluación completa con un enfoque de equipo multidisciplinario para el tratamiento, que incluye terapias no farmacológicas, farmacológicas y quirúrgicas. Objetivo: Presentar resultados quirúrgicos y farmacológicos en el tratamiento de sialorrea masiva. Material y Método: Se realizó revisión de historias clínicas de 7 pacientes portadores de sialorrea masiva. Todos los pacientes incluidos fueron refractarios a tratamiento médico. El diagnóstico fue obtenido por un equipo multidisciplinario. Se les realizó desfuncionalización quirúrgica y farmacológica de glándulas salivales. Se les aplicó Escala de Severidad (DSS) y escala de frecuencia (DFS), previo a cirugía y posterior a procedimiento hasta el año. Resultados: Mejoría clínica subjetiva posterior a desfuncionalización quirúrgica con disminución de DSS y DFS. Disminución promedio de baberos a 10/día. Conclusión: Los resultados obtenidos son buenos, si se consideran las escalas DSS, DFS y el número de baberos al día, que son mediciones tanto subjetivas y objetivas respectivamente.

Introduction: Massive Sialorrhea is the involuntary loss of saliva from the mouth, either due to excessive saliva production or decreased swallowing frequency. We speak of pathological sialorrhea when it persists beyond 4 years old. In addition to the social implications and frequent clothing changes. It can cause aspiration pneumonia and dehydration. Treatment for sialorrhea requires a comprehensive evaluation with a multidisciplinary team approach. Including non-pharmacological, pharmacological, and surgical therapies. Aim: Presentation of the results of surgical defunctionalization of the salivary glands plus injection of Botulinum Toxin in the treatment of massive sialorrhea. Material and Method: A review of the clinical records of 7 patients with massive sialorrhea was carried out. All included patients were refractory to medical treatment. The diagnosis was obtained by a multidisciplinary team. Surgical and pharmacological dysfunctionalization of salivary glands was performed. Severity Scale (DSS) and Frequency Scale (DFS) were applied before surgery and after the procedure up to a year. Results: Subjective clinical improvement after surgical defunctionalization with decreased SHD and DFS. Average decrease in bibs to 10/day. Conclusion: The evaluated strategy presented similar benefits with respect to the literature. The SHD and DFS scales and the number of bibs per day are both subjective and objective measurements, respectively, and allow the clinical improvement and quality of life of patients undergoing surgery to be evaluated individually.

Randomised, double-blind, placebo-controlled trial of glycopyrronium in children and adolescents with severe sialorrhoea and neurodisabilities: protocol of the SALIVA trial.

INTRODUCTION: Severe sialorrhoea is a common, distressing problem in children/adolescents with neurodisabilities, which has adverse health and social consequences. The SALIVA trial is designed to evaluate the efficacy and safety of a paediatric-specific oral solution of glycopyrronium along with its impact on quality-of-life (QoL), which has been lacking from previous trials of sialorrhoea treatments. METHODS AND ANALYSIS: A double-blind, placebo-controlled, randomised phase IV trial is ongoing in several centres across France. Eighty children aged 3-17 years with severe sialorrhoea (≥6 on the modified Teachers Drooling Scale) related to chronic neurological disorders in whom non-pharmacological standard of care has already been implemented or has failed, will be recruited. Patients will be randomised 1:1 to receive a 2 mg/5 mL solution of glycopyrronium bromide (Sialanar 320 µg/mL glycopyrronium) or placebo three times daily during a 3-month blinded period. After Day 84, participants will be invited into a 6-month, open-label study extension period, where they will all receive glycopyrronium. The primary endpoint of the double-blind period will be the change from baseline to Day 84 in the Drooling Impact Scale (DIS), a validated measure to assess sialorrhoea. A series of secondary efficacy endpoints involving change in total DIS, specific DIS items and response (DIS improvement ≥13.6 points) will be analysed in a prespecified hierarchy. QoL data will be collected from parents, caregivers and patients where possible using specific DIS questions and DISABKIDS questionnaires. Safety endpoints, including adverse events, will be assessed throughout the trial periods. ETHICS AND DISSEMINATION: In total, 87 children have been recruited and recruitment is now complete. Final results are expected by the end of 2023. Findings will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2020-005534-15.

Can clozapine be used by dental practitioners to increase salivary flow in patients with dry mouth? A scoping review.

OBJECTIVES: Clozapine, an atypical antipsychotic used to treat people with schizophrenia, has been proposed as a possible treatment for salivary gland hypofunction. This scoping review investigated the available literature on clozapine's impact on salivary flow, in order to determine whether it could be used by dental practitioners in low doses as a treatment for dry mouth. DATA SOURCES: An electronic search was completed using Ovid MEDLINE (1996 to Nov 2021). Key MeSH search terms included "clozapine," "Clozaril," "salivation," "salivary flow rate," "sialorrhea," "hypersalivation," and "drooling." Two reviewers independently reviewed eligible articles and extracted the data based on the inclusion and exclusion criteria. RESULTS: The initial search identified 129 studies, six of which were included in this review. Four of them (one cross-sectional and three interventional) described salivary flow rates in schizophrenic patients taking clozapine, while one of those and two others focused on the mechanism of clozapine-induced sialorrhea, with one study covering both. There were mixed findings, with one study observing a moderate association between clozapine dose and salivary flow, and the others reporting no differences. Findings on the putative mechanisms for clozapine-induced sialorrhea (CIS) were inconclusive. CONCLUSION: There is insufficient high-quality information to justify using low-dose clozapine to increase salivary flow in dental patients with salivary gland hypofunction. Well-designed interventional studies and randomized control trials are required.

Effectiveness of the pharmacological treatments for sialorrhea in patients with Parkinson's disease: a systematic review and network meta-analysis.

OBJECTIVES: The present systematic review and network meta-analysis of randomized control trials (RCTs) aimed to establish whether there are evidence-based differences in the pharmacological agents used to manage sialorrhea in patients with Parkinson's disease (PD). MATERIAL AND METHODS: The authors searched the databases: MEDLINE via PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library for clinical trials. Unpublished trials were searched on clinicaltrials.gov and the Brazilian Clinical Trials Registry. Means and standard deviations of changes in the salivary flow or drooling reported by participants due to the interventions were recorded. RESULTS: The authors analyzed 13 RCTs. Compared to the placebo, types A and B of the botulinum toxin effectively reduced the salivary flow and the severity or frequency of drooling. However, the network meta-analysis did not differentiate between the botulinum toxin types. Ipratropium bromide and glycopyrrolate did not differ from the placebo. Indirect evidence showed that ipratropium had similar results to those obtained with both types of botulinum toxin. The CINeMA approach estimated the quality of the evidence as very low for all comparisons. CONCLUSION: The best treatment for sialorrhea in patients with PD is not fully elucidated yet. Therefore, more well-conducted randomized clinical trials are required to increase the level of evidence. CLINICAL RELEVANCE: There needs to be more evidence defining the best intervention to treat sialorrhea in patients with PD. However, botulinum toxin types A and B seem to reduce sialorrhea in patients effectively.