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.

Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine.

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.

Relationships of drooling with motor symptoms and dopamine transporter imaging in drug-naïve Parkinson's disease.

OBJECTIVES: The aim of the present study was to determine the relationships of drooling with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relationships of drooling with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography(123I-FP-CIT SPECT). PATIENTS AND METHODS: Thirty-five untreated PD patients (14 men and 21 women with a mean age of 71.9 ±â€¯7.2 years) were included in this study. The patients were divided into a drooler group and non-drooler group. They underwent clinical assessments and 123I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The results showed that UPDRS motor score (p = 0.002) and akinetic-rigid score (p = 0.008) were higher and that striatal DAT availability (p = 0.03) was lower in the drooler group than in the non-drooler group. However, tremor score, age, and duration of PD showed no significant differences between the drooler group and non-drooler group. CONCLUSIONS: Drooling in untreated PD is related to an increase in motor symptoms (especially bradykinesia and axial symptoms) and to reduction of striatal DAT availability.

IncobotulinumtoxinA for hypersalivation in patients with amyotrophic lateral sclerosis: an open-label single-centre study.

The objective of this study is to discover whether incobotulinumtoxinA (inco) can reduce relative hypersalivation in patients with amyotrophic lateral sclerosis (ALS). 14 patients with ALS (8 males and 6 females, age 55.4 ± 16.3 years) received ultrasound-guided injection of inco 100 MU in both parotid glands and inco 50 MU in both submandibular glands. Saliva production was gravimetrically measured with three cotton rolls placed in the mouth. Weight increase after 5 min was measured on an electronic scale. Subjective saliva production was registered with drooling frequency scale (DFS) and drooling severity scale (DSS). Saliva production was gravimetrically reduced at week 4 (p = 0.04), week 8 (p = 0.01) but not after week 12 after BT application. DFS was reduced at week 4 (p = 0.04), week 8 (p = 0.02), but not after week 12. DSS was reduced at week 4 (p = 0.03), week 8 (p = 0.04) and week 12 (p = 0.04). Patients in our study did not experience changes in their swallowing patterns or any other safety-relevant events. Inco is effective and well tolerated for saliva reduction in patients with ALS for 8-12 weeks.

Assessing agreement between salivary alpha amylase levels collected by passive drool and eluted filter paper in adolescents with cancer.

PURPOSE/OBJECTIVES: To assess the validity of filter paper (FP) against the gold standard of passive drool (PD) for collecting salivary alpha amylase as a surrogate biomarker of psychological stress in adolescents with cancer. DESIGN: Part of a longitudinal, descriptive study of symptoms in adolescents with cancer during chemotherapy. SETTING: A pediatric hematology/oncology treatment center. SAMPLE: 33 saliva sample pairs from nine adolescents with cancer, aged 13-18 years. METHODS: Salivary alpha amylase was collected by PD and FP at four time points during a cycle of chemotherapy: days 1 (time 1) and 2 (time 2) of chemotherapy, day 7-10 (time 3), and day 1 of the next cycle (time 4). A random effects regression was used to assess the correlation between PD and FP values, and a Bland Altman analysis was conducted to assess agreement between the values. MAIN RESEARCH VARIABLES: Salivary alpha amylase. FINDINGS: The estimated correlation between PD and FP values was r = 0.91, p < 0.001. Regression results were also used to rescale FP values to the levels of the PD values because the FP values were on a different scale than the PD values. The Bland Altman analysis revealed that the agreement between the rescaled FP values and PD values was not satisfactory. CONCLUSIONS: Eluted FP may not be a valid method for collecting salivary alpha amylase in adolescents with cancer. IMPLICATIONS FOR NURSING: Psychological stress in adolescents with cancer may be linked to negative outcomes, such as greater symptom severity and post-traumatic stress disorder. Nurses need valid, efficient, biobehavioral measures to assess psychological stress in the clinical setting.

Analysis of residual saliva and minor salivary gland secretions in patients with dry mouth.

The importance of oral mucosal wetness in the condition of dry mouth and the role of salivary proteins in proper oral function are acknowledged. A negative correlation between mucosal wetness and the protein concentration of residual saliva has been reported in normosalivators. Here, to examine the suggestion that a reduction in residual salivary volume leads to a concomitant elevation of its protein concentration, the amount of residual saliva and minor salivary gland secretions, and their protein concentrations, were measured in hyposalivators and normosalivator controls. A Periotron 8000 micro-moisture meter was used to measure the thickness of the mucosal film at six selected mucosal surfaces and the minor salivary gland secretion rate at two mucosal surfaces. The unstimulated whole salivary flow rate was measured by the spitting method. The total protein concentration of all salivary samples was measured by bicinchoninic acid assay. The hyposalivators had significantly lower amounts of residual saliva and minor salivary gland secretions than the normosalivators at all selected mucosal sites except the soft palate. In both groups, the site with the thinnest coat of residual saliva was the anterior hard palate and the wettest site was the anterior dorsal mucosa of the tongue. The protein concentration of residual saliva was significantly higher in hyposalivators than normosalivators. In the minor salivary gland secretions there was no significant difference in protein concentration between the normo- and hyposalivators. When the hyposalivators were divided into two subgroups according to their severity of dryness, the reduction of residual salivary volume and the elevation of protein concentration were more apparent in the group with the more severe dry mouth. Collectively, these results indicate that oral mucosal wetness is associated with the flow rate of unstimulated whole saliva. The function of the minor salivary glands was less affected and relatively well preserved in patients with dry mouth. The increased protein concentration of residual saliva in the hyposalivators appeared to be the result of decreased salivary volume.

Salivary flow-rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data.

The extent of hypersalivation was evaluated in a group of 25 schizophrenic patients on clozapine. A high prevalence of the complaint was detected by a questionnaire; up to 80% of the patients complained of hypersalivation at night. Salivary flow-rate and composition was examined in 17 patients who agreed to participate and in a matched group of healthy controls. No significant differences were detected in composition or flow-rates of resting and stimulated saliva. The salivary flow-rates in the schizophrenic patients on clozapine did not correlate with the subjective complaint of hypersalivation. Because the severity and prevalence of the complaint was higher at night, a possibility of an altered circadian rhythm of salivation might be suggested in these patients.

Possible involvement of parotid beta-adrenergic receptors in the etiology of sialadenosis.

The concentration of beta-adrenergic receptors was determined in rat and human parotid glands, in normal tissue as well as after sympathetic denervation of the rat, and in human sialadenosis. Receptor levels were clearly elevated after denervation of the rat and in sialadenosis. The possible implications of these findings for the etiology of human sialadenosis are discussed.

Sialochemical examinations in non-tumorous parotid enlargements.

Secretion rates and the composition of isolated parotid saliva samples were samples were examined in 51 patients suffering from chronic recurrent parotitis, sialosis, or Sjögren's syndrome, and in 17 healthy controls. Evaluation of the results indicated that sialochemical examination may provide a valuable help in the differential diagnosis of parotid diseases characterized by swelling of the gland. Chronic parotitis is characterized by a significantly decreased flow rate, extremely high sodium and protein concentration and lack of secretory response to stimulation. In Sjögren's syndrome the low flow rate was found to be associated with a decreased potassium secretion rate as well as decreased flow rate and decreased sodium concentration after stimulation. In sialosis, where flow rates display a considerable individual variation, a significant increase in potassium secretion rate could be revealed.