A compound selected from alpha-pinene or mastic resin for use in the treatment of hyposalivation and xerostomia

Abstract

The invention provides methods and products for use in treating hyposalivation and / or xerostomia in an individual. The invention further provides methods for increasing salivation in an individual. The methods comprise administering a therapeutic selected from alpha-pinene and / or mastic resin. The invention further provides oral adhering troches comprising said therapeutic.

Description

[0001] Title: Methods and products for treating hyposalivation and xerostomia FIELD OF THE INVENTION The invention provides methods and products for use in treating hyposalivation and / or xerostomia in an individual. The invention further provides methods for increasing salivation in an individual. The methods comprise administering a therapeutic selected from alpha-pinene and / or mastic resin. The invention further provides oral adhering troches comprising said therapeutic. BACKGROUND OF THE INVENTION Saliva plays an essential role in preserving oral health, including, e.g. acid- buffering, protection against oral pathogens and environmental noxious compounds. In addition, saliva is involved in lubrication, digestion, and taste perception [2]. A healthy unstimulated saliva secretion rate ranges between 0.25 and 0.5 mL / min, while upon stimulation, e.g. by taste and mastication, it may increase up to approximately 0.75-2.0 mL / min [2-6]. Hyposalivation manifests when the unstimulated salivary flow rate is ≤0.1 mL / min and / or <0.7 mL / min under stimulated conditions, respectively [6-9]. Chronic hyposalivation may be a result of impaired salivary gland function and side effects of polypharmacy, as a result, triggers diverse spectrum of consequences, including increased risk of caries, oral fungal infection, and gingivitis [3, 10, 11]. Moreover, xerostomia, denoted by the patient’s subjective perception of dry mouth, may be associated with hyposalivation [5, 14]. In the general population, the prevalence of xerostomia is estimated to be approximately 20%, with increased prevalence in females (up to 30%) and in the elderly (up to 50%) [15, 19, 20]. Moreover, differences in salivary composition are pivotal in xerostomia

[0010] . For example, patients experiencing xerostomia and Sjögren syndrome may have reduced glycosylation of salivary mucins, water-retaining glycoproteins found in saliva. When glandular function of saliva production is irreversibly impaired, specific products can be applied such as salivary substitutes, mouth gels, mouth gels and sprays [15, 23]. When glandular activity is reduced, yet present, the treatment for hyposalivation and / or xerostomia involves e.g., stimulation of saliva production by for example mastication, taste, and medications with parasympathomimetic activity [23, 25]. Efficacy of these currently available remedies appears to be limited, as indicated by the varying compliance among patients

[0024] . Furthermore, said remedies are often short-lived and may also cause side-effects such as sweating, dyspepsia and nausea. As no treatment seems to be fully effective there is a continuous search for novel therapeutic approaches to promote saliva secretion. In particular, it is an object of the present invention to provide treatments for hyposalivation and / or xerostomia. Furthermore, in some embodiments the present invention aims not only at increasing saliva secretion, but also at improving the quality of saliva. SUMMARY OF THE INVENTION The disclosure provides the following preferred embodiments. However, the invention is not limited to these embodiments. In some embodiments the disclosure provides a method for treating hyposalivation and / or xerostomia in an individual, said method comprising administering to an individual in need thereof a therapeutically effective dose of a therapeutic, wherein said therapeutic is selected from alpha-pinene and / or mastic resin. In some embodiments the disclosure provides a method for increasing salivation in an individual in need thereof, said method comprising administering to said individual alpha-pinene and / or mastic resin. In some embodiments the disclosure provides a therapeutic for use in a method for treating hyposalivation and / or xerostomia in an individual, wherein said therapeutic is selected from alpha-pinene and / or mastic resin. In some embodiments the disclosure provides the methods described herein, wherein the method stimulates the production of saliva. In some embodiments the disclosure provides the methods described herein, wherein the method results in an increased salivary spinnbarkeit, a modified salivary ion composition, an increased expression of salivary mucins, an increased saliva pH and / or combination thereof. Preferably, the modified salivary ion composition comprises increased sodium concentration. Preferably said salivary mucin is selected from MUC5B and / or MUC7. In some embodiments the disclosure provides the methods described herein, wherein said therapeutic is provided in a toothpaste, a mouthwash, an oral spray, an oral gel, an oral ointment, an oral adhering troche, nasal spray, sachet, patch or powder. In some embodiments the disclosure provides the methods described herein, wherein said therapeutic is administered orally, buccally, sublabially, sublingually, nasally, or by inhalation. In some embodiments the disclosure provides the methods described herein, wherein said individual has a decreased unstimulated salivary flow rate and / or a decreased stimulated salivary flow rate and / or a complaint of a dry mouth. In some embodiments the disclosure provides an oral adhering troche comprising alpha-pinene, preferably in an amount of at least 1% by weight, more preferably in an amount of at least 2% by weight. In some embodiments the disclosure provides an oral adhering troche comprising mastic resin, preferably in an amount of at least 1.5% by weight, more preferably in an amount of at least 2.5% by weight. In some embodiments the disclosure provides the oral adhering troches described herein, further comprising one or more polyol molecules selected from xylitol, erythritol, sorbitol, mannitol, maltitol, isomalt, and lactitol, preferably wherein polyol molecule is xylitol. In some embodiments the disclosure provides the oral adhering troches described herein, further comprising one or more adhesives, one or more binders, and / or one or more lubricating substances. In some embodiments, the disclosure provides methods for increasing salivation, treating hyposalivation, and / or treating xerostomia in an individual in need thereof, said method comprising administering alpha-pinene and / or mastic resin to said individual. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Schematic overview and timeline of saliva collection from chronic dry mouth patients. Unstimulated whole saliva (UWS), chew stimulated whole saliva (CH-SWS), acid stimulated whole saliva (A-SWS) and mastic resin stimulated saliva (MRS) were collected as described in Example 2. Questionnaires including Xerostomia Inventory (XI), Visual Analogue Scales 1 and 2 (VAS), Regional Oral Dryness Inventory (RODI) were administered before and after collection. Figure 2: Effects of mastic resin volatiles on saliva secretion (A) andspinnbarkeit (B) (N=41). (A) The median (± IQR) flow rates of unstimulated wholesaliva (UWS) (0.05 mL / min ± 0.10), chew stimulated whole saliva (CH-SWS) (0.57 mL / min ± 0.82), acid stimulated whole saliva (A-SWS) (1.48 mL / min ± 1.41) and mastic resin stimulated saliva (MRS) (0.11 mL / min ± 0.15). (B) The median (± IQR) spinnbarkeit of UWS (4.36 mm ± 22.36), CH-SWS (4.42 mm ± 1.08), A-SWS (4.46 mm ± 2.38) and MRS (6.30 mm ± 51.40). * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001. Figure 3: Salivary mucin levels (N=29) of unstimulated and stimulated salivasamples. (A) MUC5B concentrations in UWS (4.76 mg / mL ± 8.40), CH-SWS (3.89mg / mL ± 9.95), A-SWS (2.43 mg / mL ± 5.95) and MRS (7.30 mg / mL ± 9.96). (B) MUC7 levels in UWS (0.51 AU ± 1.06), CH-SWS (0.18 AU ± 0.43), A-SWS (0.44 AU ± 0.80) and MRS (0.37 AU ± 0.90). Data are expressed as median ± IQR. * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001. UWS = unstimulated whole saliva; CH-SWS = chew stimulated whole saliva; A-SWS = acid stimulated whole saliva; MRS = mastic resin stimulated saliva Figure 4: Correlation between salivary mucins and spinnbarkeit (N=29). (A). Positive correlation between MUC5B and spinnbarkeit was observed in MRS samples, but not in UWS. (B). Positive correlation between MUC7 and spinnbarkeit. * P ≤ 0.05, ** P ≤ 0.01. UWS = unstimulated whole saliva; CH-SWS = chew stimulated whole saliva; A-SWS = acid stimulated whole saliva; MRS = mastic resin stimulated saliva DETAILED DESCRIPTION OF THE INVENTION The present disclosure provides methods for treating hyposalivation or xerostomia in an individual. The method may comprise administering to an individual in need thereof a therapeutically effective dose of a therapeutic, wherein said therapeutic is selected from alpha-pinene or mastic resin. The inventors now surprisingly demonstrated that volatile compounds from mastic resin, as well as its main aromatic compound alpha-pinene, showed stimulating effects on saliva production (i.e. sialagogic effect) in healthy subjects, but also in patients with impaired salivary gland function and / or reduced salivary flow rate (such as xerostomia patients or patients afflicted with hyposalivation). As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of hyposalivation or xerostomia, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to an individual that perceives sensation of dryness in the mouth. Furthermore, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors such as use of therapies that may lead to hyposalivation and / or xerostomia, side effects of medicines, polypharmacy, auto-immune diseases, chronic stress). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. In some embodiments, treatment includes reducing the feeling of dry mouth. The term “hyposalivation” (also known as salivary gland hypofunction) as described herein refers to a reduction in saliva production, salivary flow, and / or volume of saliva as compared to normal saliva production, salivary flow and / or volume of saliva in a healthy person. A healthy unstimulated saliva secretion rate ranges between 0.25 and 0.5 mL / min, while upon stimulation, e.g. by taste and mastication, it may increase up to approximately 0.75-2.0 mL / min [2-6]. Unstimulated salivary flow rate of ≤0.1 mL / min, and / or salivary flow rate under stimulated conditions of <0.7 mL / min indicate hyposalivation [6-9]. Chronic hyposalivation is a result of impaired salivary gland function. Xerostomia, also commonly known as dry mouth, is a subjective sensation of oral dryness. Xerostomia may have an underlying cause or may have no identifiable cause. For example, xerostomia may be associated with or result from hyposalivation. In particular xerostomia may be associated with hypofunction of salivary glands. In some embodiments, xerostomia is observed in individuals with normal function of salivary glands. For example, xerostomia may be caused by dehydration.. Xerostomia may also be associated with or result from a change in composition of saliva, for example from serous to mucous saliva (e.g. due to dehydration) compared to healthy saliva or from mucous to serous saliva. In particular, too mucous, sticky saliva may result in mouth dryness due to reduced water content which may not provide sufficient lubrication of oral cavity. On the other hand, too serous saliva may lead to fast evaporation and consequently to mouth dryness. Xerostomia may be associated with aging. For example, xerostomia may be prevalent in elderly population such as in individuals of 65 years or more. Furthermore, xerostomia may be drug induced (e.g. xerogenic drugs such as anticholinergic drugs, anorectics, analgesics, antihistamines, antidepressants, antipsychotics, antihypertensives, antiparkinsonian drugs and diuretics), caused by autoimmune conditions such as Sjögren’s syndrome or celiac disease, and radiation therapy. Both hyposalivation and xerostomia may result in a diverse spectrum of consequences, including increased risk of caries, oral fungal infection (e.g. oral candidiasis), and gingivitis due to the loss of the protective properties of saliva [3, 10, 11]. Additional symptoms include e.g., acid erosion, disturbed taste sensation (dysgeusia), altered smell sensation (dysosmia), burning mouth syndrome, impaired lubrication, difficulties swallowing (dysphagia), sleep disorders (e.g. disturbed sleep due to the sensation of dry mouth), chewing and speaking difficulties, bad breath (halitosis), tongue fissures and lip ruptures [12, 13]. As xerostomia is a subjective sensation, different scoring systems have been developed to standardize assessment of xerostomia, including the Xerostomia Inventory (XI), the Regional Oral Dryness Inventory (RODI) and the Clinical Oral Dryness Score (CODS) [15-18]. The XI questionnaire consists of 11 validated questions on a 5-point scale and a total score is calculated by adding up the points of each question, with a minimum score of 11 (indicating no xerostomia) and a maximum score of 55 (indicating extreme xerostomia)

[0017] . The RODI questionnaire measures the intra-oral perceived dryness containing 9 schematic illustrations of different regions in the mouth, at each location the patient indicated the severity of the perceived oral dryness using a 5-point scale ranging from 1 = “no dryness” to 5 = “severe dryness” [18, 39]. The CODS questionnaire consists of 10 validated questions on a 1-point scale with a total score varying from 0 to 10, where total score of 1-3 indicates mild dryness, total score of 4-6 indicates moderate dryness and total score of 7-10 indicates severe dryness. In some embodiments, an individual as described herein is an individual with a decreased unstimulated salivary flow rate and / or a decreased stimulated salivary flow rate. In some embodiments, an individual has the unstimulated salivary flow rate equal to or less than 0.1 mL / min and / or the stimulated salivary flow rate of less than 0.7 mL / min. In some embodiments, an individual has a complaint of a dry mouth. In some embodiments, an individual has a decreased unstimulated salivary flow rate, a decreased stimulated salivary flow rate and / or a complaint of a dry mouth. In preferred embodiments, the individual is a human. In some embodiments the therapeutic is mastic resin. Mastic resin is a resin obtained as an exudate from a plant classified in the genus Pistacia. Preferably, mastic resin is obtained from Pistacia lentiscus L., more preferably from a cultivar P. lentiscus L. cv. Chia (cultivated on the Greek island of Chios). Notably, said sub- species are known for their high yield of mastic. Mastic resin may be obtained from other species, such as P. lentiscus L. var. emarginata Engl., P. lentiscus L. var. latifolia Coss. Other species of Pistacia include P. atlantica, P. palestina, P. saportae, P. terebinthus, P. vera and P. integerrima. Mastic resin may comprise at least 60%, preferably at least 65%, more preferably at least 70%, still more preferably at least 72%, such as around 75% of alpha-pinene. Mastic resin may further comprise compounds such as beta-pinene, beta-myrcene, camphene, limonene, beta-caryophyllene, linalool and perillene. In some embodiments the therapeutic is alpha-pinene. Alpha-pinene (also referred herein as α-pinene) or 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene is an unsaturated bicyclic monoterpene. Alpha-pinene is one of the two isomers of pinene, the other one being beta-pinene. Alpha-pinene comprises alkenyl group and a reactive four-membered ring. Alpha-pinene is a chiral compound. Racemic mixture of alpha- pinene has a CAS number 80-65-8. Enantiomer (1S,5S)- or (−)-alpha-pinene has a CAS number 7785-26-4. Enantiomer (1R,5R)- or (+)-alpha-pinene has a CAS number 7785-70-8. Alpha-pinene is a natural compound and may be extracted from a natural source. In some embodiments, alpha-pinene is obtained from natural sources such as plants. For example, alpha-pinene may be obtained from plants belonging to the genus Pistacia, preferably from Pistacia lentiscus L., more preferably from a cultivar P. lentiscus L. cv. Chia. Alpha-pinene may also be found in and obtained from the oils of many coniferous (i.e. cone-bearing) plant species such as in the genus Pinus, the oils of plant species in the genus Eucalyptus, the essential oil of species in the genus Salvia (such as S. Rosmarinus) and genus Satureja (such as S. myrtifolia). Alpha- pinene can be extracted using methods known in the art. For example, hydrodistillation, solvent extraction, supercritical fluid extraction may be used. Alternatively, alpha-pinene can be produced synthetically. Racemic mixture as well as enantiomers are also commercially available (e.g. Sigma Aldrich). As shown herein in Example 1, both mastic resin crude extract and alpha- pinene oil have acetylcholinesterase (AChE) inhibitory properties, potentially prolonging the binding of acetylcholine (ACh) on muscarinic receptors and contributing to increased saliva secretion. As shown in Example 1, a significant increase was observed in saliva secretion of healthy subjects through olfactory stimulation, 27% with mastic resin volatiles and 26% with alpha-pinene volatiles, without affecting the salivary ion composition. Additionally, exposure to mastic resin volatiles resulted in elevated concentrations of salivary MUC5B. Furthermore, as shown in Example 2, beneficial effect of mastic resin was further confirmed in patients afflicted with hyposalivation. Mastic resin volatile compounds not only increased saliva secretion, but also improved quality of saliva. In some embodiments, the therapeutic and methods describe herein increase salivation. The term “increasing salivation” or “stimulating salivation” refers to promoting the production and / or secretion of saliva. Production of saliva may be assessed by measuring salivary flow rate. Salivary flow rate is typically expressed in mL of saliva per minute. Methods for salivary flow rate determination are known in the art, such as a passive drool method. For example, salivary flow rate may be determined by collecting saliva produced in a period of time and dividing said amount by said time period. Typically, the individual is instructed to swallow once and to allow saliva to pool on the floor of the mouth for a period of time such as five minutes, followed by spitting or drooling said saliva into a pre-weighed or graduated container such as tube

[0040] . Other methods for determining salivary flow rates also include methods using salivary flow rate instrument such as BokaFloTM, oral moisture- checking device (OMCD, Life Co. Ltd). In general, 1 gram of saliva equals 1 ml. Accordingly, the amount of collected saliva may either be weighed or measured volumetrically. In some embodiments, the therapeutic and methods described herein increase the salivary flow rate to value greater than 0.1 mL / min, preferably greater than 0.15 mL / min, more preferably greater than 0.2 mL / min such as between 0.25 mL / min and 0.5 mL / min. In some embodiments, the therapeutic and methods described herein may result in increased perceived mouth moisture levels. Perceived mouth moisture levels can be determined, for example, using Visual Analogue Scales (VAS). Preferably, the therapeutic and methods described herein result in an increased VAS-score compared to VAS-score of unstimulated whole saliva. In some embodiments therapeutic and methods described herein may improve the quality of said saliva. In particular, said therapeutic and methods may have a beneficial effect on the composition of saliva, such as on salivary spinnbarkeit, salivary ion composition, expression of salivary mucins, pH of saliva and / or combination thereof. Preferably, said therapeutic and methods result in an increased salivary spinnbarkeit, a modified salivary ion composition, an increased expression of salivary mucins, an increased saliva pH and / or combination thereof. The therapeutic and methods described herein may result in an increased salivary spinnbarkeit. The term “spinnbarkeit” also known as spinnability or fibrosity, refers to the stringy or stretchy property of viscoelastic fluids such as saliva, mucus and albumen. As used herein, spinnbarkeit refers to the stringy or stretchy properties of saliva. Salivary spinnbarkeit also reflects the ability of saliva to adhere to surfaces within the mouth. Spinnbarkeit may be measured with methods known in the art, for example using instrument such as the NevaMeter (Ishikawa Iron Works, Kitakyushu, Japan). Spinnbarkeit value, typically expressed in milimeters (mm), represents the ability of the measure fluid to deform and stretch before breaking. In particular, spinnbarkeit value represents the length of a fluid thread (e.g. thread of saliva) when said fluid is stretched and before said fluid thread breaks. The higher the spinnbarkeit value, the greater the spinnbarkeit. Depending on salivary spinnbarkeit, saliva can be classified as serous or mucous. The term “serous saliva” refers to saliva with spinnbarkeit of less than 6 mm. Typically, said serous saliva has watery consistency (i.e. fluid-like) and is rich in enzymes. The term “mucous saliva” refers to saliva with spinnbarkeit equal to or greater than 6 mm. Typically, said mucous saliva is viscous in nature (i.e. thicker) and rich in mucins. The composition of saliva may also vary depending on the salivary gland from which said saliva is produced. For example, parotid glands produce more serous type of saliva, while sublingual glands produce saliva that is mainly mucous in nature. Furthermore, submandibular glands produce a mixture of both serous and mucous saliva. In some embodiments, the therapeutic and methods described herein may result in an increased salivary spinnbarkeit compared to the spinnbarkeit of unstimulated whole saliva. Spinnbarkeit of unstimulated whole saliva in healthy individuals is typically more mucous in nature, while it can shift to serous consistency in conditions such as hyposalivation and xerostomia. Preferably, the therapeutic and methods described herein result in salivary spinnbarkeit equal to or greater than 6 mm. In other words, the therapeutic and methods described herein preferably result in mucous consistency of saliva. In some embodiments, the therapeutic and methods described herein may result in a modified ion composition of saliva. The modified ion composition may include modified concentrations of cations and / or anions in said saliva. Preferably said therapeutic and methods result in an increased cation (e.g. sodium, potassium, ammonium, magnesium, calcium ion) concentration in saliva, more preferably in an increased sodium concentration compared to said concentration in an unstimulated whole saliva. The ion composition of saliva may be evaluated by means known in the art, such as capillary electrophoresis. In some embodiments, the therapeutic and methods described herein may result in an increased expression of salivary mucins. Mucins are a family of high molecular weight, glycosylated proteins with the ability to form gels. Salivary mucins are secreted mucins and integral components of saliva. Examples of salivary mucins include, but are not limited to, mucin-5B (MUC5B) and mucin-7 (MUC7). The water- retaining glycoprotein MUC5B (~1 MDa) plays a crucial role in forming the hydrophilic gel essential for oral lubrication, influencing the salivary spinnbarkeit. Another salivary mucin, MUC7 (~125 kDa), is monomeric and exhibits limited viscoelastic properties

[0021] . In contrast to MUC5B, the carbohydrate side chains of MUC7 are shorter, predominantly composed of sialylated di- and trisaccharides. MUC5B features more heterogeneous and larger side chains (between 2 and >20 residues)

[0010] . Patients experiencing xerostomia and Sjögren syndrome may have reduced glycosylation of both MUC5B and MUC7 [10, 21, 22]. The therapeutic and methods described herein preferably result in an increased expression of MUC5B or MUC7, more preferably in an increased expression of MUC5B and MUC7. Expression levels of salivary mucins may be determined using any means known in the art, such as enzyme-linked immunosorbent assay (ELISA),immunoassays, polyacrylamide gel electrophoresis including two dimensional gelelectrophoresis and / or using staining such as Coomassie Blue staining, silver staining and / or periodic acid-Schiff staining, multidimensional protein identification technology, surface plasmon resonance, liquid chromatography-mass spectrometry (LC-MS), matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF). In some embodiments, the therapeutic and methods described herein preferably result in an increased pH of saliva compared to unstimulated whole saliva. Normally, salivary pH is neutral, with values in a range between 6.2 to 7.6. Said increased pH of saliva is preferably in said range. In some embodiments, the therapeutic and methods described herein may result in reduced dryness of posterior palate. Perceived sensation of dryness may be determined using, for example, RODI questionnaire. The therapeutic as described herein may have a characteristic scent and / or flavour. Specifically, alpha-pinene is a volatile compound that contributes to the distinct scent of mastic resin commonly described as fresh and woody with hints of citrus, lemongrass and pine. Scent of alpha-pinene may also be enantiospecific. Furthermore, the taste of alpha-pinene and mastic resin is commonly described as sweet-bitter, earthy, and / or herbaceous. Without wishing to be bound by theory, the therapeutic as described herein is hypothesized to stimulate salivation through two potential pathways via olfactory exposure. Firstly, after inhaling the scent of the therapeutic, volatile compounds (e.g. alpha-pinene) bind to receptors on the olfactory bulb which triggers a signal to the salivary superior nucleus in the pons of the brain. The action potential is then transmitted via the chorda tympani and lingual nerves to the submandibular ganglion, proceeding into the sublingual glands (SL), submandibular glands (SM) and minor salivary glands. Saliva secretion is the triggered from said glands. The second mechanism may involve the inhibition of acetylcholinesterase (AChE). In particular, the therapeutic may directly inhibit AChE in the acini of palate. Said posterior palate is located in the proximity of the nasal cavity and is innervated by the lesser palatine nerve. This inhibition potentially leads to prolonged acetylcholine (ACh) stimulation of the ACh receptor, triggering the production of (mucous) saliva from the palate. The therapeutic as described herein may be administered, e.g., orally, buccally, sublabially, sublingually, nasally, or by inhalation. The term “buccally administering” refers to oral administration around and / or at buccal area (i.e. cheek area), in particular for example between the gums and the inner linings of the cheek. The term “sublabially administering” or “sublabial administration” refers to administration between the lip and the gum. The term “sublingually administering” refers to administration under the tongue. The nasal administration and administration by inhalation also include delivery via olfactory exposure as described herein. Additionally, since the therapeutic is or comprises volatile compound(s), said therapeutic when administered in oral cavity may also act within nasal cavity, specifically via olfactory exposure. The therapeutic as described herein may be provided in various formulations. The therapeutic as described herein may be provided in a form for delivery within or through the oral cavity. For example, the therapeutic may be provided in a form of toothpaste, mouthwash, oral spray, oral gel, oral ointment, or oral adhering troche. The therapeutic may also be provided in a form for nasal administration or administration by inhalation. For example, the therapeutic may be provided in a form of nasal spray, sachet, patch, or powder. The therapeutic and / or scent of said therapeutic is then inhaled by the individual from said forms and may provide effect through olfactory stimulation. Preferably, the therapeutic is provided in a toothpaste, a mouthwash, an oral spray, an oral gel, an oral adhering troche, or a nasal spray. The therapeutic may also be provided in an oral care product (e.g., gum), perfume, detergent, cosmetic, air dispenser and impregnated into material such as clothing, facial tissue, and bedding. The therapeutic may be administered for example once or multiple times per day as needed, e.g., twice, three times, four times, or five times per day. Preferably the therapeutic is administered twice per day, more preferably once per day. Depending on the severity of hyposalivation or xerostomia, the therapeutic may be administered more often. The therapeutic may be administered once a day every day for prevention. In some embodiments, the therapeutic is administered just before sleeping. The therapeutic may be provided in an amount of between 0.3 grams to 5 grams, e.g., in a sachet. In some embodiments, mastic resin is provided in an amount of between 0.5 grams to 5 grams e.g., in a sachet. In preferred embodiments, mastic resin is provided in a form of a sachet in an amount of around 1 gram. In some embodiments, alpha-pinene is provided in an amount of between 0.3 grams to 3.5 grams e.g., in a sachet. In preferred embodiments, alpha-pinene is provided in a form of sachet in an amount of around 0.7 grams. The invention further provides an oral adhering troche comprising mastic resin and / or alpha-pinene. The term “oral adhering troche” refers to a formulation designed to dissolve slowly in the mouth while adhering to areas within the oral cavity (e.g. oral mucosa). The oral adhering troche may be made in a variety of shapes (e.g. circular, square, lozenge, patch) and sizes (e.g. between 5-20 mm). Furthermore, the oral adhering troche may be in the form of a single layer, or it may be in a multilayer, e.g., bilayer form. In some embodiments, a bilayer adhering troche is provided comprising of an adhesive and a non-adhesive layer. Methods of producing oral adhering troches are known to the skilled person. The oral adhering troche can adhere to areas within the oral cavity, such as to gums, gumline, mucosal tissue around or at cheek area (buccal area), mucosal tissue around or at lip area (such as between the lip and the gum, i.e. sublabial area), teeth, structures attached to teeth (e.g. orthodontic braces), or mucosa under the tongue (i.e. sublingual area). In some embodiments, the oral adhering troche is fully dissolving, meaning that it completely erodes or dissolves over a period of time. In some embodiments, the oral adhering troche as described herein is an extended-release dosage, meaning that the therapeutic (i.e. mastic resin or alpha- pinene) is released from said troche over an extended period of time. In some embodiments, the oral adhering troche may be a sustained-release dosage or a controlled-release dosage. In some embodiments, the oral adhering troche comprises mastic resin. The oral adhering troche may comprise mastic resin in an amount between 0.5% to 9% by weight, preferably between 1% to 8% by weight, more preferably between 1.5% to 7% by weight. In some embodiments, the oral adhering troche comprises mastic resin in an amount of at least 0.5%, at least 0.8%, at least 1.0%, preferably at least 1.5%, more preferably at least 2.5% by weight. In some embodiments, the oral adhering troche comprises alpha-pinene. The oral adhering troche may comprise alpha-pinene in an amount between 1% to 5% by weight, preferably between 1.5% to 4% by weight, more preferably between 2% to 3% by weight. In some embodiments, the oral adhering troche comprises alpha-pinene in an amount of at least 1% by weight, more preferably at least 2% by weight. As is clear to a skilled person, the alpha-pinene may also be provided in the form of mastic resin. The oral adhering troche as described herein may further comprise one or more polyol molecules selected from xylitol, erythritol, sorbitol, mannitol, maltitol, isomalt, and lactitol. Said polyol molecules may further stimulate the production of saliva. Preferably, the oral adhering troche as described herein further comprises xylitol. The oral adhering troche as described herein preferably comprises between 50% and 90% by dry weight of xylitol. In some embodiments, the oral adhering troche may further comprise one or more adhesives (e.g. acacia gum, gelatin), one or more binders, one or more lubricating substances (e.g. cellulose gum). Preferably, said binder dissolves slowly to ensure the troche to erode or dissolve slowly. Examples of suitable binder include cellulose gums such as carboxymethylcellulose (CMC), hydroxyproplycellulose (HPC) and hydroxyproplymethylcellulose (HPMC), carrageenan, xanthan gum, konjac gum, locust bean gum, agar and pectin. As used herein, "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, the verb “to consist” may be replaced by “to consist essentially of” meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The word “approximately” or “about” when used in association with a numerical value (approximately 10, about 10) preferably means that the value may be the given value of 10 more or less 1% of the value. All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. The invention is further explained in the following examples. These examples do not limit the scope of the invention, but merely serve to clarify the invention. EXAMPLES Example 1: Effect of mastic resin and α-pinene on saliva production in healthy subjects In this study, in vitro and in vivo (in healthy subjects) effects of mastic resin and alpha-pinene were evaluated. With regards to this study, mention is made of Faruque et al., 2023, Biomedicine & Pharmacotherapy, 168, the contents of which are incorporated by reference herein in their entirety. Firstly, the inhibitory effects of freshly prepared mastic resin extract oil, alpha-pinene oil and alpha-pinene enantiomers ((+)- and (-)-alpha-pinene) on acetylcholinesterase (AChE) activity were measured in vitro. All four, and especially mastic resin extract oil (by 207%), significantly decreased the AChE activity compared to the baseline (Figure 1 of Faruque et al., 2023). Furthermore, effect of mastic resin and alpha-pinene on saliva production was evaluated in healthy subjects. In particular, eighty healthy participants were recruited, half of which were exposed to mastic resin extract oil (MRS) and the other half to alpha-pinene oil (APS). Salivary flow rates were evaluated under unstimulated conditions (unstimulated whole saliva, UWSPRE and UWSPOST) and stimulated conditions (mastic resin stimulated saliva, MRS; and alpha-pinene stimulated saliva, APS). Exposure to mastic resin extract oil resulted in significantly increased salivary flow rate (MRS) compared to the baseline unstimulated salivary rate (UWSPRE) (Figure 2A of Faruque et al., 2023). Similarly, the secretion of saliva after exposure to alpha-pinene was significantly increased (APS) compared to the baseline unstimulated salivary flow rate (Figure 3A of Faruque et al., 2023). Furthermore, data revealed that mastic resin and alpha-pinene stimulation did not alter the quality of saliva. In particular, no significant changes in spinnbarkeit between MRS samples and UWSPRE were observed. Similarly, the spinnbarkeit of APS samples was similar to the spinnbarkeit of UWSPRE (Figures 2B and 3B of Faruque et al., 2023). Data also revealed no significant differences in cation and anion concentrations between MRS samples and control unstimulated samples taken at t=8min (Table 1 of Faruque et al., 2023). Furthermore, exposure to mastic resin resulted in increased salivary MUC5B levels compares to control samples, while alpha-pinene did not have an effect on the levels of salivary MUC5B compared to control samples (Figure 4 of of Faruque et al., 2023). Thus, this study demonstrated effect of mastic resin and alpha-pinene on saliva stimulation in healthy subjects. Example 2: Effect of mastic resin on saliva production in chronic dry mouth patients Although mastic resin and alpha-pinene exhibited beneficial effects in healthy volunteers, such effects cannot be easily extrapolated to patients afflicted with hyposalivation or xerostomia. Therefore, the effect of mastic resin volatiles on saliva production was subsequently evaluated in chronic dry mouth (xerostomia) patients with confirmed decreased saliva production. Material and methods Patient cohort A total of 41 patients with decreased levels of unstimulated whole saliva (UWS) secretion (<0.25 mL / min), were recruited between February 2022 and September 2023. Eligibility criteria required patients to be at least 18 years of age and an UWS flow rate <0.25 mL / min

[0038] as determined by spitting method of Navazesh

[0040] . Patients were excluded from the study if they were unable / hampered to breathe through their nose at the time of the visit. The patients were instructed not to consume food or drinks (except for a small sip of water) or use deodorants or perfumes for 1 h prior to the visit. Patients received written and verbal information about the study and written informed consent was obtained. Questionnaires Prior to the visits, each patient was asked to complete the XI questionnaire, RODI and report medication usage. Before and after the saliva sampling, the patients completed the RODI and assessed their mouth moisture level using 10-centimeter Visual Analogue Scales (VAS). The VAS scores were obtained by measuring the length of the line marked by the participant. Odor pleasantness was also assessed using VAS. Preparation of mastic resin sachets Mastic resin sachets were prepared as described in Example 1. One gram of mastic resin (Saghez, Iran) was placed in one 3.5 x 3 cm 64 µM polypropylene mesh sachet (Chicopee Industries, Gainesville, GA, U.S.A.). The sachet was then subjected to liquid nitrogen for 60 s and crushed until the content was transformed into a fine powder. The powdered mastic resin sachet was then freeze-dried O / N at a temperature of -100°C and under a vacuum pressure of 0.340 mbar using Christ LT- 105 (Salm en Kipp, Breukelen, the Netherlands). For each experiment, the sachets were freshly prepared, stored in closed falcon tubes at room temperature (RT) and used within 24 h. Each patient received one sachet. Saliva collection As part of the diagnostic routine, the saliva collection procedure was conducted in the following order: unstimulated whole saliva (UWS), chew-stimulated whole saliva (CH- SWS), citric-acid stimulated saliva (A-SWS) and mastic resin volatile stimulated saliva (MRS) as depicted in Figure 1. Each patient was instructed to swallow once, to seat upright with a slightly tilted head and not to speak, move or swallow during saliva collection. First, the UWS was collected according to the spitting method of Navazesh

[0040] . The patient allowed the saliva to pool on the floor of the mouth for 5 min and then carefully drooled it into a pre-weighed conical tube with a SnapTecTM cap (Eppendorf, Hamburg, Germany). If patients were unable to maintain saliva in their mouth for the full 5 min, they were allowed to expel once during the collection. Subsequently, CH-SWS was collected for 5 min using a 5 x 5 cm flat piece of tasteless wax (Parafilm “M”, American National CAI, Chicago, USA), with saliva being expelled after chewing into the assigned tube every 30 s

[0041] . Directly afterwards, A-SWS was obtained by applying 4% citric acid solution (300µL) on both sides of the tongue using a cotton swab. Patients expelled saliva whenever they sensed it, while citric acid was reapplied at 20 s intervals, over a 3 min period. After completing A-SWS, the patient was instructed to rinse off residual citric acid with 15 mL tap water for 1 min, followed by a 3-min break to avoid stimulus overlap [42, 43]. Subsequently, MRS saliva was collected, as described in Example 1. Patients were unaware of the type of odor during the test and were instructed to continuously hold the mastic resin sachet at the nasal septum. They were further instructed to deeply inhale the mastic odor through both nostrils once at 30-second intervals for 5 min

[0044] . The collected saliva was drooled into the assigned tube. Saliva measurements: flow rate, spinnbarkeit, pH, ion composition, MUC5B and MUC7 content Immediately after collection, the saliva samples were weighed to determine the volume (1g of saliva is equal to 1mL) and kept on ice. Saliva flow rate was calculated by dividing the weight of saliva by the collection time to obtain mL / min as final units. Then, the salivary pH was assessed using pH test strips (Merck, New Jersey, USA, ref: 1095420001 and 1095430001) and spinnbarkeit was measured with the NevaMeter (Ishikawa Iron Works, Kitakyushu, Japan) directly after collection. Spinnbarkeit was categorized in two groups: serous (<6 mm) or mucous (≥6 mm) saliva as described by Faruque et al (2023)

[0045] . After these measurements, samples were centrifuged at 4000 g for 10 min at 4 °C, to remove debris and stored at -20 °C until further analysis. The ion composition of the saliva samples was analyzed by Capillary Electrophoresis (CE) (CAPEL-205 Lumex Instruments Canada, Mission, BC, Canada) according to the manufacturer instructions. Saliva samples were centrifuged at 14.000 g at RT for 10 min and supernatant was diluted 1:10 in miliQ H2O. Identification and quantitation of the analyzed cations (ammonium, potassium, sodium, magnesium and calcium) and anions (chloride, nitrite, sulphate, nitrate, fluoride and phosphate) were performed by indirect detection by measuring UV absorption at 267 nm and 254 nm in the CE, respectively. Electrophoresis was performed in untreated fused-silica capillaries of 60- cm length (effective length 50 cm) and 75 μm internal diameter. The capillary was held at 20 °C and the applied voltage was + 25 kV for cations and –25 kV for anions. Samples were injected at 30 mbar for 5 s for cations and 30 mbar for 10 s for anions. Freshly prepared cation and anion standard mixes were used as internal references. ELFORUN-205 software (Envico, Zoeterwoude, the Netherlands) was used for instrument control, data acquisition, real-time electropherogram visualization and electropherogram peak surface processing in the CE. MUC5B and MUC7 levels were determined by ELISA as described previously [46, 47]. Specific antibodies F2 and 2A4 were used for MUC5B and MUC7 detection, respectively. Purified human salivary MUC5B (5 mg / mL) was used as a standard and diluted in a range between 6 µg / mL until 0.09 µg / mL in coating buffer (0.1 M NaHCO3, pH 9.6). MUC5B data were analyzed with a four-parameter-logistic curve fit using SkanIT software 3.1.0.4 RE (Thermo Fisher Scientific, Waltham, Massachusetts, U.S.A). Data for MUC7 was calculated in arbitrary units (AU), as described before [46, 48]. Statistical analysis The statistical analysis was performed using IBM SPSS version 26 (IBM, Armonk, NY, USA). The sample size calculation was performed with G*power 3.1.9.7. resulting in a sample size of 40 patients. Friedman and Wilcoxon’s rank test were used to compare the saliva secretion rates and spinnbarkeit. VAS scores were compared with a paired samples T-test and RODI was assessed using a Mann-Whitney U test between UWS and MRS. Mann-Whitney U test was used to compare the ion concentrations. MUC5B and MUC7 levels were compared using Friedman and Wilcoxon’s rank test. Spearman rank correlation was conducted to measure the correlation between spinnbarkeit and mucins. The level of significance was set at P ≤ 0.05. Graphs were generated with programming language R in Rstudio (integrated development environment (IDE) version 4.1.3) and Graphpad Prism 8.0 (GraphPad Software, Inc., San Diego, CA). Results Patient cohort A total of 41 patients (28 females and 13 males) with age range of 21 to 84 years (mean 60 ± 15 years) volunteered and were sampled. The characteristics of these patients, including salivary pH are shown in Table 1. The average XI score represented 33.7 ± 8.8 (range 15-53). Flow rates and spinnbarkeit for unstimulated and stimulated saliva (CH-SWS, A-SWS and olfactory MRS) were measured, with the following median ± IQR values:^ UWS: 0.05 mL / min ± 0.10 and spinnbarkeit: 4.36 mm ± 22.36^ CH-SWS: 0.57 mL / min ± 0.82 and spinnbarkeit: 4.42 mm ± 1.08^ A-SWS: 1.48 mL / min ± 1.41 and spinnbarkeit: 4.46 mm ± 2.38^ MRS: 0.11 mL / min ± 0.15 and spinnbarkeit: 6.30 mm ± 51.40These measurements revealed that 31 patients were diagnosed with hyposalivation and had an average flow rate of 0.03 mL / min ± 0.03. Two of the patients with hyposalivation had a diagnosis with Sjögren's syndrome. It is worth noting that 36 patients were on medications, with 29 being on xerogenic medications [49-53]. Out of these 29 patients, 24 specifically used xerogenic medications with known anticholinergic activity. Furthermore, four patients with a history of chemotherapy were all diagnosed with hyposalivation. Similarly, among the four patients who underwent radiotherapy, two were diagnosed with hyposalivation.

[0002] Table I. Patients characteristics Characteristics Patient cohort N 41 Age (years) Mean ± SD 60 ± 15Range 21-84Sex (n) Male 13Female 28Use of medications (n) yes 36no 5Type of medication (n) ADHD 1 Allergy 6 Anticoagulant 4Antidepressants 5 Anxiety 3 Asthma and Respiratory 6 Blood Pressure and cholesterol 16 Cardiovascular 5 Diabetes 5 Diuretics 2 Eye 3Gastrointestinal 14 Hormone replacement therapy 5Inflammatory Bowel Disease 2Migraine 1Musculoskeletal 2 Mood stabilizers 2 Neuroleptics 4 Pain Relievers 11Sleep 5Thyroid 6 Vitamins and minerals 17No medication 5Treatment (n) Radiotherapy 4Chemotherapy 4 XI-scores Mean ± SD 33.7 ± 8.8Range 15-53 pH (Mean ± SD) UWS 6.42 ± 0.44 CH-SWS 6.94 ± 0.08 A-SWS 5.94 ± 1.17 MRS 6.75 ± 0.42XI = xerostomia inventory UWS = unstimulated whole saliva; CH-SWS = chew stimulated whole saliva; A-SWS = acid stimulated whole saliva; MRS = mastic resin stimulated saliva Effects of olfactory mastic resin stimulation on salivary parameters Compared to baseline UWS, the median flow rate significantly increased by olfactory MRS with 0.06 ml / min (P<0.001) (Figure 2A). The saliva flow rate also increased by chewing with 0.52 ml / min (P<0.001) and by acid stimulation with 1.43 ml / min (P<0.001) compared to UWS. The median spinnbarkeit of MRS (6.30 mm ± 51.40), significantly exceeded that of UWS (4.36 mm ± 22.36, P<0.001), indicating a shift from serous consistency during rest to mucous consistency with olfactory mastic resin stimulation (≥ 6mm) (Figure 2B). Olfactory MRS also demonstrated significantly higher spinnbarkeit than CH- SWS and A-SWS (both P<0.001). Spinnbarkeit of UWS was significantly higher than of CH-SWS (P=0.028) but not of A-SWS (P=0.953). Additionally, the pH of olfactory MRS saliva showed a mild increase of 0.33 compared to UWS (P<0.001). VAS-score for mouth moisture level increased from 2.7±2.0 for UWS to 3.7±2.4 for MRS (P=0.001) and RODI indicated significant reduced dryness at the posterior palate shortly post-MRS (P=0.04). Pleasantness of mastic resin scent was rated 6.0 ± 2.3 overall on a 10 cm VAS scale (Table 2). Table 2. RODI and VAS scores UWS MRS RODI Various oral locations P-value Median ± IQR Median ± IQR Upper lip 3.0±1.3 3.0±1.2 0.853Anterior palate 3.2±1.5 2.9±1.0 0.273Inside of cheeks 2.8±1.4 2.4±1.0 0.250Posterior palate 3.4±1.3 2.9±1.0 0.040 *Lower lip 3.0±1.4 3.0±1.1 0.968Floor of mouth 2.5±1.3 2.5±1.0 0.889Back part of tongue 3.0±1.3 3.2±1.2 0.676Front part of tongue 3.3±1.5 2.7±1.2 0.059Throat 3.2±1.3 3.0±1.2 0.413VAS scores Mean ± SD Mean ± SD P-value VAS mouth moisture levels 2.7±2.1 3.7±2.4 0.001 ***VAS mastic resin odor pleasantness 6.0±2.3IQR = interquartile range * P ≤ 0.05, ** P ≤ 0.01 UWS = unstimulated whole saliva; MRS = mastic resin stimulated saliva RODI = Regional Oral Dryness Inventory; VAS = Visual Analogue Scale Salivary ion composition The ion composition was examined using CE in UWS and olfactory MRS samples from 25 patients, who delivered enough saliva for this experiment, out of the total 41 patients. Cation and anion concentrations are presented in Table 3. Interestingly, sodium concentrations doubled in olfactory MRS (median ± IQR: 0.006 mg / mL ± 0.006, P = 0.004). Table 3. Salivary anion and cation concentrations in UWS and olfactory MRS samples of 25 patients (median ± IQR). Anions UWS (mg / min) MRS (mg / min) P-value Chloride 0.107 ± 0.080 0.135 ± 0.115 0.101Nitrite 0.001 ± 0.001 0.001 ± 0.001 0.124Sulphate 0.004 ± 0.004 0.004 ± 0.003 0.048 *Nitrate 0.006 ± 0.011 0.004 ± 0.077 0.491Fluoride 0.001 ± 0.002 0.002 ± 0.002 0.130Phosphate 0.122 ± 0.126 0.094 ± 0.113 0.607 Cations Ammonium 0.003 ± 0.002 0.003 ± 0.004 0.892Potassium 0.032 ± 0.022 0.039 ± 0.037 0.443Sodium 0.003 ± 0.003 0.006 ± 0.006 0.004 **Magnesium 0.0002 ± 0.0001 0.0002 ± 0.0002 0.210Calcium 0.001 ± 0.001 0.001 ± 0.001 0.404UWS vs MRS difference assessed with Mann-Whitney U test; * P ≤ 0.05, ** P ≤ 0.01 UWS = unstimulated whole saliva; CH-SWS = chew stimulated whole saliva; A-SWS = acid stimulated whole saliva; MRS = mastic resin stimulated saliva Salivary MUC5B and MUC7 levels after olfactory exposure to mastic resin volatiles Olfactory effects of mastic resin volatiles on salivary MUC5B and MUC7 levels were examined by ELISA on saliva samples from 29 patients out of the total 41, who delivered enough saliva for analysis. MUC5B concentrations were significantly higher in olfactory MRS (median±IQR: 7.30 mg / mL ± 9.96) compared to CH-SWS (3.89 mg / mL ± 9.95) and A-SWS (2.43 mg / mL ± 5.95) with p-values of 0.016 and <0.001, respectively (Figure 3A). Although not significantly, MUC5B levels in MRS samples (7.30 mg / mL ± 9.96) were also higher compared to MUC5B level in UWS samples (4.76 mg / mL ± 8.40, P=0.162). MUC7 levels were significantly higher in olfactory MRS (median±IQR: 0.37 AU ± 0.90) compared to CH-SWS exclusively (0.18 AU ± 0.43, P<0.001) (Figure 3B). Spinnbarkeit positively correlated with MUC5B concentrations in olfactory MRS saliva (R=0.399, P=0.002), but not in UWS (Figure 4A). Positive spinnbarkeit-MUC7 correlation was observed in UWS (R=0.259, P=0.049) and in olfactory MRS saliva (R=0.375, P=0.004) (Figure 4B). Nevertheless, MRS sample demonstrated higher correlation coefficient and with higher degree of significance. Discussion In this study, we demonstrated the surprising beneficial effect of olfactory stimulation with mastic resin volatiles in a group of chronic dry mouth patients with decreased unstimulated saliva secretion. The data revealed a significant increase in saliva secretion, along with marked improvements in the quality of saliva and relief from dryness in the posterior palate. Notably, we detected increased spinnbarkeit, mild, yet significant increase in pH, higher sodium concentration, and elevated levels of MUC5B and MUC7 with olfactory mastic resin stimulation. To the knowledge of the inventors, this study demonstrates for the first time surprising in vivo effect of mastic resin volatiles in treating hyposalivation and / or xerostomia. The salivary glands are innervated by the multiple branches of the cranial nerves (VII), which play a role in the olfactory-salivary reflex. Mastic resin appears to increase salivation and spinnbarkeit through this reflex and it may be caused in two ways. First, when volatile compounds e.g. from mastic resins, are inhaled, the olfactory nerves may transmit the odor signal from the olfactory bulb to the salivary nucleus located in the pons of the brain. This process activates the parasympathetic pathway, leading to the release of ACh from parasympathetic nerve endings likely into the sublingual (SL) and submandibular glands (SM)

[0054] , which are innervated through the facial nerve chorda tympani and lingual nerve [54, 55]. ACh then binds to muscarine receptors, mainly to M3, which are found on the acini of these glands [56- 58]. This binding triggers salivation. Several studies have reported that odors induce secretion from the SL and SM in humans, but not from the parotid glands [59-62]. SL and SM are known to secrete seromucous to mucous saliva which may account for the increased spinnbarkeit observed in our study after olfactory exposure to mastic resin. The second mechanism behind increased saliva secretion and improved quality during exposure to olfactory mastic resin, may involve the inhibition of AChE in the postsynaptic cleft between the nerve ending and the acini [1, 63]. Typically, after stimulation, ACh is degraded by AChE, thus removing the stimulus. AChE inhibition leads to persisted ACh stimulation and prolonged saliva secretion. Mastic contains several known AChE inhibiting compounds such as α-pinene, β-pinene, β-myrcene, camphene, limonene, β-caryophyllene and linalool. These pinenes and terpene compounds are small hydrophobic substances known to cross the blood-brain-barrier [72-76]. Therefore, we postulate that they also penetrate the mucosal epithelium and palatal glands directly, inhibiting AChE activity at the acini in these areas, e.g., the posterior palate. Saliva from palatal glands is rich in MUC5B [10, 77-80]. In line, we found increased salivary MUC5B levels in patients during olfactory mastic exposure and, a strong positive correlation was found between spinnbarkeit and salivary mucin (MUC5B and MUC7) levels with olfactory MRS, likely explaining the increased spinnbarkeit. Inoue et al (2008) noted that MUC5B contributes to viscosity and MUC7 to spinnbarkeit

[0021] . MUC5B and MUC7 serve both as lubricants and protect against pathogens

[0081] . Interestingly, after exposure to mastic resin volatiles, patients revealed a significant reduction in dryness at the posterior palate (P<0.05). This finding may correlate with the enhanced spinnbarkeit, secretion of mucins and the proposed AChE inhibitory mechanism. Saliva secretion increased with citric acid stimulation together with a slight rise in spinnbarkeit (Figure 2). However, in daily life, frequent consumption of acidic food and beverages increases the risk of dental enamel erosion [82, 83], making this habit unadvisable. In contrast, mastic resin presents a better non-invasive alternative, enhancing secretion and resulting in higher spinnbarkeit and mucin levels compared to acid and chew stimulation. Accordingly, mastic resin provides an all-round and longer-lasting lubrication and effectiveness, which not only improves saliva secretion but also improves quality of saliva. Notably, 36 patients were on xerogenic medications such as, antidepressants, antipsychotics, antihypertensives, antihistamines, cardiovascular, respiratory agents, diuretics, opiods, gastrointestinal, endocrine (diabetes, thyroid), musculoskeletal and certain hormones

[0020] . Some of these drugs exhibit anticholinergic activity on salivary glands, inhibiting ACh from binding to the M3 receptors causing reduction of the salivary reflex [84-87]. Interestingly, patients experiencing enhanced sialagogic effects during olfactory stimulation with mastic resin also included those on anticholinergic medications (data not shown). We speculate that the AChE-inhibiting compounds in mastic resin may have contributed to this effect during the 5-min stimulation. Alternatively, mastic resin volatiles may also directly stimulate mucous saliva from the palatal glands, which are in close proximity to the nasal cavity. Previous studies of Abdelmawla et al (1999) and Cappetta et al (2018) postulated that certain antidepressants may reduce parasympathetic salivary neuron activity [88, 89]. These results demonstrate that mastic resin act as a surprisingly powerful sialagogue in chronic dry mouth patients with decreased saliva secretion. Mastic resin demonstrated a bona fide in vivo effect on saliva secretion, pH, spinnbarkeit, sodium, MUC5B, and MUC7 levels. Notably, it provided relief from dryness in the posterior palate. Up to now, said surprising effects of mastic resin and alpha-pinene were not demonstrated in patients afflicted with hyposalivation and / or xerostomia and were not thought possible. Accordingly, these findings highlight mastic resin as a beneficial and non-invasive sialagogic treatment ready for clinical application. References [1] M. Faruque, K. Nazmi, A. van Splunter, M.L. Laine, F.J. Bikker, Sialagogic Effects Through Olfactory Stimulation with Mastic Resin and α-pinene Volatiles in vivo, Biomedicine & Pharmacotherapy 168 (2023) 115699. [2] E.C.I.V. A. van Nieuw Amerongen, A. Vissink, Speeksel, speekselklieren en mondgezondheid. -2e herziene druk, 2nd ed., Bohn Stafleu Van Loghum, Houten, 2008. [3] M.D. Turner, Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management, Dent Clin North Am 60(2) (2016) 435-43. [4] C. Dawes, A.M. Pedersen, A. Villa, J. Ekstrom, G.B. Proctor, A. Vissink, D. Aframian, R. McGowan, A. Aliko, N. Narayana, Y.W. Sia, R.K. Joshi, S.B. Jensen, A.R. Kerr, A. Wolff, The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI, Arch Oral Biol 60(6) (2015) 863-74. [5] M. Tanasiewicz, T. Hildebrandt, I. Obersztyn, Xerostomia of Various Etiologies: A Review of the Literature, Adv Clin Exp Med 25(1) (2016) 199-206. [6] A. Villa, C.L. Connell, S. Abati, Diagnosis and management of xerostomia and hyposalivation, Ther Clin Risk Manag 11 (2015) 45-51. [7] J. Saleh, M.A. Figueiredo, K. Cherubini, F.G. Salum, Salivary hypofunction: an update on aetiology, diagnosis and therapeutics, Arch Oral Biol 60(2) (2015) 242-55. [8] A.M. Pedersen, A. Bardow, S.B. Jensen, B. Nauntofte, Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion, Oral Dis 8(3) (2002) 117-29. [9] L.M. Sreebny, Saliva in health and disease: an appraisal and update, Int Dent J 50(3) (2000) 140-61.

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Claims

Claims 1. A therapeutic for use in a method for treating hyposalivation and / or xerostomia in an individual, wherein said therapeutic is selected from alpha-pinene and / or mastic resin.

2. The therapeutic for use according to claim 1, wherein the method stimulates the production of saliva.

3. The therapeutic for use according to claim 1 or 2, wherein the method results in an increased salivary spinnbarkeit, a modified salivary ion composition, an increased expression of salivary mucins, an increased saliva pH and / or combination thereof.

4. The therapeutic for use according to claim 3, wherein the modified salivary ion composition comprises increased sodium concentration.

5. The therapeutic for use according to claim 3, wherein the salivary mucin is selected from MUC5B and / or MUC7.

6. The therapeutic for use according to any one of the preceding claims, wherein said therapeutic is provided in a toothpaste, a mouthwash, an oral spray, an oral gel, an oral ointment, an oral adhering troche, nasal spray, sachet, patch or powder.

7. The therapeutic for use according to any one of the preceding claims, wherein said therapeutic is administered orally, buccally, sublabially, sublingually, nasally, or by inhalation.

8. The therapeutic for use according to any one of the preceding claims, wherein said individual has a decreased unstimulated salivary flow rate and / or a decreased stimulated salivary flow rate and / or a complaint of a dry mouth.

9. An oral adhering troche comprising alpha-pinene, preferably in an amount of at least 1% by weight, more preferably in an amount of at least 2% by weight.

10. An oral adhering troche comprising mastic resin, preferably in an amount of at least 1.5% by weight, more preferably in an amount of at least 2.5% by weight.

11. The oral adhering troche of claim 9 or 10, further comprising one or more polyol molecules selected from xylitol, erythritol, sorbitol, mannitol, maltitol, isomalt, and lactitol, preferably wherein polyol molecule is xylitol.

12. The oral adhering troche of any one of the preceding claims, further comprising one or more adhesives, one or more binders, and / or one or more lubricating substances.

13. A method for increasing salivation in an individual in need thereof, said method comprising administering to said individual alpha-pinene and / or mastic resin.

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