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Objectives: Anticholinergics cause dry mouth and are highly relevant for dentists, but little is known about the relationships between intake and the occurrence of subjective and objective dry mouth with age. The German anticholinergic burden score (GACB) is a novel anticholinergic score that re-evaluates medications, particularly, those with classification discrepancies., Material and Methods: We retrospectively investigated the GACB in older patients receiving dental care, evaluated whether GACB is related to xerostomia and unstimulated salivary secretion, and determined the influence of increasing age (beginning at 50 years of age). The GACB score quantified cumulative anticholinergic effects: 0 for no effect, 1 for possible, 2 for moderate, and 3 for strong. Cross-sectional data in patients ≥ 50 years were collected, including xerostomia with the visual analog scale, unstimulated salivary flow rates, and the GACB scores., Results: Among 172 patients (mean age 65.67 ± 9.51 years), 23.8% had a GACB score ≥ 1. A moderate negative correlation was observed between GACB and unstimulated salivary flow rates ( r ̅ $\mathop{r}\limits^{&#773;}$  = -0.51). Patients with GACB ≥ 1 had fewer teeth (mean 21.76 ± 5.41) than those with GACB = 0 (24.07 ± 5.57). Moreover, unstimulated hyposalivation was observed in 61.0% with GACB ≥ 1 versus 6.8% with GACB = 0 (p < 0.001). Escalating chronic systemic conditions and prescribed medications were recorded with increasing age; those aged 76-80 years had the highest burden., Conclusions: The GACB quickly and reliably assesses anticholinergic exposure and risks for oral health in older patients. Routine use in those aged ≥ 50 years could enable early identification of risks and initiation of preventive dental measures., Trial Registration: German Registry for Clinical Trials: DRKS00032877 (https://www.germanctr.de; date of registration: 17.10.2023)., (© 2024 The Author(s). Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Salivation is easily taken for granted, but without normal salivation, simple essential tasks such as chewing and swallowing become difficult, with consequences for quality of life, nutrition and oral health. Many important drug classes cause dry mouth as a side effect, contributing substantially to patient non-compliance. Available treatments are mostly palliative. Cannabis user complaints of dry mouth prompted a study that showed that basal salivation is likely regulated by cannabinoid CB1 receptors on neurons that innervate the submandibular gland. But what about stimulated salivation? The adjoining parotid gland releases saliva in response to olfactory or other cues and contributes a large portion of the net salivation in humans. We investigated cannabinoid regulation of stimulated salivation using functional and protein-expression studies in mice. In developing a model of stimulated salivary responses to food-related odorants in mice, we noted sex-dependent responses to food-related cues. Only male mice learned to salivate in response to the odor of peanut butter while only female mice responded to a chocolate hazelnut spread. Both males and females responded to sugar or marmite. Testing peanut butter, we found that the cannabinoid receptor agonist CP55940 (0.5 mg/kg, IP) lowered baseline salivation, as shown previously, but also prevented the odorant-induced increase in salivation. CB1 receptors are expressed in axons innervating the parotid gland, paralleling our findings in the submandibular gland. Notably, we also found that CB1 deletion impaired some responses (those to peanut butter and chocolate hazelnut spread) but not others (sugar or marmite). In mice, the CB1 antagonist SR141716 (4 mg/kg, IP) prevented a previously learned salivary response to peanut butter. We find that CB1 receptors are expressed in a subset of glomeruli in coronal sections of olfactory bulb that may serve as a site of action for scent-specific effects of CB1 receptors. We additionally observe CB1 expression in accessory olfactory bulb. In summary, we find a novel sex-dependence in responses to a subset of food-related odorant cues and that cannabinoid receptors regulate some of these responses. We propose that CB1 receptors act at the parotid gland to inhibit stimulated salivation but also in the olfactory system, where functional CB1 receptors are required for salivary responses to specific appetitive odors., (© 2024. The Author(s).)

Background: Olfactory stimulation with mastic resin, derived from the Pistacia lentiscus tree, demonstrated a bona fide sialagogic effect in healthy volunteers [1]. Its main volatile compound, α-pinene, also showed this effect. The current study aimed to validate the effect of mastic resin volatiles in chronic dry mouth patients with confirmed decreased saliva secretion., Methods: 41 chronic dry mouth patients with decreased unstimulated saliva secretion (<0.25 mL/min) were exposed to mastic resin volatiles as part of the diagnostic routine at the Saliva Clinic of Academic Centre for Dentistry Amsterdam. During their visit, dry-mouth questionnaires were conducted and samples of unstimulated whole saliva, chew-stimulated saliva, acid-stimulated saliva and mastic resin stimulated saliva were collected. Saliva flow rate, spinnbarkeit, pH, ion composition, MUC5B and MUC7 levels in all samples were analyzed., Results: Salivary flow rates increased by all stimuli when compared to the baseline unstimulated saliva (P<0.001). During olfactory mastic resin stimulation, the salivary spinnbarkeit (P<0.001) and sodium concentration (P<0.01) were increased compared to unstimulated saliva. MUC5B and MUC7 levels were increased during olfactory mastic resin stimulation compared to chew-stimulated saliva (P=0.016 and P<0.001, respectively). Spinnbarkeit correlated positively with MUC5B (R=0.399, P=0.002) and MUC7 levels (R=0.375, P=0.004). Results of dry-mouth questionnaires indicated reduced posterior palate dryness shortly after olfactory mastic resin stimulation (P=0.04)., Conclusions: Olfactory mastic resin stimulation increased mucous saliva secretion and reduced posterior palate dryness in a group of chronic dry mouth patients. These findings, validated in patients, underscore mastic resin scent as a beneficial and non-invasive sialagogic treatment for clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: To evaluate whether the severity of xerostomia in older polymedicated patients impacts oral health-related quality of life (OHRQoL)., Background: Medication-associated xerostomia is common in older people. Xerostomia may impair OHRQoL., Materials and Methods: This cross-sectional study included older hypertensive patients from two health centres. We assessed the severity of xerostomia and OHRQoL using the Xerostomia Inventory (XI) tool, and the Oral Health Impact Profile-14 (OHIP-14) instrument, respectively. We measured unstimulated (UWS) and stimulated (SWS) salivary flows. Univariate and multiple linear regression analyses evaluated the associations of XI and OHIP-14 and different explanatory variables., Results: Of the 218 patients enrolled, 51.8% had xerostomia, and 38.1% and 27.5% suffered from UWS and SWS hyposalivation, respectively. Patients with xerostomia, UWS, and SWS hyposalivation scored significantly higher on the XI. However, only those with xerostomia or UWS hyposalivation had significantly higher OHIP-14 scores. A moderate correlation was observed between XI and OHIP-14 scores. The multiple regression model showed that factors with the greatest impact on XI were the patient's complaint of xerostomia, UWS flow rate, age and sex. However, only the XI score was significantly associated with the OHIP-14 score., Conclusion: Xerostomia has a negative impact on OHRQoL in older polymedicated patients, but this impact is less than in other types of xerostomia. Longitudinal studies are needed to determine whether changes in the detected explanatory variables influence XI and OHIP scores in these patients., (© 2023 The Authors. Gerodontology published by Gerodontology Association and John Wiley & Sons Ltd.)

Background: It remains unclear how the salivary flow and the fat content of food affect bolus formation during mastication., Objectives: We aimed to clarify: (1) how hyposalivation affects jaw-closing and hyoid-elevating muscle activities in bolus formation, and (2) if the effect of hyposalivation on muscle activity depends on the fat content of food., Methods: Eighteen healthy male volunteers were instructed to freely ingest four test foods: Plain, Fat without seasoning, Fat with seasoning, and Soft rice crackers. Masseter and suprahyoid electromyographic activities were recorded before and 30 min after the administration of atropine sulfate, a muscarinic receptor antagonist that induces hyposalivation., Results: Hyposalivation extended the masticatory duration significantly in all the test foods except Fat with seasoning. Masticatory cycle time was significantly longer with vs without hyposalivation for the Soft (p = .011). Suprahyoid activity/cycle was significantly greater with vs without hyposalivation (p = .013). Masticatory cycle time was significantly longer at the late stage with vs without hyposalivation for the Soft (p < .001). Suprahyoid activity/cycle was significantly greater at the middle (p = .045) and late stages (p = .002) with vs without hyposalivation for the Soft and greater at the late stage with vs without hyposalivation for the Plain (p = .043). Changes in masticatory cycle time and suprahyoid activity/cycle for these foods had significantly positive relationship (p < .001)., Conclusion: Hyposalivation-induced changes in masticatory behaviours resulted from the middle and late stage suprahyoid activity. Fat content and seasoning compensate for salivary flow inhibition., (© 2024 John Wiley & Sons Ltd.)

Background: Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats., Methods: Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues., Results: Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration., Conclusions: Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation., (© 2024. The Author(s).)

Background: Arterial hypertension is a systemic condition that affects about 35% of the world population. The drugs that are used for its control can produce hyposalivation. This work evaluated the effect of photobiomodulation on salivary flow rate, salivary pH, total protein concentration, and calcium concentration in individuals using antihypertensive medications., Material and Methods: 41 subjects were randomly allocated in one of two groups: control (placebo) and photobiomodulation. The subjects had their salivary glands (20 sites) irradiated with a laser emitting at 808 nm, 4J/site once a week for 4 weeks and had their salivary flow measured before and after the whole treatment., Results: The intragroup analysis (before and after treatment) shows a significant difference for both non-stimulated and stimulated salivary flow in the photobiomodulation group (p = 0.0007 and p = 0.0001, respectively). Comparing the placebo with the photobiomodulation group, significant differences were found for both non-stimulated (p = 0.0441) and stimulated salivary flow (p = 0.0441) after the treatment. No significant differences were found in pH, total protein concentration, calcium concentration., Conclusion: Despite the usage of drugs that influence the nervous system and typically result in a reduction of saliva production, photobiomodulation demonstrated a remarkable ability to enhance saliva production by a significant 75%., Competing Interests: Declaration of competing interest All authors report lack of competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This in vivo mouse model study was conducted to investigate the temporal alteration of the function of CD36 in salivary secretion. CD36 was highly expressed in the parotid gland of BALB/c mice. No significant variations were shown in the CD36 levels in the 8-, 48-, and 72-week-old animals. However, pilocarpine-induced salivary secretion was reduced in an age-dependent manner, showing a significantly low level at the age of 72 weeks. Pilocarpine-induced salivary secretion was significantly reduced by pretreatment with a CD36 inhibitor at 8 and 48 weeks, but not at 72 weeks. In senescence-accelerated mice (SAM), the pilocarpine-induced salivary secretion was significantly reduced at the age of 56 weeks, and a significantly lower amount of CD36 was demonstrated in the parotid gland, compared with the control. These results suggest that the involvement of parotid CD36 in mouse salivary secretion is altered with age., (© 2024. The Author(s).)

Background: Few studies have examined health related Quality of Life (HR-QoL) during the treatment of head and neck cancer (HNC) with even fewer focusing on the impact of oral mucositis (OM) on HR-QoL. Studies performed during treatment of HNC makes it possible to follow fluctuations in HR-QoL, OM and other treatment related side effects. The aim was to prospectively analyze HR-QoL, changes in clinical variables and the impact of OM on HR-QoL during HNC treatment., Materials and Methods: Patients were recruited before commencing curative cancer treatment and were given professional oral care weekly during oncologic treatment. HR-QoL was reported before, during (week 2, 4 and 6) and three months after treatment using the EORTC Quality of Life questionnaires C30 and H&N35 and the stimulated whole salivary secretion rate was determined at the same time-points. OM (erythema and ulceration) was registered using the Oral Mucositis Assessment Scale (OMAS), at baseline, weekly during treatment and post treatment. Differences in HR-QoL between different timepoints were analyzed. To analyze the impact of OM on HR-QoL the patients were categorized into two groups: no/mild OM (OMAS ulceration score 0-1) or severe OM (OMAS ulceration score ≥ 2) and HR-QoL was compared between the two OM groups at three timepoints during treatment., Results: Fifty-seven patients (43 men, 14 women), with a mean age of 58 years were included. Patients reported progressively impaired HR-QoL, with peak issues noted at weeks 4 and 6, particularly in social eating, senses, appetite loss, sticky saliva, and decreasing salivary secretion rates were determined. Patients with severe OM reported worse HR-QoL compared to those with no/mild OM. Persistent problems 3 months post treatment were appetite loss, dry mouth, senses (smell and taste) and problems with social eating., Conclusion: Patients experienced exacerbated symptoms and problems weeks 4 and 6 of oncological treatment, especially among those with severe OM, stressing the importance of clinically monitoring the patients to reduce and alleviate their symptoms. Persistent problems three months post treatment are likely associated with the reduced salivary secretion rate indicating that patients should be monitored also after completed oncological treatment., (© 2024. The Author(s).)

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.

Although salivation is essential during eating behavior, little is known about the brainstem centers that directly control the salivary glands. With regard to the inferior salivatory nucleus (ISN), the site of origin of the parasympathetic preganglionic cell bodies that innervate the parotid glands, previous anatomical studies have located it within the rostrodorsal medullary reticular formation. However, to date there is no functional data that shows the secretory nature of the somas grouped in this region. To activate only the somas and rule out the activation of the efferent fibers from and the afferent fibers to the ISN, in exp. 1, NMDA neurotoxin was administered to the rostrodorsal medullary region and the secretion of saliva was recorded during the following hour. Results showed an increased secretion of parotid saliva but a total absence of submandibular-sublingual secretion. In exp. 2, results showed that the hypersecretion of parotid saliva after NMDA microinjection was completely blocked by the administration of atropine (a cholinergic blocker) but not after administration of dihydroergotamine plus propranolol (α and β-adrenergic blockers, respectively). These findings suggest that the somata of the rostrodorsal medulla are secretory in nature, controlling parotid secretion via a cholinergic pathway. The data thus functionally supports the idea that these cells constitute the ISN., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Intraglandular injection of botulinum toxin type A (BoNT/A) effectively treats sialorrhea. Myoepithelial cells (MECs) are essential for salivary secretion. The role of MECs in BoNT/A-inhibited salivary secretion, and its underlying mechanisms remain unknown., Materials and Methods: BoNT/A was injected into rat submandibular glands (SMGs). At 1, 2, 4, 8, and 12 weeks postinjection, salivary flow rate of SMGs was measured. Electron microscopy, immunohistochemistry, immunofluorescence, and Western blot analysis were used to detect morphological and functional changes in MECs and chemical denervation in SMGs., Results: BoNT/A temporarily decreased salivary secretion in rat SMGs and this inhibitory effect lasted 4 weeks. During the inhibitory period, MECs atrophied and expressed reduced α-smooth muscle actin (α-SMA), vimentin, and phosphorylated myosin light chain 2 (p-MLC2), suggesting that BoNT/A attenuated MEC contractility. Furthermore, BoNT/A cleaved synaptosome-associated protein 25 (SNAP-25) and decreased the expression and activity of acetylcholinesterase (AChE), indicating that BoNT/A-induced chemical parasympathetic denervation of SMGs by cleaving SNAP-25., Conclusions: BoNT/A temporarily caused MEC atrophy and decreased MEC contractility in rat SMGs, which contributed to reversible inhibition of salivary secretion. The underlying mechanisms involved temporary parasympathetic denervation caused by SNAP-25 cleavage. These findings provide new insights into the mechanisms of BoNT/A-inhibited salivary secretion., (© 2023 Wiley Periodicals LLC.)

Dry mouth is a multifaceted condition which is caused by reduced salivary secretion. This study aimed to evaluate and compare the effects of different lozenge surface textures, tastes and acidity levels on stimulated salivary secretion for increased oral moistening in participants without hyposalivation. This randomized, double-blind, clinical crossover trial with before and after comparison involved 33 healthy volunteers. Five lozenges, including a baseline control (C), apple (A), sour (S), sour apple (SA) and granular pectin (P) were tested on five different days with all the subjects. Salivary flow, pH value, and subjective feeling (visual analog scale) were measured before and after consuming the lozenge each day. Throughout all trial days the unstimulated whole salivary flow (UWSF) averaged 0.65 ± 0.26 ml/min. Lozenges S, SA, and P showed higher stimulated whole salivary flow (SWSF) than C (P < 0.001) by more than 0.5 ml/min. Lozenge P, with a rough surface, demonstrated the highest difference between UWSF and SWSF, 2.41 ± 0.69 ml/min. The stimulated saliva with the lozenges containing acidifiers (S, SA and P) was more than 1.4 pH units lower compared to lozenges C and A (P < 0.001). Subjects reported the strongest subjective feeling of increased saliva with lozenges SA and P. Overall lozenges SA and P provided the best objective results in enhancing salivary flow rate and subjective feeling of increased salivary flow., Competing Interests: The authors deny any conflict of interest., (Copyright 2024 SWISS DENTAL JOURNAL SSO – Science and Clinical Topics. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

β-Adrenergic signaling blockade is a mainstay of hypertension management. One percent of patients taking β-blockers develop reduced salivary gland (SG) function. Here we investigate the role of SG progenitor cells in β-blocker-induced hyposalivation, using human SG organoid cultures (SGOs). Compared with control SGs, initial low SG progenitor cell yield from patients taking β-blockers was observed. When passaged, these SGOs recovered self-renewal and upregulated Notch pathway expression. Notch signaling was downregulated in situ in β-adrenergic receptor-expressing luminal intercalated duct (ID) cells of patients taking β-blockers. Control SGOs treated with β-adrenergic agonist isoproterenol demonstrated increased proportion of luminal ID SGO cells with active Notch signaling. Control SGOs exposed to isoproterenol differentiated into more mature SGOs (mSGOs) expressing markers of acinar cells. We propose that β-blocker-induced Notch signaling reduction in luminal ID cells hampers their ability to proliferate and differentiate into acinar cells, inducing a persistent hyposalivation in some patients taking β-blocking medication., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with diabetes commonly experience hyposalivation, which induces discomfort in eating, swallowing, dryness, smell, and speaking, as well as increases the incidence of periodontal disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently used as antidiabetic drugs that lower glucose levels by utilizing similar mechanisms; however, additional protective functions of each gliptin have been discovered. In this study, the protective roles of gemigliptin, a DPP4 inhibitor, against salivary dysfunction under diabetic conditions were investigated. Streptozotocin-induced diabetic rats received gemigliptin 10 mg/kg or 100 mg/kg via oral gavage for 3 weeks. The weights of salivary gland tissues, saliva secretion, and antioxidant capacity in salivary glands were reduced after diabetes induction, but were significantly preserved following gemigliptin treatment. In salivary gland analysis, expression of apoptotic proteins, as well as amylase and aquaporin-5 (AQP5) protein expression, were increased following gemigliptin treatment. Furthermore, the number of TUNEL-positive cells decreased after gemigliptin treatment. Therefore, gemigliptin has protective roles against salivary dysfunction observed in diabetes, mediated via antioxidant, anti-apoptotic, and salivary secretion mechanisms. These results may help in selecting a suitable drug for patients with diabetes experiencing salivary dysfunction., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: To investigate the biochemical and morphological effects of ethanol (EtOH) binge drinking during pregnancy on parotid glands (PG), submandibular glands (SMG), and saliva of offspring rats., Methods: Pregnant Wistar rats (n = 8) were exposed to EtOH consumption (3 g/kg/day - 20 % w/v) for three consecutive days. The saliva of 40-day-old offspring rats was collected to determine amylase activity and total protein concentration. PG and SMG were collected to performe oxidative biochemistry, morphometric and immunohistochemistry analyses (Student's t-test, p < .05)., Results: EtOH consumption during pregnancy significantly decreased the total protein concentration and decreased amylase activity. In the PG, the EtOH group showed increased lipid peroxidation and decreased antioxidant capacity against peroxyl. In the SMG, the EtOH group showed increased lipid peroxidation and NOx metabolite levels. PG exposed to EtOH showed a decrease of acini, ducts, and total parenchymal area. SMG exposed to EtOH showed an increase in the total stromal area. The expression of CK-19 and Vimentin were found not different between groups., Conclusions: For the first time, a three-day EtOH binge-drinking protocol during pregnancy is associated with oxidative stress and morphometric alterations in the salivary glands of offspring rats and with the functional reduction of the main salivary enzyme (amylase)., Clinical Relevance: EtOH consumption during pregnancy altered the morphology and physiology of the salivary glands of offspring rats., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sialorrhea, or excessive saliva beyond the margin of the lip, is a common problem in many neurological diseases. Previously, sialorrhea has been underrecognized in Parkinson's disease (PD) patients. Despite this, many patients rank sialorrhea as one of the most debilitating complaints of Parkinson's disease. Previous treatment for sialorrhea has been suboptimal and has been plagued by significant side effects that are bothersome and can be dangerous in patients with a concurrent neurodegenerative disease. This review sought to review the anatomy, function, and etiology of sialorrhea in PD. It then sought to examine the evidence for the different treatments of sialorrhea in PD, and further examined newer evidence for safety and efficacy in minimally invasive treatment such as botulinum toxin.

Background: Hypersalivation and drooling are commonly reported in clozapine-treated patients. Current management strategies have been evaluated using subjective measures. Many case reports describe the successful use of atropine in the treatment of the condition., Aims: To measure the effect and safety of sublingual atropine on nocturnal unstimulated saliva secretion. Secondary aims were to evaluate the patient's satisfaction with the atropine effect on hypersalivation (or sialorrhea), drooling, and sleep., Method: Twenty-one clozapine-treated patients with hypersalivation, or drooling, were randomised to take a single 600-μg dose of sublingual atropine drops or a matching placebo. The saliva secretion was measured over 5 min at baseline and 2 h after the administration of the study medication., Results: Sublingual atropine reduced the saliva secretion significantly more than the placebo (mean difference = - 57.21%, 95% CI: - 104.30, - 10.11, P = 0.02). A significant decrease in standing pulse rate was recorded in the participants in the atropine group (- 5.8 (- 9.54, - 2.15), P = 0.002). Subjectively, more patients in the atropine group found their pillow to have less saliva the following morning and found their sleep to be better., Conclusions: Sublingual atropine drops significantly reduces nocturnal unstimulated clozapine-induced saliva secretion. More research is required to compare the effect of sublingual atropine with other anticholinergic medications and different dosage forms., Trial Registration: ACTRN12618000051246.

Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, Food and Drug Administration-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications. The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ 9 -THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg) against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys. Pretreatment with 0.1 mg/kg Δ 9 -THC blocked nicotine-induced emesis and reduced hypersalivation in all subjects and blocked LiCl-induced emesis and reduced hypersalivation in three of four subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in three of four subjects and LiCl-induced emesis in one of four subjects and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ 9 -THC and mAEA were reversed by rimonabant pretreatment, providing verification of cannabinoid receptor type 1 mediation. These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ 9 -THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggest that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side effect liability. SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a paucity of animal models. The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ 9 -tetrahydrocannabinol and endocannabinoid analog methanandamide in nonhuman primates., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

A considerable number of patients arriving in dental offices are being treated with ongoing medication for a variety of chronic diseases. As a result, dentists must be familiar with the potential side effects these therapeutic agents may have on the tissues of the oral cavity, and in particular on the salivary gland. Salivary gland function may be altered by a wide range of medications, leading to effects such as xerostomia, hyposalivation, hypersalivation or even swelling of the glands. These disorders can cause a variety of other health complications. This review will focus on the most common groups of drugs responsible for salivary gland dysfunction, including psychoactive drugs, antidepressants, antipsychotics, antihypertensives, and antihistamines.

Objective: To investigate the mechanism of cAMP-PKA signaling pathway mediated by Chinese medicine formula Shaoyao Gancao Decoction (, SGD) on the regulation of aquaporin 5 (AQP5) and muscarinic receptor 3 (M3R) levels in Sjögren's syndrome (SS)., Methods: Of the 30 mice, 5 were randomly selected as control, and others were used for creating SS model. After successful modeling, mice were randomly divided into 5 groups (n=5 per group) and intragastrically administered with saline (8 mL/kg), pilocarpine (1.4 mg/kg), or low, medium and high doses SGD (0.14, 0.21, 0.35 g/kg Radix paeoniae with 0.01 g/kg Radix glycyrrhizae, respectively) for 6 weeks. Human labial gland acinar cells were treated with pilocarpine or varying doses of SGD with saline as the placebo. Hematoxylin and eosin staining was used to observe the histopathological changes of the submandibular glands of mice. The serum levels of anti-SS antigen A (SS-A), anti-SS antigen B (SS-B), M3R, and α-fodrin in submandibular glands of mice were measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to observe the spatial localization of AQP5 and M3R in acinar cells. Reverse transcriptase polymerase chain reaction and Western blot were used to detect the expressions of PKA, cAMP, Epac1, AQP5, M3R, nuclear factor kappa-B (NF-κB), and tumor necrosis factor (TNF)-α in submandibular gland tissues and cells of each group., Results: Compared to normal mice, body weight, 5-min salivary secretion, 30-min secretion of tears and breakup time of tear film of model mice decreased at 1-6 weeks after immunization (all P<0.05), whereas water intake increased (all P<0.05). In the model group, glands of the submandibular glands showed atrophy, accompanied by acini of different sizes, decreased numbers and loose arrangement, with catheter dilatation and different degrees of lymphocyte infiltration. Conditions of mice in SGD groups were improved. The positive expression of AQP5 and M3R were higher in the acinar cells treated with all doses SGD compared to the normal group; serum levels of SS-A, SS-B, and α-fodrin were lower, and that of M3R was higher in all doses SGD treated animals than the model or pilocarpine treated ones (all P<0.05). Compared to the model and pilocarpine groups, the mRNA and protein levels of NF-κB and TNF-α were lower in mice or cells treated with medium or high-dose SGD (all P<0.05), while those of PKA, Epac1, AQP5 and M3R were higher (all P<0.05)., Conclusion: SGD can improve symptoms of SS by regulating the cAMP-PKA signaling pathway and increasing AQP5 and M3R levels.

Xerostomia is a self-conscious symptom. High-mobility group box 1 (HMGB1) promotes pro-inflammatory effects in many diseases. This study aimed to clarify the role of HMGB1 in Sjögren syndrome (SS)-triggered xerostomia. Nonobese diabetic (NOD)/Ltj mice were used to establish an SS-triggered xerostomia model. The results showed that saliva production was decreased and anti-Sjögren syndrome B (anti-SSB) level was increased in SS. PCR, Western blot, and immunohistochemistry experiments indicated that the HMGB1 and aquaporin 5 (AQP5) levels were enhanced and diminished in SS compared with those in the control, respectively. While the mice were treated with anti-HMGB1, xerostomia was reversed due to the elevated saliva production and reduced anti-SSB level. In addition, it was found that the inhibition of HMGB1 restrained the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) axis activation. The TLR4 and p-IκB levels were alleviated, while the IκBα and NF-κB p65 levels were augmented. The NF-κB p65 binding activity was attenuated via the electrophoretic mobility shift assay (EMSA) after anti-HMGB1 treatment. Moreover, the repression of HMGB1 facilitated the expression of AQP5. These findings demonstrate that suppression of HMGB1 ameliorates SS-triggered xerostomia via suppressing the HMGB1/TLR4/NF-κB signaling pathway and upregulating AQP5 expression.

Dry mouth, hyposalivation, or xerostomia is a significant problem in diabetic patients; however, there has been no way to relieve these symptoms. This study's aim was to evaluate the effects of Ixeris dentata (IXD) in combination with lactobacillus extract on the salivation rate in diabetes-induced dry mouth, and its mechanism was also investigated. In the streptozotocin (STZ)-induced diabetes model, the dry mouth condition was established as a model. Here, rats were treated with water or IXD through the sublingual spray, and subsequently treated with or without a spray of lactobacillus extract. In diabetes condition, the salivary flow rate, amylase activity, and aquaporin-5 and Na + /H + exchanger (NHE-1) expressions were markedly decreased, whereas they were more significantly recovered in the sequential treatment of IXD-lactobacillus extract than in each single treatment. Furthermore, oxidative stress and its related ER stress response were especially regulated in the IXD/lactobacillus extract condition, where the following anti-oxidative enzymes, glutathione assay (GSH: GSSG) ratio, superoxide dismutase (SOD), and glutathione peroxidase (GPx), were involved. This study suggests that the combination of IXD and lactobacillus would be a potential alternative medicine against diabetes-induced hyposalivation and xerostomia.

Objectives: To investigate the impact of gustatory stimulants of salivary secretion (GSSS) on Sjögren's syndrome patients' self-perception of xerostomia, oral health-related quality of life (OHRQoL) and salivary secretion., Methods: A total of 110 Sjögren's syndrome patients were randomly allocated to be treated with either a malic acid lozenge or a citric acid mouthwash and then crossed over. Before and after the interventions, the Xerostomia Inventory 5 (SXI-5-PL) and the Oral Health Impact Profile (OHIP-14-PT) questionnaires (both in the Portuguese language) were administered to patients. Unstimulated, mechanical and gustatory-stimulated salivary flows were determined. Repeated measures and between-subject analyses were performed. Statistical significance was set at 5%., Results: After the intervention and within each group, both GSSS elicited a reduction in the SXI-5-PL and OHIP-14-PT scores and an increase in salivary output, significant in the malic acid lozenge group. The malic acid treatment resulted in a greater effect size and percentage improvement than citric acid mouthwash. The malic acid lozenge also produced a significant greater salivary output than the citric acid rising solution., Conclusions: In Sjögren's syndrome patients, lozenges containing malic acid increased saliva production and xerostomia relief, resulting in improved quality of life., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Zn 2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn 2+ can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl 2 solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn 2+ increased cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn 2+ -induced [Ca 2+ ] i increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn 2+ also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn 2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.

The most important salivary glands are the paired parotid and submandibular glands. Adults produce 1 to 1.5 liters of saliva which are then regularly swallowed. When the act of swallowing is disturbed, salivation occurs. More rarely, the cause can be found in increased saliva production, for example, when caused through medication. Sialorrhea impairs the quality of life substantially and is frequently often socially stigmatizing. Therapy includes conservative measures such as functional dysphagia therapy, oral or transdermal application of anticholinergics, as well as, in selected cases, radiation and surgical measures. Over the last 20 years local injection of botulinum toxin has been successfully applied in the treatment of this condition. With approval of this therapy by the European agencies, this measure will become the therapy of choice for pronounced therapy-resistant sialorrhea., Competing Interests: WHJ ist Berater und Referent für Pharm Allergan, Ipsen Pharma und Merz Pharmaceuticals und war PI der SIAXI-Studie. TB ist Berater für Merz Pharmaceuticals und Pharm Allergan und Referent für Merz Pharmaceuticals, Pharm Allergan und Ipsen Pharma RL ist Referent für die Merz Pharmaceuticals. BS hat keine Interessenskonflikte. AS ist Berater und Referent für die Merz Pharmaceuticals. MW ist Referent für Referent für Pharm Allergan, Ipsen Pharma und Merz Pharmaceuticals., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The purpose of this study was to clarify the influence of consuming yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (1073R-1-yogurt) on influenza virus-bound salivary immunoglobulin A (IgA) levels, in the elderly residents of nursing homes. Methods: A double-blind, parallel-group, randomized controlled trial was conducted with 96 elderly volunteers residing in 2 nursing homes. During the trial, participants consumed 100 g of 1073R-1-yogurt every morning for 12 weeks, whereas the control participants consumed yogurt fermented with a different Lactobacillus strain (control yogurt). Saliva was collected before the trial and after 4, 8 and 12 weeks of yogurt ingestion. Results: Our data indicated that consumption of 1073R-1-yogurt affected influenza A virus subtype H3N2-bound IgA levels in saliva ( p  = .001). In addition, saliva flow rate and total IgA levels increased in response to the yogurt intake period in both the 1073R-1 and control yogurt groups ( p  = .04). Conclusions: Our study suggests that continuous daily ingestion of 1073R-1-yogurt may help prevent infection with influenza A virus subtype H3N2 in elderly subjects with weakened immunity, by increasing the production of influenza A virus subtype of H3N2-bound salivary IgA.

Objectives: SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset., Methods: Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined., Results: Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice., Conclusion: AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Physostigmine is a tertiary amine carbamate acetylcholinesterase inhibitor. Its ability to cross the blood-brain barrier makes it an effective antidote to reverse anticholinergic delirium. Physostigmine is underutilized following the publication of patients with sudden cardiac arrest after physostigmine administration in patients with tricyclic antidepressant (TCA) overdoses. We completed a narrative literature review to identify reported adverse effects associated with physostigmine administration., Discussion: One hundred sixty-one articles and a total of 2299 patients were included. Adverse effects occurred in 415 (18.1%) patients. Hypersalivation (206; 9.0%) and nausea and vomiting (96; 4.2%) were the most common adverse effects. Fifteen (0.61%) patients had seizures, all of which were self-limited or treated successfully without complication. Symptomatic bradycardia occurred in 8 (0.35%) patients including 3 patients with bradyasystolic arrests. Ventricular fibrillation occurred in one (0.04%) patient with underlying coronary artery disease. Of the 394 patients with TCA overdose, adverse effects were described in 14 (3.6%). Adverse effects occurred in 7.7% of patients treated with an overdose of an anticholinergic agent compared with 20.6% of patients with non-anticholinergic agents. Five (0.22%) fatalities were identified., Conclusions: In conclusion, significant adverse effects associated with the use of physostigmine were infrequently reported. Seizures were self-limited or resolved with benzodiazepines, and all patients recovered neurologically intact. Physostigmine should be avoided in patients with QRS prolongation on EKG, and caution should be used in patients with a history of coronary artery disease and overdoses with QRS prolonging medications. Based upon our review, physostigmine is a safe antidote to treat anticholinergic overdose.

Background: Allotransplantation of submandibular salivary glands (SMGs) could be an alternative treatment option for severe keratoconjunctivitis sicca in noncandidates for autologous SMG transplantation. This study was conducted to evaluate the effect of allogeneic mesenchymal stem cell (MSC) therapy on the survival of allotransplanted SMGs., Methods: Thirty-six SMG allotransplantations (n = 6 per group) were performed in New Zealand white rabbits and randomly divided into the following groups: allograft control (Allo-Ctrl), low-dose FK506 (FK506-L), high-dose FK506 (FK506-H), allogeneic MSCs, MSCs+FK506-L, and MSCs+FK506-H. Rabbits were closely observed for 2 weeks. Gland viability and rejection were assessed by monitoring interleukin-2 levels by ELISA, sialoscintigraphy, M3-muscarinic acetylcholine receptor expression, histological evaluation, and apoptosis assay., Results: Intraoperatively, all glands showed patency and saliva flow except 1 gland. Sialoscintigraphy revealed significantly higher saliva production within the MSC-treated glands. Histologically, MSC-treated glands showed higher glandular tissue preservation and less acini atrophy. The MSCs+FK506-H group revealed significantly lower apoptosis percentage. The highest survival was observed in the MSCs+FK506-H group, followed by the FK506-H and MSCs+FK506-L groups, and lastly less in the FK506-L and MSCs groups., Conclusions: Concurrent administration of MSCs with FK506-H (0.16 mg/kg) resulted in higher survival rate with greater glandular tissue preservation and salivary secretion. MSCs with FK506-L (0.08 mg/kg) could be an alternative to FK506-H (0.16 mg/kg) in salivary gland allotransplantation.

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals." P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R -/- ) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R -/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R -/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E 2 (PGE 2 ) release from primary parotid cells of wild-type but not P2X7R -/- mice. To attempt to uncover the mechanism underlying differential PGE 2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE 2 release in P2X7R -/- mice. Irradiated P2X7R -/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

Deltamethrin (DLM) is a commonly used pesticide that helps to control crop destruction, disease, and nuisance insects. In rodents DLM can produce choreoathetosis, salivation, and decreased acoustic startle responses (ASR). Herein, adult Sprague Dawley rats were assessed for ASR 2 h after DLM delivered in 5 ml/kg corn oil, however no decrease was observed. Therefore, a test-retest protocol was used to reduce variability, and the effects on ASR on postnatal day 15 (P15) and adult rats were assessed 2, 4, 6, and 8 h after DLM administration (0, 1, 2, or 4 mg/kg for P15 rats and 0, 2, 8, or 25 mg/kg for adults). In a separate set of rats identically treated, DLM levels were determined in blood and brain. DLM (8 or 25 mg/kg) in adult rats decreased ASR up to 4 h, whereas in P15 rats decreases were observed between 2 and 8 h. The adult 25 mg/kg group showed consistent signs of salivation and tremor, whereas in P15 rats salivation was observed in the 2 and 4 mg/kg groups and tremor was observed at all doses over the 8-h period. Mortality was observed in all P15 dose groups but not in adults. Dose-dependent increases of DLM in blood and brain regardless of age were observed. At approximately equivalent whole brain concentrations, effects were more pronounced in P15 rats than in adult rats. Comparable brain levels of DLM do not explain differences in ASR and tremor between the P15 and adult rats. These data indicate age-dependent differences in sensitivity to DLM., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea., Methods: We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm., Results: 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1)., Conclusion: Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.

GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.

Objective: The aim of this study was to determine the effects of prolonged hyperoxia on salivary glands and salivary secretion in mice., Design: Male C57BL/6 J mice were kept in a 75% oxygen chamber (hyperoxia group) or a 21% oxygen chamber for 5 days. We measured the secretion volume, protein concentration, and amylase activity of saliva after the injection of pilocarpine. In addition, we evaluated the histological changes induced in the submandibular glands using hematoxylin and eosin and Alcian blue staining and assessed apoptotic changes using the TdT-mediated dUTP nick end labeling (TUNEL) assay. We also compared the submandibular gland expression levels of heme oxygenase-1 (HO-1), superoxide dismutase (SOD)-1, and SOD-2 using the real-time polymerase chain reaction., Results: In the hyperoxia group, salivary secretion was significantly inhibited at 5 and 10 min after the injection of pilocarpine, and the total salivary secretion volume was significantly decreased. The salivary protein concentration and amylase activity were also significantly higher in the hyperoxia group. In the histological examinations, enlargement of the mucous acini and the accumulation of mucins were observed in the submandibular region in the hyperoxia group, and the number of TUNEL-positive cells was also significantly increased in the hyperoxia group. Moreover, the expression levels of HO-1, SOD-1, and SOD-2 were significantly higher in the hyperoxia group., Conclusion: Our results suggest that hyperoxia reduces salivary secretion, and oxidative stress reactions might be involved in this., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Whole-brain radiation therapy (WBRT) delivers a substantial radiation dose to the parotid glands, but the parotid glands are not delineated for avoidance and xerostomia has never been reported as an adverse effect. Minimizing the toxic effects in patients receiving palliative treatments, such as WBRT, is crucial., Objective: To assess whether xerostomia is a toxic effect of WBRT., Design, Setting, and Participants: This observational cohort study enrolled patients from November 2, 2015, to March 20, 2018, at 1 academic center (University of North Carolina Hospitals) and 2 affiliated community hospitals (High Point Regional Hospital and University of North Carolina Rex Hospital). Adult patients (n = 100) receiving WBRT for the treatment or prophylaxis of brain metastases were enrolled. Patients who had substantial baseline xerostomia or did not complete WBRT or at least 1 postbaseline questionnaire were prospectively excluded from analysis and follow-up. Patients received 3-dimensional WBRT using opposed lateral fields covering the skull and the C1 or C2 vertebra. Per standard practice, the parotid glands were not prospectively delineated., Main Outcomes and Measures: Patients completed the University of Michigan Xerostomia Questionnaire and a 4-point bother score at baseline, immediately after WBRT, at 1 month, at 3 months, and at 6 months. The primary end point was the 1-month xerostomia score, with a hypothesized worsening score of 10 points from baseline., Results: Of the 100 patients enrolled, 73 (73%) were eligible for analysis and 55 (55%) were evaluable at 1 month. The 73 patients included 43 women (59%) and 30 men (41%) with a median (range) age of 61 (23-88) years. The median volume of parotid receiving at least 20 Gy (V20Gy) was 47%. The mean xerostomia score was 7 points at baseline and was statistically significantly higher at each assessment period, including 21 points immediately after WBRT (95% CI, 16-26; P < .001), 23 points (95% CI, 16-30; P < .001) at 1 month, 21 points (95% CI, 13-28; P < .001) at 3 months, and 14 points (95% CI, 7-21; P = .03) at 6 months. At 1 month, the xerostomia score increased by 20 points or more in 19 patients (35%). The xerostomia score at 1 month was associated with parotid dose as a continuous variable and was 35 points in patients with parotid V20Gy of 47% or greater, compared with only 9 points in patients with parotid V20Gy less than 47% (P < .001). The proportion of patients who self-reported to be bothered quite a bit or bothered very much by xerostomia at 1 month was 50% in those with parotid V20Gy of 47% or greater, compared with only 4% in those with parotid V20Gy less than 47% (P < .001). At 3 months, this difference was 50% vs 0% (P = .001). Xerostomia was not associated with medication use., Conclusions and Relevance: Clinically significant xerostomia occurred by the end of WBRT, appeared to be persistent, and appeared to be associated with parotid dose. The findings from this study suggest that the parotid glands should be delineated for avoidance to minimize these toxic effects in patients who undergo WBRT and often do not survive long enough for salivary recovery.

Sichuan pepper is a plant belonging to the genus Zanthoxylum and family rue. To evaluate whether Sichuan pepper oil boosts saliva secretion using an encapsulated food product containing the oil in subjects presenting with mouth dryness. We evaluated subjective symptoms that changed with a decrease in salivary secretion in the subjects by evaluating the number of Candida colonies and by conducting interviews. The study results demonstrated that salivary secretion increased by 39.4% ± 37.6% after single ingestion of the product, and an additional 8.7% ± 13.2% and 6.3% ± 31.2% following continuous ingestion over 2 and 4 weeks, respectively. These findings suggested that the product rapidly promotes and maintains salivation. Regarding the proliferation of Candida colonies in subjects with mouth dryness, a negative correlation was observed between Candida colony number and salivary secretion quantity. Additionally, interviews revealed that subjective symptoms, such as mouth dryness, discomfort and pain in the mouth, difficulty swallowing the saliva, and feeling of stickiness in the mouth, improved shortly after single ingestion of the product, and mouth dryness was reduced by continuous consumption of the product. These findings indicated that the product studied promotes rapid salivary secretion, is effective in reducing the number of oral Candida colonies, and improves subjective symptoms such as mouth dryness., Competing Interests: This study did not receive any specific funding. The authors have stated explicitly that there are no conflicts of interest related to this article.

Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol (CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na + -K + -2Cl - cotransporter, transmembrane member 16A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca 2+ in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca 2+ and Ca 2+ ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups. Moreover, salivation induced by the Ca 2+ -ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca 2+ entry, resulting in hyposalivation in mouse submandibular glands.

Objective: To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice., Methods: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction., Results: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05)., Conclusions: ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.

Objectives: To analyze the role of patient compliance as a factor in evaluating the effectiveness of continuous sialogogues to prevent salivary side effects from 131 I therapy in differentiated thyroid cancer patients., Methods: Differentiated thyroid cancer patients who were clinically scheduled for an 131 I therapy at MedStar Washington Hospital Center between 2012 and 2013 were given instructions for continuous sialogogues per standard clinical protocol. The prospective survey was given at multiple time points., Results: Ninety-nine patients consented to participate of whom 94 participants had complete data. The mean prescribed 131 I activity was 121 ± 50 mCi (4.5 ± 1.9 GBq), range 27.5-288 mCi (1.0-10.7 GBq ). Overall, only 10% (9/94) of patients were compliant with continuous sialogogues. Even though all patients took sialogogues on the first day of post-therapy, 17% of participants did not continuously take sialogogues during the first day, 60% during the first night, and 72% on the second day despite rigorous instructions to continue for two days., Conclusion: Despite repetitive instructions to use sialogogues continuously, most patients (90%) were not compliant. In future studies, strict monitoring and evaluation of patient compliance will be crucial when assessing the effect of continuous versus intermittent or delayed initiation of sialogogues., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objectives: Medication-induced hyposalivation can increase the risk for oral complications, including dental caries and tooth loss. This problem is particularly important in people with dementia because of their declining ability to maintain oral care. The objective of this study was to describe the association between the number of xerostomic medications used and tooth loss and restorative and dental preventive treatment in a population of persons with dementia., Design: A longitudinal population-based register study with a 3-year follow-up was conducted. Data were extracted from the Swedish Dementia Registry (SveDem), the Swedish Prescribed Drug Register (SPDR), the Swedish National Patient Register (SNPR), and the Dental Health Register (DHR)., Setting and Participants: Participants were persons with dementia who were registered in the SveDem at the time of their dementia diagnosis., Measures: The exposure was continuous use of xerostomic medications over the 3 years prior to dementia diagnosis (baseline). The outcomes were the incidence of tooth extractions, tooth restorations, and dental preventive procedures. Poisson regression models were used to estimate incidence rate ratios (IRRs) for the association between the exposure and outcomes, adjusting for relevant confounders., Results: A total of 34,037 persons were included in the analysis. A dose-response relationship between the exposure and tooth extractions was observed. Compared with nonusers of xerostomic medication, the rate of tooth extractions increased with increasing number of xerostomic medications used (IRR = 1.03, 1.11, and 1.40 for persons using an average >0-1, >1-3, and >3 xerostomic medications, respectively). However, the risk for having new dental restorations and receiving preventive procedures did not differ between groups., Conclusion: Continuous use of xerostomic medications can increase the risk for tooth extraction in people with dementia. This study highlights the importance of careful consideration when prescribing xerostomic medications to people with dementia, and the need for regular and ongoing dental care., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Xerostomia and hyposalivation are debilitating side effects for patients treated with ionizing radiation for head and neck cancer. Despite technological advances, collateral damage to the salivary glands remains a significant problem for patients and severely diminishes their quality of life. During the wound healing process, restoration of junctional contacts is necessary to maintain polarity, structural integrity, and orientation cues for secretion. However, little is known about whether these structural molecules are impacted following radiation damage and more importantly, during tissue restoration. We evaluated changes in adherens junctions and cytoskeletal regulators in an injury model where mice were irradiated with 5 Gy and a restoration model where mice injected postradiation with insulin-like growth factor 1 (IGF1) are capable of restoring salivary function. Using coimmunoprecipitation, there is a decrease in epithelial (E)-cadherin bound to β-catenin following damage that is restored to untreated levels with IGF1. Via its adaptor proteins, β-catenin links the cadherins to the cytoskeleton and part of this regulation is mediated through Rho-associated coiled-coil containing kinase (ROCK) signaling. In our radiation model, filamentous (F)-actin organization is fragmented, and there is an induction of ROCK activity. However, a ROCK inhibitor, Y-27632, prevents E-cadherin/β-catenin dissociation following radiation treatment. These findings illustrate that radiation induces a ROCK-dependent disruption of the cadherin-catenin complex and alters F-actin organization at stages of damage when hyposalivation is observed. Understanding the regulation of these components will be critical in the discovery of therapeutics that have the potential to restore function in polarized epithelium.

Hypofunction of the salivary gland causes several life-disrupting side effects such as dental caries, oral candidiasis, loss of taste, and swallowing disorders. No satisfactory therapy has been established to treat salivary hypofunction. Pilocarpine represents a potential treatment for dry mouth due to Sjögren's syndrome (SS). Although subjective improvement was consistently observed with pilocarpine therapy, the mechanism was unclear. In this study, we investigated the mechanism of recovery in salivation following treatment with pilocarpine. We first examined the effectiveness of pilocarpine in SS patients as quantified by the Saxon test and the visual analogue scale average. We found that salivation ability and subjective symptoms improved by continuous administration of pilocarpine. These results demonstrated that long-term medication for dry mouth patients was more effective. However, as the mechanism remained unclear, molecular biological mechanisms were analyzed based on the effects of continuous administration of pilocarpine using model mice. In the molecular biological analysis, continuous administration of pilocarpine was effective in both ICR and SS model mice. Gene and protein expression of muscarinic acetylcholine receptor 3 (M3R) increased in salivary glands following continuous administration of pilocarpine compared with single administration. Therefore, continuous administration of pilocarpine effectively induced M3R expression, thereby activating salivation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The patient with xerostomia (sensation of dry mouth) or inadequate saliva (salivary gland hypofunction) may present with a wide range of clinical signs and symptoms affecting the oral cavity and systemic health. Recognition of these clinical presentations allows the dental healthcare professional to perform objective tests to identify the status of salivary gland function. Based on these results, recommendations for treatment using over-the-counter and prescription medications can be made. This article discusses clinical indications related to salivary gland hypofunction, testing methodologies, and treatment approaches.

Background: Patients with irritable bowel syndrome (IBS) frequently present with alterations of autonomic activity, especially higher sympathetic activity. Salivary alpha-amylase (sAA) has been implicated as a non-invasive biomarker to reflect the sympathetic activity. Thus, the current study aimed to determine if alterations of sAA secretion could be addressed in IBS patients., Methods: We recruited twenty-five IBS patients as well as twenty-four age- and sex-matched healthy controls (HCs). Basal and stimulated (by gustatory stimulation with citric acid) saliva samples were collected from each participant, with respective salivary flow rate (SFR) calculated accordingly. Western blotting (WB) was applied to determine the sAA amount by introducing human sAA protein of known quantity. Then the sAA amount ratio was calculated, as expressed by the stimulated sAA amount to basal sAA amount., Results: We observed high variability of the basal and stimulated sAA amount in both groups. An apparently higher prevalence of psychiatric disorders was detected in the IBS group, which was consistent with previous studies. Interestingly, we found elevated basal sAA amount in the IBS patients relative to HCs, which implicated higher sympathetic activities in IBS population. Moreover, we observed blunted sAA response to the gustatory stimulation in the IBS patients, which might be of pathophysiological importance for IBS., Conclusion: This is the first attempt to associate sAA secretion with the pathophysiology of IBS. Our results suggest an autonomic dysfunction in IBS patients.

Cholinergic syndrome is an acute adverse reaction associated with irinotecan. Development of cholinergic syndrome can be ameliorated or prevented by administering various anticholinergics, including atropine sulfate or scopolamine butylbromide. Although many of the side effects are transient and non-life-threatening, their onset is painful and can lower a patient's quality of life (QoL). This retrospective study was performed to identify predictive factors of the development of irinotecan-related cholinergic syndrome in order to develop future strategies for improving the QoL of patients undergoing chemotherapy. We enrolled 150 cancer patients who underwent chemotherapy, which included irinotecan, in our outpatient chemotherapy center between October 2014 and January 2017. For regression analysis, variables related to the development of irinotecan-related cholinergic syndrome were extracted from the patient's clinical records. The degree of cholinergic syndrome was classified as follows: grade 0 = not developed; grade 1 = developed but did not require anticholinergic drugs; and grade 2 = developed and required anticholinergic drugs or stopping the chemotherapy due to cholinergic syndrome. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of irinotecan-related cholinergic syndrome. Threshold measurements were determined using a receiver operating characteristic analysis (ROC) curve. Significant factors identified for the development of cholinergic syndrome included female sex [odds ratio (OR) 2.183, 95% confidence interval (CI) 1.010-4.717; P = 0.0471] and irinotecan dose (OR 1.014, 95% Cl 1.007-1.021; P = 0.0001). ROC curve analysis of the group likely to develop cholinergic syndrome indicated that the threshold for the irinotecan dose was 175 mg or above (area under the curve = 0.69). In conclusion, female sex and irinotecan dose were identified as significant predictors of the development of cholinergic syndrome.

Background: Despite enormous progresses in understanding pathophysiology of the lower urinary tract, antimuscarinics remain the chief clinically well-established approach for improving symptoms of overactive bladder (OAB). Dry mouth on the other hand remains one of the most untolerated systemic side effects of these drugs that limits their uses and results in high discontinuation rate. Three novel drugs have been recently approved by US Food and Drug Administration for treatment of OAB: trospium, darifenacin, and solifenacin., Aims: This study has been conducted to provide clear head to head comparative studying of histological and ultrastructural effect of those newly emerging drugs on parotid and submandibular salivary glands and to demonstrate the differential expression of CXCL10 to make a cogent structural and molecular assessment of the relative tolerability of these drugs and the potential mechanisms of occurrence of dry mouth., Methods: Fifty male Sprague Dawley rats were equally divided into five groups: Group I (control), Group II (oxybutynin-treated), Group III (trospium-treated), Group IV (darifenacin-treated) and Group V (solifenacin-treated). Histological and ultrastructural studies were performed on parotid and submandibular glands. Measurement of salivary flow, PCR analysis and immunohistochemical assessment of CXCL10 expression have been carried-out., Results: Muscarinic receptor antagonists led to various histological, morphometric and ultrastructural changes together with diminished salivary secretion and up-regulation of CXCL10 expression with the mildest alterations observed with solifenacin., Conclusions: Solifenacin has shown the least adverse effects to salivary glands. CXCL10 is involved in degenerative changes of salivary glands induced by muscarinic antagonists., (Published by Elsevier GmbH.)

Objective: Bone marrow cell extract (BMCE) was previously reported to restore salivary gland hypofunction caused by irradiation injury. Proteins were shown to be the main active factors in BMCE. However, BMCE therapy requires multiple injections and protein denaturation is a concern during BMCE storage. This study aimed to preserve, by lyophilization (freeze-drying), the bioactive factors in BMCE., Methods: We developed a method to freeze-dry BMCE and then to analyze its ingredients and functions in vivo. Freeze-dried (FD) BMCE, freshly prepared BMCE (positive control), or saline (vehicle control) was injected into the tail vein of mice that had received irradiation to damage their salivary glands., Results: Results demonstrated that the presence of angiogenesis-related factors and cytokines in FD-BMCE remained comparable to those found in fresh BMCE. Both fresh and FD-BMCE restored comparably saliva secretion, increased cell proliferation, upregulated regenerative/repair genes, protected salivary acinar cells, parasympathetic nerves, and blood vessels from irradiation-damaged salivary glands., Conclusion: Lyophilization of BMCE maintained its bioactivity and therapeutic effect on irradiation-injured salivary glands. The advantages of freeze-drying BMCE are its storage and transport at ambient temperature., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)