Therapeutic Strategies for Dry Mouth Management with Emphasis on Electrostimulation as a Treatment Option

Objectives. Xerostomia is a subjective sensation of dry mouth. It is commonly associated with salivary gland hypofunction. Both changes in the composition of the saliva and a reduction in the quantity secreted may be an objective finding of dry mouth. Although there are no currently available cures for the conditions resulting in dry mouth, there are several treatment options that give hope for patients who suffer from xerostomia. Individuals with some residual salivary gland function, which are contraindicated to pharmacological therapies, would benefit the most from identifying novel, alternative effective methods for stimulating production of saliva. The aim of this study was to give an overview of the latest and most relevant data related to treatment modalities for the management of dry mouth conditions. Data Resources and Study Selection. The present review was prepared by searching the National Library of Medicine database using the relevant medical terms and their combinations. A total of thirty-three studies met the inclusion criteria. Data were extracted by one author and verified by another. Conclusion. A number of patients showed positive treatment outcomes, and the adverse effects of both electrical stimulation (ES) and acupuncture have been reported as mild and transient. In patients who have undergone radiotherapy, acupuncture is shown to increase salivation. However, in patients with Sjogren’s syndrome, the effects of ES devices seem to be elusive. Moreover, due to the instability of the findings in relation to longevity of clinical effect, patient satisfaction, quality of life, and clinical effectiveness of such treatments, the results remain vague.

Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline

PURPOSE To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy. Additional information can be found at www.asco.org/supportive-care-guidelines .

Mitochondria-targeted antioxidant protects against irradiation-induced salivary gland hypofunction

A severe consequence of radiation therapy in patients with head and neck cancer is persistent salivary gland hypofunction which causes xerostomia and oral infections. We previously showed that irradiation (IR) of salivary glands in mice triggers initial transient increases in mitochondrial reactive oxygen species (ROSmt), mitochondrial [Ca2+] ([Ca2+]mt), and activated caspase-3 in acinar cells. In contrast, loss of salivary secretion is persistent. Herein we assessed the role of ROSmt in radiation-induced irreversible loss of salivary gland function. We report that treatment of mice with the mitochondrial-targeted antioxidant, MitoTEMPO, resulted in almost complete protection of salivary gland secretion following either single (15 Gy) or fractionated (5 × 3 Gy) doses of irradiation. Salivary gland cells isolated from MitoTEMPO-treated, irradiated, mice displayed significant attenuation of the initial increases in ROSmt, ([Ca2+]mt, and activated caspase-3 as compared to cells from irradiated, but untreated, animals. Importantly, MitoTEMPO treatment prevented radiation-induced decrease in STIM1, consequently protecting store-operated Ca2+ entry which is critical for saliva secretion. Together, these findings identify the initial increase in ROSmt, that is induced by irradiation, as a critical driver of persistent salivary gland hypofunction. We suggest that the mitochondrially targeted antioxidant, MitoTEMPO, can be potentially important in preventing IR-induced salivary gland dysfunction.

Retroductal Delivery of Epidermal Growth Factor Protects Salivary Progenitors after Irradiation

Salivary gland hypofunction after irradiation is associated with a deficit of epithelial stem/progenitors in salivary glands. Although epidermal growth factor (EGF) is known to stimulate the proliferation of epithelial cells, the therapeutic effect of EGF on salivary epithelial stem/progenitors remains undetermined. In this study, we administered EGF to submandibular glands (SMGs) via a retrograde route through the SMG excretory duct before fractionated irradiation and examined whether EGF could protect salivary epithelial progenitor cells from radiation and alleviate radiation-induced salivary hypofunction. EGF-treated mice exhibited greater body and gland weights at 12 wk after irradiation than untreated mice. The retroductal delivery of EGF improved salivary secretory function and increased salivary amylase activity in a dose-dependent manner. Histological examinations highlighted the amelioration of the loss of keratine-14+ (KRT14+) basal ductal and/or MIST1+ acinar cells, as well as induction of fibrosis, following irradiation in EGF-treated mice. An additional in vitro experiment using a salivary gland organoid irradiation model indicated that the radioprotective effects of EGF promoted the growth and inhibited the apoptotic cell death of salivary epithelial cells. Our results suggest that retroductal delivery of EGF may be a promising therapeutic option for preventing radiation-induced salivary gland hypofunction.

The use of Schirmer strips to measure salivary and lacrimal flow in non-Sjögren patients

Introduction Oral and ocular dryness are the most common symptoms reported during ophthalmological and dental examinations. It is becoming a serious and growing problem due to the huge variety of affecting factors and with population aging. Objectives The purpose was to demonstrate an application of the Schirmer test for xerostomia. Subsequently, to compare and correlate the results achieved from the lacrimal Schirmer test and salivary Schirmer test in non-Sjögren patients. Methods Study group consisted of 642 patients with/without subjective or/and objective symptoms of dry eye or mouth who did not fulfill the criteria for diagnosis of Sjögren syndrome. The lacrimal Schirmer test (lST) and the salivary Schirmer tests (sST) were performed (sSTm was put on the floor of the mouth, sSTp in front of the parotid gland duct). The results were recorded after 1 min (sSTm), 3 min (sSTp), and 5 min (lST). Results The lST and sST test scores were considerably higher in the healthy group than in others, p < 0.001. The results of sST1 and sST2 decreased with the appearance of subjective and objective symptoms, p < 0.001. There were positive correlations between lST and sSTm outcomes between the groups, p < 0.001. Conclusions We present the Schirmer test adapted to measure salivary gland hypofunction that is a time-saving tool in our daily practice. Results of this study reveal an excellent correlation between the eye Schirmer test and the salivary Schirmer tests. Clinical relevance The salivary Schirmer tests seem to be rapid, convenient, and reliable objective screening tools for salivary gland hypofunction in non-Sjögren patients.

Older age, smoking, tooth loss and denture-wearing but neither xerostomia nor salivary gland hypofunction are associated with low intakes of fruit and vegetables in older Danish adults

Xerostomia and salivary gland hypofunction are prevalent conditions in older people and may adversely influence the intake of certain foods, notably fruit and vegetables. Here, we aimed to investigate whether xerostomia and salivary gland hypofunction were associated with a lower intake of fruit and vegetables. The study included 621 community-dwelling adults, mean age 75⋅2 ± 6⋅4 years, 58⋅9 % female, who had participated in the Copenhagen City Heart Study follow-up, and undergone interviews regarding food intake (preceding month), oral and general health (xerostomia, taste alterations, diseases, medication, alcohol consumption and smoking), clinical oral examination and measurements of unstimulated and chewing-stimulated whole saliva flow rates. The average total energy intake (8⋅4 ± 2⋅7 MJ) and protein energy percentage (14⋅8 ± 3⋅1 %) were slightly below recommendations. The average fruit (234⋅7 ± 201⋅2 g/d) and vegetables (317⋅3 ± 157⋅4 g/d) intakes were within recommendations. Xerostomia and hyposalivation were more prevalent in women than in men (16⋅4 v. 7⋅1 %, P < 0⋅001 and 40⋅7 v. 27⋅5 %, P < 0⋅001). Multiple linear regression analyses revealed that older age (β −0⋅009, se 0⋅003, P = 0⋅005), smoking (β −0⋅212, se 0⋅060, P = 0⋅0005) and wearing complete dentures/being partially or fully edentulous (β −0⋅141, se 0⋅048, P = 0⋅003), but neither xerostomia nor salivary flow rates were associated with an inadequate fruit and vegetable intake, after adjustment for covariates. Older age, smoking, tooth loss and denture-wearing were stronger determinants of low fruit and vegetable intakes than xerostomia and salivary hypofunction supporting the importance of dietary counselling and maintenance of oral health and an adequate masticatory performance.

Salivary Gland Dysfunction in Stroke Patients Is Associated with Increased Protein Glycoxidation and Nitrosative Stress

Stroke is one of the leading causes of disability and death worldwide. Despite intensive medical care, many of the complaints directly threatening the patient’s life marginalize their dental needs after the stroke. Recent studies indicate reduced saliva secretion in stroke patients in addition to the increased incidence of caries and periodontal disease. Since oxidative stress plays a vital role in the pathogenesis of salivary gland hypofunction and neurodegenerative disorders (including stroke), this is the first to evaluate the relationship between salivary gland activity and protein glycoxidation and nitrosative damage. The content of glycation and protein oxidation products and nitrosative stress was assessed in nonstimulated (NWS) and stimulated (SWS) whole saliva of stroke patients with normal salivary secretion and hyposalivation (reduced saliva production). The study included 30 patients in the stroke’s subacute phase and 30 healthy controls matched by age and sex. We have shown that stroke patients with hyposalivation show increased contents of protein glycation (↑Amadori products and ↑advanced glycation end products), glycoxidation (↑dityrosine), and nitration (↑nitrotyrosine) products compared to stroke cases with normal salivary secretion and control group. Interestingly, higher oxidative/nitrosative stress was found in NWS, which strongly correlates with salivary flow rate, total protein content, and salivary amylase activity. Such relationships were not observed in the control group. Summarizing, oxidative and nitrosative stress may be one of the mechanisms responsible for the impairment of saliva secretion in stroke patients. However, extraglandular sources of salivary oxidative stress in stroke patients cannot be excluded. Further studies to assess salivary gland hypofunction in stroke cases are necessary.

Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients

BackgroundThe most manifest long-term consequences of radiation therapy in the head and neck cancer patient are salivary gland hypofunction and a sensation of oral dryness (xerostomia).MethodsThis critical review addresses the consequences of radiation injury to salivary gland tissue, the clinical management of salivary gland hypofunction and xerostomia, and current and potential strategies to prevent or reduce radiation injury to salivary gland tissue or restore the function of radiation-injured salivary gland tissue.ResultsSalivary gland hypofunction and xerostomia have severe implications for oral functioning, maintenance of oral and general health, and quality of life. Significant progress has been made to spare salivary gland function chiefly due to advances in radiation techniques. Other strategies have also been developed, e.g., radioprotectors, identification and preservation/expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, and application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture.ConclusionMany advances to manage salivary gland hypofunction and xerostomia induced by radiation therapy still only offer partial protection since they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects. Intensity-modulated radiation therapy (IMRT), and its next step, proton therapy, have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients.Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for regaining function and/or regeneration of radiation-damaged salivary gland tissue.