**6. Treatments**

Treatment design to alleviate dry-mouth symptoms should be personalized to the individual patient, based on available treatment. The treatments of xerostomia can be classified into the following categories: (1) patient education, (2) prevention, (3) symptomatic treatment, (4) systemic and topical salivary stimulants, and (5) regenerative and gene therapies.

#### **6.1. Patient education**

Patients should receive detailed information about the potential causes of dry mouth and the potential sequelae of impaired salivary secretion, such as dental caries, candidiasis, and mucosal complications. Therefore, patients should be encouraged to have preventive oral health care such as dental hygiene habits and regular dental visits [61]. Another palliative action to minimizing symptoms and preventing oral complications is water intake, drinking water frequently, and remaining hydrated is an important treatment for symptoms of dry mouth [1].

#### **6.2. Preventive therapies**

lips, angular cheilitis, and dry mucosa. Also, caries, candidiasis, halitosis, or loss of appetite and weight could be observed [25, 57, 58]. This collection of clinical parameters has been indicated as

The side effects associated with xerostomia are microbial colonization and proliferation in the oral cavity, dental or decreased demineralization, accumulation of stones in the teeth, dehydration of the mucosa, reduction of rates of elimination of substances from the mouth and lubrication of the oral mucosa reduced [13]. When the production of saliva decreases, the buffering capacity of the saliva is reduced, and thus the environment of the oral cavity is vulnerable to acidification, which in addition to determining changes in the normal flora (ecological imbalance) has contributed to the increase in the number of some microorganisms such as *Candida albicans* (a salivary flow less than 0.1 mL/min may cause an increase in the incidence of this fungus) and *Streptococcus mutans* (Gram-negative bacteria). A higher proportion of these microorganisms results in greater acidification of the oral cavity environment, and thus contribute to the enamel demineralization and caries progression. There is a study related to it in which subjects with low salivary flow rate also had significantly more dental caries compared to those with a higher saliva flow rate [58]. In addition, high caries prevalence has been reported to be associated with significantly poorer quality of life compared to

The infection of the oral mucosa with *C. albicans* affects the lubrication of oral tissues, favoring an increase in the risk of caries and severity of periodontal disease. Candidiasis can also cause burning sensation, glossodynia, glossitis, and angular cheilitis (in areas where the lips are dry or cracked). Patients with prostheses may have reduced retention of the prostheses, pain, and ulcers [59]. The prevalence of oral Candida in the normal population has been estimated to range from 23 to 68% and 68 to 100% among SS patients. Studies have attributed the higher

Treatment design to alleviate dry-mouth symptoms should be personalized to the individual patient, based on available treatment. The treatments of xerostomia can be classified into the following categories: (1) patient education, (2) prevention, (3) symptomatic treatment, (4) sys-

Patients should receive detailed information about the potential causes of dry mouth and the potential sequelae of impaired salivary secretion, such as dental caries, candidiasis, and mucosal complications. Therefore, patients should be encouraged to have preventive oral health care such as dental hygiene habits and regular dental visits [61]. Another palliative action to minimizing symptoms and preventing oral complications is water intake, drinking water frequently, and remaining hydrated is an important treatment for symptoms of dry mouth [1].

temic and topical salivary stimulants, and (5) regenerative and gene therapies.

simply estimated for recognizing most patients with xerostomia [38, 47].

22 Salivary Glands - New Approaches in Diagnostics and Treatment

prevalence of oral Candida carriage in this disease to xerostomia [60].

low caries prevalence [13].

**6. Treatments**

**6.1. Patient education**

Pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction have been studied. The use of chemical radioprotectors represents an obvious strategy to improve the therapeutic index in radiotherapy. However, the vast majority of these are either too weak in terms of radioprotection, too toxic, or without any apparent mechanisms to ensure selective normal tissue protection [62]. The sulfhydryl compound amifostine (WR-2721; 2-[(3-aminopropyl) amino] ethylphosphorothioic acid), is an oxygen scavenger that may protect salivary glands from free-radical damage during radiation therapy without attenuation of the anti-tumor effects in many experiments performed [63]. Amifostine has been approved for prevention of xerostomia, in head and neck squamous cell carcinoma patients undergoing radiotherapy [64]. A recent systematic review that included randomized controlled trials suggested that the drug amifostine prevents the feeling of dry mouth in people receiving radiotherapy to head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (3 months after radiotherapy) [65]. However, amifostine has adverse effects such as nausea, vomiting, hypotension, transient, hypocalcemia, and allergic reactions [66]. Then, the benefits of amifostine should be weighed against its high cost and side effects. Another cytoprotective compound described in literature is the bioactive factor Keratinocyte growth factor-1 (KGF-1, also known as FGF-7) [67]. In a phase II Study, recombinant KGF (Palifermin) appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy but not standard radiation therapy [68].

Current preventative therapies also include surgical salivary glands relocation outside the radiation field [69]. Jha et al. described a surgical transfer of a submandibular salivary gland to the submental space in order to prevent radiation-induced xerostomia in patients with neoplasias of the pharynx and larynx [70].

#### **6.3. Symptomatic treatment**

Saliva substitutes can provide some relief since provide higher viscosity and protection to the oral mucosa [39]. An ideal saliva substitute must simulate natural human saliva, providing long lasting and intense hydration of the oral mucosa, be inexpensive, edible, easy-to-swallow but retainable in the mouth and should allow a minimal number of applications [71]. Saliva substitutes are available in various formulations, e.g., lozenges, sprays, mouth rinses, gels, oils, chewing gums, or toothpastes. Most available in the market contain carboxymethylcellulose (CMC), mucins, xanthan gum, hydroxyethylcellulose, linseed oil, or polyethylene oxide [72]. Subjective impressions of patients suffering from severe xerostomia showed that artificial saliva containing mucins and xanthan gum are better in their rheological and moisturizing properties than those with CMC [73], because mucin-based substitutes had viscosities that were more similar to natural saliva. Recently, it was reported that a polysaccharide-based oral rinse was effective in symptom control in patients with xerostomia and may lead to an increase in saliva production [74]. Other studies include the use of natural products, in this line, a recent doubleblinded, placebo-controlled clinical trial, evaluated the efficacy of topical lycopene-enriched virgin olive oil. It showed an improvement of oral quality of life and reduction of xerostomia symptoms [75]. Also, gelatinous substitutes of saliva showed a significant reduction of the dryness-related complaints in patients suffering from severe xerostomia [76]. A randomized, double-blind, crossover study in patients affected by medication-induced xerostomia showed that two commercial mouthwash plus gel (GUM® Hydral versus Biotène® Oralbalance) achieve a significant improvement in oral health and xerostomia-related quality of life [77]. Recently, a novel edible saliva substitute, oral moisturizing jelly (OMJ), showed a higher grade of satisfaction than a commercially available saliva gel [78]. In addition to the persistent feeling of dry mouth, people who suffer from xerostomia are very susceptible to bacterial, fungal, and other transmittable mouth infections. It is important that products also include human saliva's enzymes (lactoperoxidase, lysozyme, and lactoferrin). Other important feature is to obtain a continuous oral lubrication. In this context, advances in hydrogel technologies and development of buccal mucoadhesive polymers, allows the continuous release of substances that maintain oral hydration and also offer dental-care benefits for its use in treatment of xerostomia [79]. Other strategy involves the use of modified prosthetic structure designed to retain saliva or substitutes in patients who usually wear a dental prosthesis [4, 80].

effective treatment for xerostomia linked to SS, improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events [7, 90]. Rituximab (anti-CD20 monoclonal antibody) and infliximab (anti-tumoral necrosis factor—TNF—monoclonal antibody) improved subjective and objective symptoms related to primary SS [91].

Xerostomia: An Update of Causes and Treatments http://dx.doi.org/10.5772/intechopen.72307 25

Topical salivary stimulants includes sugar-free chewing gum and jellybeans, they can increase salivary secretion by mechanical stimulation and improve the sensation of dry mouth. These products usually contain fluoride, chlorhexidine, calcium phosphate, and xylitol releasers [92, 93], which inhibits the growth of cariogenic bacteria and reduces the incidence of caries [94]. Direct stimulation with electrostimulating device mounted on an intra-oral removable appliance has been used in patients with salivary dysfunction with good results and no significant side-effects [95, 96]. Moreover, non-invasive electrical stimulation systems such as transcutaneous electrical nerve stimulation (TENS) was highly effective in stimulating whole salivary flow in patients with xerostomia and hyposalivation caused by DM and postmenopausal condition [97, 98]. Acupuncture as a method of xerostomia treatment is also cited, a recent randomized and controlled pilot trial of acupuncture showed that acupuncture has beneficial effects on SS symptoms [99]. Other pilot study showed a preliminary evidence that auricular acupressure therapy may be effective in reducing xerostomia intensity in maintenance hemodialysis patients [100].

Stem cell replacement therapy may be a good option to treat radiation-induced hyposalivation. Stem cell therapy attempts the repair of damaged salivary glands at the cellular level. In this regard, bone marrow stem cells, adipose tissue-derived stromal cells, dental pulp cells have been tested as a form of treatment for hyposalivation after radiotherapy [39]. Interestingly, human salivary stem/progenitor cells (hSSPCs) (derived from parotid and submandibular glands) can be cultured using the salisphere technique and can be introduced to a damaged salivary gland tissue to replace dead or damaged cells. In this context, Pringle et al. showed the presence of SSPCs in cultured human salipheres [101]. These cells were capable of self-renewal and differentiation, which when transplanted into irradiated recipients and restored glandular function. Considering that an ultimate goal is to develop fully functioning bioengineered organs to replace lost or damaged. It was recently reported that a population of SSPCs can be reliably isolated and expanded in sufficient number, suitable for use in a unique 3D hydrogel model of a human implantable salivary gland [102]. However, independent and collaborative work in stem cells research and tissue engineering is still necessary to have fully functional human salivary glands.

Gene therapy involves injecting a vector with genetic information into a tissue to result in some beneficial change. Originally, gene transfer was considered for use in treating congenital genetic disorders, but the basic principles have now been applied virtually to every organ, for acquired as well as inherited disorders. Regarding salivary glands, Baum et al., in phase I/II study, showed an increased saliva flow rate from the targeted parotid gland, as well as a reduction in symptoms related to the radiation-induced xerostomia in subjects treated with the transferring of cDNA for human aquaporin-1 (hAQP1) through an adenoviral (Ad5) vector (AdhAQP1) [103]. Additionally, others genes (Gli1, human keratinocyte growth factor, and Tousled like kinase 1B) have been targeted and have shown promise in preventing salivary

**6.5. Glandular regeneration and gene therapy**

#### **6.4. Systemic and topical salivary stimulants**

Pilocarpine and cevimeline are two systemic US Food and Drug Administration-approved systemic sialogogues for treatment of dry mouth; both can increase secretions and diminish xerostomic complaints in patients, although they must have functional salivary gland cells. Pilocarpine is a cholinergic parasympathomimetic agent that stimulates muscarinic cholinergic receptors on the surfaces of exocrine glands [81] and has been indicated for the treatment of xerostomia [2, 82]. The usual oral dosage for pilocarpine is 5–10 mg three times per day. The initial recommended dose is 5 mg three times per day oral route (OR), which can be increased up to 30 mg/day depending on response and tolerance. The onset of action is 30 min, and the duration of action is approximately 2–3 h. Common side effects include gastrointestinal upset, sweating, tachycardia, bradycardia, increased pulmonary secretions, increased smooth muscle tone, and blurred vision. Contraindications include gall bladder disease, angle closure glaucoma, and renal colic [39, 83]. Cevimeline is a salivary gland stimulant with a stronger affinity for M3 muscarinic receptors [84]. Since it has no effect on M2 receptors, it shows fewer adverse effects when compared to pilocarpine, and besides, it has a long lasting action. The recommended dose is 30 mg three times a day OR, and the most common associated side effect is dyspepsia. Bethanecol is another drug whose action mechanism is on M3 receptors. It has been used to decrease unwanted effects caused by antidepressant and antipsychotic drugs [85]. The dose indicated is four times a day in doses from 10 to 50 mg OR. Adverse effects, despite being infrequent, include nausea and diarrhea. Other drugs that have been put forward include drug with mucolytic properties such us bromhexine improved salivary secretion in patients with SS [86, 87]. Nizatidine, an H2 receptor antagonist alone or in combination with cisapride, showed a significant increase in salivary secretions of dry mouth patients [88, 89]. In addition, other drugs, such as neostigmine, distigmine, yohimbine, nicotinic, and malic acid have also been attributed positive effects in the treatment of xerostomia [3]. Medicinal herbs, such as jaborandi, betel nut, Iceland Moss and Longo Vital, also can stimulate salivary secretion [4].

In the case of tissue autoimmune-related xerostomia, immunologic agents have been used. Interferon alpha (IFN-α), a protein with antiviral and immunomodulating traits, was an effective treatment for xerostomia linked to SS, improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events [7, 90]. Rituximab (anti-CD20 monoclonal antibody) and infliximab (anti-tumoral necrosis factor—TNF—monoclonal antibody) improved subjective and objective symptoms related to primary SS [91].

Topical salivary stimulants includes sugar-free chewing gum and jellybeans, they can increase salivary secretion by mechanical stimulation and improve the sensation of dry mouth. These products usually contain fluoride, chlorhexidine, calcium phosphate, and xylitol releasers [92, 93], which inhibits the growth of cariogenic bacteria and reduces the incidence of caries [94]. Direct stimulation with electrostimulating device mounted on an intra-oral removable appliance has been used in patients with salivary dysfunction with good results and no significant side-effects [95, 96]. Moreover, non-invasive electrical stimulation systems such as transcutaneous electrical nerve stimulation (TENS) was highly effective in stimulating whole salivary flow in patients with xerostomia and hyposalivation caused by DM and postmenopausal condition [97, 98]. Acupuncture as a method of xerostomia treatment is also cited, a recent randomized and controlled pilot trial of acupuncture showed that acupuncture has beneficial effects on SS symptoms [99]. Other pilot study showed a preliminary evidence that auricular acupressure therapy may be effective in reducing xerostomia intensity in maintenance hemodialysis patients [100].

#### **6.5. Glandular regeneration and gene therapy**

dryness-related complaints in patients suffering from severe xerostomia [76]. A randomized, double-blind, crossover study in patients affected by medication-induced xerostomia showed that two commercial mouthwash plus gel (GUM® Hydral versus Biotène® Oralbalance) achieve a significant improvement in oral health and xerostomia-related quality of life [77]. Recently, a novel edible saliva substitute, oral moisturizing jelly (OMJ), showed a higher grade of satisfaction than a commercially available saliva gel [78]. In addition to the persistent feeling of dry mouth, people who suffer from xerostomia are very susceptible to bacterial, fungal, and other transmittable mouth infections. It is important that products also include human saliva's enzymes (lactoperoxidase, lysozyme, and lactoferrin). Other important feature is to obtain a continuous oral lubrication. In this context, advances in hydrogel technologies and development of buccal mucoadhesive polymers, allows the continuous release of substances that maintain oral hydration and also offer dental-care benefits for its use in treatment of xerostomia [79]. Other strategy involves the use of modified prosthetic structure designed to retain saliva or

Pilocarpine and cevimeline are two systemic US Food and Drug Administration-approved systemic sialogogues for treatment of dry mouth; both can increase secretions and diminish xerostomic complaints in patients, although they must have functional salivary gland cells. Pilocarpine is a cholinergic parasympathomimetic agent that stimulates muscarinic cholinergic receptors on the surfaces of exocrine glands [81] and has been indicated for the treatment of xerostomia [2, 82]. The usual oral dosage for pilocarpine is 5–10 mg three times per day. The initial recommended dose is 5 mg three times per day oral route (OR), which can be increased up to 30 mg/day depending on response and tolerance. The onset of action is 30 min, and the duration of action is approximately 2–3 h. Common side effects include gastrointestinal upset, sweating, tachycardia, bradycardia, increased pulmonary secretions, increased smooth muscle tone, and blurred vision. Contraindications include gall bladder disease, angle closure glaucoma, and renal colic [39, 83]. Cevimeline is a salivary gland stimulant with a stronger affinity for M3 muscarinic receptors [84]. Since it has no effect on M2 receptors, it shows fewer adverse effects when compared to pilocarpine, and besides, it has a long lasting action. The recommended dose is 30 mg three times a day OR, and the most common associated side effect is dyspepsia. Bethanecol is another drug whose action mechanism is on M3 receptors. It has been used to decrease unwanted effects caused by antidepressant and antipsychotic drugs [85]. The dose indicated is four times a day in doses from 10 to 50 mg OR. Adverse effects, despite being infrequent, include nausea and diarrhea. Other drugs that have been put forward include drug with mucolytic properties such us bromhexine improved salivary secretion in patients with SS [86, 87]. Nizatidine, an H2 receptor antagonist alone or in combination with cisapride, showed a significant increase in salivary secretions of dry mouth patients [88, 89]. In addition, other drugs, such as neostigmine, distigmine, yohimbine, nicotinic, and malic acid have also been attributed positive effects in the treatment of xerostomia [3]. Medicinal herbs, such as jaborandi, betel nut, Iceland Moss and Longo Vital, also can stimulate salivary secretion [4].

In the case of tissue autoimmune-related xerostomia, immunologic agents have been used. Interferon alpha (IFN-α), a protein with antiviral and immunomodulating traits, was an

substitutes in patients who usually wear a dental prosthesis [4, 80].

**6.4. Systemic and topical salivary stimulants**

24 Salivary Glands - New Approaches in Diagnostics and Treatment

Stem cell replacement therapy may be a good option to treat radiation-induced hyposalivation. Stem cell therapy attempts the repair of damaged salivary glands at the cellular level. In this regard, bone marrow stem cells, adipose tissue-derived stromal cells, dental pulp cells have been tested as a form of treatment for hyposalivation after radiotherapy [39]. Interestingly, human salivary stem/progenitor cells (hSSPCs) (derived from parotid and submandibular glands) can be cultured using the salisphere technique and can be introduced to a damaged salivary gland tissue to replace dead or damaged cells. In this context, Pringle et al. showed the presence of SSPCs in cultured human salipheres [101]. These cells were capable of self-renewal and differentiation, which when transplanted into irradiated recipients and restored glandular function. Considering that an ultimate goal is to develop fully functioning bioengineered organs to replace lost or damaged. It was recently reported that a population of SSPCs can be reliably isolated and expanded in sufficient number, suitable for use in a unique 3D hydrogel model of a human implantable salivary gland [102]. However, independent and collaborative work in stem cells research and tissue engineering is still necessary to have fully functional human salivary glands.

Gene therapy involves injecting a vector with genetic information into a tissue to result in some beneficial change. Originally, gene transfer was considered for use in treating congenital genetic disorders, but the basic principles have now been applied virtually to every organ, for acquired as well as inherited disorders. Regarding salivary glands, Baum et al., in phase I/II study, showed an increased saliva flow rate from the targeted parotid gland, as well as a reduction in symptoms related to the radiation-induced xerostomia in subjects treated with the transferring of cDNA for human aquaporin-1 (hAQP1) through an adenoviral (Ad5) vector (AdhAQP1) [103]. Additionally, others genes (Gli1, human keratinocyte growth factor, and Tousled like kinase 1B) have been targeted and have shown promise in preventing salivary hypofunction in a preclinical mouse [104, 105]. On the other hand, the use of small-interfering RNA (siRNA)-based gene silencing has provided protection of salivary gland from radiationinduced apoptosis at preclinical level [106].

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