Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.

Oral health-related quality of life in oral cancer patients: systematic review and meta-analysis.

Aim: The purpose of this meta-analysis was to evaluate the impact of oral health on quality of life in oral cancer patients (OCPs). Methods: PubMed, Scopus and Web of Science databases were searched for publications on oral health-related quality of life (OHRQoL) in OCP and the information was extracted according to the PRISMA guidelines. A random effect model was used to obtain the pooled standard mean differences of Oral Health Impact Profile (OHIP)-14 questionnaire responses in meta-analysis. Results: total of 12 research papers were analyzed and revealed poor OHRQoL in OCPs (standard mean difference: 2.53; 95% CI: 1.55-3.50; p < 0.00001) compared with healthy individuals due to the effects of oncotherapy. Moreover, OHRQoL deteriorated with combinations of different treatment modalities. Conclusion: Oral health and oncotherapy can affect the quality of life in OCPs.

Diffusion-weighted imaging as a follow-up modality for evaluation of major salivary gland function in nasopharyngeal carcinoma patients: a preliminary study.

PURPOSE: To investigate the value of diffusion-weighted imaging (DWI) in assessing dynamic changes of major salivary gland function during follow-up post radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: 31 consecutive patients with pathologically confirmed NPC scheduled for RT underwent six routine follow-up MRI examinations including DWI sequence prior to (pre-RT) and 1, 3, 6, 9, and 12 months post RT. Mean apparent diffusion coefficient (ADC) values of bilateral parotid glands (PGs) and submandibular glands (SMGs) were measured. Objective measurement of salivary flow rate (SFR) under unstimulated (uSFR) and stimulated conditions (sSFR) as well as subjective xerostomia assessment according to a patient-rated questionnaire were conducted before each MRI. Variance analysis was used to evaluate dynamic changes of ADC, SFR and xerostomia questionnaire summary scores (XQ-sum) at different timepoints and the correlation between ADC and XQ-sum. Pearson's correlation test was used to evaluate the correlations between pre- and post-RT changes of ADC (ΔADC) and SFR (ΔSFR) or mean RT dose. RESULTS: At each timepoint, ADCs of PGs were significantly lower than of SMGs, uSFR was significantly lower than sSFR. For both PGs and SMGs, ADCpost-RT were all higher than ADCpre-RT, with significant differences. ADC1m-post-RT initially increased and changed little to ADC3m-post-RT, ADC6m-post-RT, ADC9m-post-RT, and ADC12m-post-RT, then gradually declined over time. The dynamic change trends of SFR were negatively paralleled to those of ADC, while that of XQ-sum was similar. Dose-response relationships were detected between salivary gland mean RT dose and ΔADC. In PGs, negative correlations between ΔsSFR9m-post-RT and ΔADC9m-post-RT, and ΔsSFR12m-post-RT and ΔADC12m-post-RT were detected. In SMGs, negative correlations between ΔsSFR12m-post-RT and ΔADC12m-post-RT, and ΔuSFR12m-post-RT and ΔADC12m-post-RT were also detected. The ADCs of patients with severe subjective xerostomia were significantly higher, while patients with moderate subjective xerostomia presented a tendency toward higher ADCs compared to those with mild xerostomia from 6 to 12 months post RT. CONCLUSION: As part of routine follow-up MRI in NPC patients, DWI might be a promising modality for follow-up assessing the dynamic changes of major salivary gland function and might be more powerful in the late post-RT period.

Persistent disruption of lateral junctional complexes and actin cytoskeleton in parotid salivary glands following radiation treatment.

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

[Radiation-associated changes in salivation of patients with cancer of maxillofacial region]. / Radioindutsirovannye izmeneniia sliunootdeleniia u patsientov so zlokachestvennymi novoobrazovaniiami cheliustno-litsevoi oblasti.

The radiation has an antitumor effect and causes radiation reactions and damage to surrounding tissues within the framework of combined antitumor treatment of patients with cancer of maxillofacial region. It also has an irreversible effect on the production of saliva by large and small salivary glands, and this must be taken into account when planning radiation therapy for this group of patients.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.

BACKGROUND: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin). AUTHORS' CONCLUSIONS: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.

Intraglandular Transplantation of Adipose-Derived Stem Cells for the Alleviation of Irradiation-Induced Parotid Gland Damage in Miniature Pigs.

PURPOSE: In a previous study, the authors verified the protective efficacy of adipose-derived stem cells (ADSCs) on the prevention of salivary gland (SG) damage induced by irradiation in mice. As a critical step before implementation in clinical practice, the present study investigated the protective effect of ADSCs in a miniature pig SG model, because miniature pigs share many characteristics with humans. MATERIALS AND METHODS: Third-passage autologous ADSCs at a concentration of 4 × 106 cells/mL were transplanted by intraglandular injection into parotid glands (PGs) immediately after local irradiation at a single dose of 20 Gy. The injection process was repeated twice a week for 6 consecutive weeks. At 12 weeks after irradiation, functional and histologic evaluations were performed by measuring salivary flow rate (SFR) and hematoxylin and eosin and periodic acid-Schiff staining. Immunohistochemical and transmission electron microscopic examinations also were conducted to evaluate amylase (AMY) production, microvessel density (MVD), and microstructural changes. RESULTS: The irradiated PGs showed remarkable decreases in SFR, AMY production, and MVD. However, transplantation of ADSCs alleviated irradiated PG morphology and function by preserving more functional acinar cells and increasing SFR and AMY production. In addition, greater MVD was observed in the ADSC-treated group than in the irradiated group. CONCLUSIONS: These results indicated that intraglandular transplantation of autologous ADSCs is an effective method to protect PGs against damage from irradiation in miniature pigs, which might have clinic application in the future.

Immediate effects of photobiomodulation on saliva production. / Efeitos imediatos da fotobiomodulação na produção de saliva.

PURPOSE: To verify the immediate effects of photobiomodulation on the production of salivary flow and the correlation of demographic, anthropometric and medication use data. METHODS: The study included 100 healthy individuals, aged between 18 and 76 years (mean 27.2 years), randomly split into an experimental group and a placebo group. Assessments of anthropometric measurements, self-perception of saliva production and sialometry were performed. Next, LASER irradiation was carried out at an infrared wavelength (808 nanometers) with 100 milliwatts (mw) of power at five intraoral points: on the sublingual glands and bilaterally on the submandibular and parotid glands, at doses of 9, 18 and 24 joules (J). Sialometry was repeated after each application. The control group received the same procedures with placebo equipment. RESULTS: There was a statistical association in the self-perception of reduced saliva in the experimental group for the 24J dose and in sialometry and in the reduction in salivary flow for the 18J and 24J doses and an increase to 9J, in both groups. There was no association when comparing the experimental and placebo groups. Multiple multinomial regression analysis revealed that the reduction or increase in salivary flow is independent of demographic, anthropometric and medication use variables. CONCLUSION: The bioinhibitory action of photobiomodulation on healthy salivary glands occurred at a dose of 18J and 24J, while the biostimulant action happened at a dose of 9J, regardless of demographic, anthropometric variables and medication use. The self-perception of reduced salivary flow occurred at 24J.

OBJETIVO: Verificar os efeitos imediatos da fotobiomodulação na produção do fluxo salivar e a correlação dos dados demográficos, antropométricos e de uso de medicamentos. MÉTODO: Participaram do estudo 100 indivíduos saudáveis, com idade entre 18 e 76 anos (média 27,2 anos), divididos de forma randomizada em grupo experimental e grupo placebo. Foram realizadas as avaliações das medidas antropométricas, autopercepção da produção de saliva e a sialometria. Na sequência, realizou-se a irradiação do LASER no comprimento de onda infravermelho (808 nanômetros) com 100 miliwatts (mw) de potência em cinco pontos intraorais: nas glândulas sublingual e bilateralmente nas submandibulares e parótidas, nas doses 9, 18 e 24 joules (J). A sialometria foi repetida após cada aplicação. O grupo controle recebeu os mesmos procedimentos com equipamento placebo. RESULTADOS: Houve associação estatística na autopercepção de redução da saliva no grupo experimental para a dose de 24J e na sialometria e na redução do fluxo salivar para as doses 18J e 24J e aumento para 9J, em ambos os grupos. Não houve associação quando comparado entre os grupos experimental e placebo. A análise de regressão multinomial múltipla revelou que a redução ou o aumento do fluxo salivar independe das variáveis demográficas, antropométricas e uso de medicamentos. CONCLUSÃO: A ação bioinibitória da fotobiomodulação sobre as glândulas salivares saudáveis ocorreu em dose de 18J e 24J, já ação bioestimulante na dose 9J, independe das variáveis demográficas, antropométricas e uso de medicamentos. A autopercepção da redução do fluxo salivar ocorreu em 24J.

Radiation-induced Xerostomia is Related to Stem Cell Dose-dependent Reduction of Saliva Production.

PURPOSE: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (Dmean,SCR) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and Dmean,SCR is explained by a dose-dependent reduction of saliva production. METHODS AND MATERIALS: In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual (FLOWSMSL) glands, and patient-reported daytime (XERDAY) and nighttime (XERNIGHT) xerostomia were prospectively measured before, at 6 months, and 12 months after RT. Using linear mixed effect models, the relationship of the mean dose to the parotid glands (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub), and oral cavity (Dmean,oral) with salivary flow and xerostomia was analyzed while correcting for known confounders. RESULTS: Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (P ≤ .03), while Dmean,non-SCR did not affect FLOWPAR (P ≥ .11). To illustrate, increasing Dmean,SCR by 10 Gy at a fixed Dmean,non-SCR reduced FLOWPAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 mL/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (P < .001). For example, increasing Dmean,sub by 10 Gy reduced FLOWSMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (P ≤ .05), while Dmean,sub increased XERNIGHT scores (P = .01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores by 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions; ie, FLOWPAR only influenced XERDAY (P < .001, 10.92 points lower XERDAY per 1 mL/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (P ≤ .004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR, whereas the effects of Dmean,oral on XERDAY and Dmean,sub on XERNIGHT were independent of salivary flow. CONCLUSIONS: Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.

Evaluation of photobiomodulation in the salivary production of patients with hyposalivation induced by antihypertensive drugs - A blind, randomized, controlled clinical trial.

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

Short-term and bystander effects of radiation on murine submandibular glands.

Many patients treated for head and neck cancers experience salivary gland hypofunction due to radiation damage. Understanding the mechanisms of cellular damage induced by radiation treatment is important in order to design methods of radioprotection. In addition, it is crucial to recognize the indirect effects of irradiation and the systemic responses that may alter saliva secretion. In this study, radiation was delivered to murine submandibular glands (SMGs) bilaterally, using a 137Cs gamma ray irradiator, or unilaterally, using a small-animal radiation research platform (SARRP). Analysis at 3, 24 and 48 h showed dynamic changes in mRNA and protein expression in SMGs irradiated bilaterally. Unilateral irradiation using the SARRP caused similar changes in the irradiated SMGs, as well as significant off-target, bystander effects in the non-irradiated contralateral SMGs.

Sialoadenitis secondary to ¹³¹I therapy for well-differentiated thyroid cancer.

Radioiodine (¹³¹I) is an important therapy for patients who have well-differentiated thyroid cancer. However, ¹³¹I may also result in side effects in multiple organs and glands. The glands that are frequently affected are the salivary glands with the major untoward effects including sialoadenitis and increased risk of second primary malignancy. This report will review sialoadenitis secondary to ¹³¹I therapy including (1) proposed mechanisms, (2) incidence and clinical presentations, (3) possible approaches to improve prevention, (4) management, and (5) sequelae of sialoadenitis (e.g. xerostomia and salivary duct obstruction). A discussion of second primary malignancies is beyond the scope of this review. With a better understanding of the above, dentists, oral surgeons, otolaryngologists, endocrinologists, nuclear medicine physicians, and nuclear radiologists will be more likely to implement more effective preventive measures to reduce the incidence and severity of ¹³¹I-induced sialoadenitis, and if it does occur, to identify and treat sialoadenitis sooner, thereby potentially reducing not only the severity of the initial symptoms, but also the severity of subsequent sequelae.

Investigations on parotid gland recovery after IMRT in head and neck tumor patients.

PURPOSE: in recent years, the role of intensity-modulated radiotherapy (IMRT) for head and neck irradiation has increased. The main motivation is sparing the parotid gland and reduction of xerostomia. Generally, relative parotid volumes have been evaluated for treatment outcome and planning constraints, neglecting that absolute parotid volumes can vary significantly. The aim of the present study was to investigate changes in parotid gland function and set this in relation to absolute volumes. MATERIAL AND METHODS: 46 head and neck patients were treated by sparing at least the contralateral parotid gland. The mean dose to the contralateral gland was limited to 26 Gy. Parotid function was measured with scintigraphy before and at 3, 6, 9, and 12 months after radiotherapy. Gland recovery was correlated with absolute parotid gland volumes and mean dose. Finally the dose-effect relationship was investigated. RESULTS: the dose-volume histograms (DVHs) for the ipsi- and contralateral glands were significantly different. A correlation between absolute volumes receiving certain doses and the function loss after 3, 6, 9, and 12 months was found. The most significant correlation was found for the absolute volume that received at least 40 Gy (aV40). ED50 values of 23-38 Gy were observed for more than 50% function loss and and 52-68 Gy afor more than 75% function loss. CONCLUSION: the mean dose, aV40 or aV26, revealed similar correlations with the excretion rate and with recovery. Hence, also absolute volumes can be used for treatment planning. Longer recovery times show higher ED50 values indicating partial regeneration of gland functions.

Effects of low-level laser treatment on mouth dryness.

UNLABELLED: Mouth dryness (MD) is usually followed by inadequate mechanical cleaning of the mouth and decrease in the levels of salivary antimicrobial proteins (including secretory immunoglobulin A (sIgA)). It is accompanied by difficulties during speaking and food swallowing, with an unpleasant taste, burning sensations in the mouth and higher susceptibility to oral diseases. Low-level laser treatment (LLLT) can intensify cell metabolism and its application on salivary glands could improve salivation. The purpose of this study was to evaluate the effects of LLLT on salivation of patients suffering from MD. The study included 17 patients with MD. Their major salivary glands were treated with low intensity laser BTL2000 on 10 occasions. The whole unstimulated and stimulated saliva quantities were measured just before the 1st, after the 10th and thirty days following the last (10th) treatment. In the samples of unstimulated saliva concentrations of sIgA were estimated by using ELISA method and its quantity in the time unit was calculated. The visual analogue scale (VAS) score was used to assess burning and/or pain intensity at these three time points. Statistical tests revealed significant salivation improvement quantitatively and qualitatively, i.e. increase in the quantity of saliva and sIgA. VAS score was also significantly improved and no side effects were observed. CONCLUSIONS: According to the results of this study, application of LLLT to xerostomic patients' major salivary glands stimulates them to produce more saliva with better antimicrobial characteristics and improves the difficulties that are associated with MD. This simple non-invasive method could be used in everyday clinical practice for the treatment of MD.

Evaluation of photobiomodulation in salivary production of patients with xerostomy induced by anti-hypertensive drugs: Study protocol clinical trial (SPIRIT compliant).

INTRODUCTION: Hypertension (systemic arterial hypertension [SAH]) is a systemic condition that affects about 30% of the world population, according to data from the World Health Organization (WHO). Drugs used to control this disease have the potential to induce xerostomia, an oral condition in which the decrease of the salivary flow is observed and whose presence leads to the increase of the index of caries, periodontal disease, loss of the teeth, dysgeusia, difficulty of mastication, dysphagia, bad breath and oral burning and impairment of prothesis installed in the buccal cavity, including retention of removable and total dentures. METHODS: This is a randomized, placebo-controlled, blind clinical protocol that aims to analyze the impact of phobiomodulation (PBM) on salivary glands of patients with antihypertensive drug induced xerostomia. Patients will be divided into 2 groups: G1: older adults with xerostomia induced by antihypertensive drugs and treatment with PBM (n = 30); G2: placebo PBM (n = 30). The irradiation will be made using a diode laser emitting at 808 nm with 100 mW and 40 seconds of exposure per site at the salivary glands. Twenty sites will be irradiated weekly for 4 weeks. Non-stimulated and stimulated salivary flow will be analyzed before and after the treatment. RESULTS: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. CONCLUSION: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. TRIAL REGISTRATION: Clinicaltrials.gov - NCT03632096.

The effect of radiotherapy on taste sensation in head and neck cancer patients - a prospective study.

BACKGROUND: One of the main side effects of head and neck (H&N) radiation therapy (RT) is alteration in taste sensation. It causes significant morbidity and has a major effect on quality of life (QoL). The aim of this study was to prospectively define the effect of RT on taste sensation (general, and four basic tastes) and correlate these findings with changes in saliva secretion and QoL questionnaires. METHODS: Patients with H&N cancer treated with RT, in which the oral cavity was expected to receive a mean dose of 30 Gray (Gy). Patients were evaluated by Whole-Saliva Sialometry, validated Taste Strips and European Organization for Research and Treatment of Cancer H&N QoL questionnaires prior to RT (T0), mid-point of radiotherapy dose (T1), at the end of radiotherapy (T2) and 1 (T3), 3 (T4) and 12 months (T5) after completion of treatment course. RESULTS: Twenty-eight patients were recruited, and 21 patients completed study procedures and were analyzed. Median age was 66 years (range 18-90). The most common tumor site was the oral cavity. The median prescribed radiation dose to the high dose volume was 66 (range 60-70). The median mean and max dose to the oral cavity were 25.1 (range 14-69) and 64.9 (range 30-70), respectively. There was a significant decrease in overall taste sensation between T0 and T1 and T2. With specific tastes, there were significant decreases in sensation of sweet and salty, a trend with bitter and no change with sour. All returned to baseline at T3 and onwards. There was no significant correlation between the max or mean dose to the oral cavity and overall taste sensation or between doses to different areas of the tongue and overall or specific tastes. At T0 there was a significant positive correlation between overall taste sensation and whole-saliva sialometry, and at T1 and T2 there were strong trends. There were significant declines in QoL scores during RT. CONCLUSIONS: We found a significant immediate reduction in taste sensation due to RT in H&N cancer patients with taste recovery 1 month after treatment completion. There were strong trends to a correlation with saliva production that requires further exploration.

Saliva substitutes for the treatment of radiation-induced xerostomia--a review.

GOAL: The aim of this review is to summarize the in vitro and in vivo evidence on the performance of contemporary saliva substitutes in the treatment of xerostomia and hyposalivation caused by radiation therapy for head and neck malignancies. METHODS: A literature search was conducted during July to September 2008 in PubMed, using the query terms "saliva substitute", "saliva substitute and xerostomia", "artificial saliva", and "artificial saliva and xerostomia"; for clinical studies, only studies in patients suffering from radiation-induced xerostomia have been included in the review. RESULTS AND CONCLUSION: Fifty-two studies met the inclusion criteria and were allotted either to the in vitro topics "viscosity", "lubrication", "wetting properties", "antimicrobial effects", and "enamel and dentin de- and remineralization", or to the in vivo topics "clinical acceptance" or "influence on plaque formation and oral mucosa and microflora". The findings suggest that there are significant differences in the performance of various saliva substitutes concerning the review parameters, yet indicate that further in vitro and in vivo studies on the properties of saliva substitutes are necessary.

Salivation triggered by pilocarpine involves aquaporin-5 in normal rats but not in irradiated rats.

1. Using rats, we examined the muscarinic receptor subtype mediating pilocarpine-induced parotid salivary secretion and the contributions of ion transporter systems (effluxes of K+ and Cl(-)) and aquaporin-5 (AQP5) translocation to this response in parotid glands in irradiated-induced xerostomia. 2. Salivary secretion was significantly lower in irradiated compared with sham-irradiated (normal) rats. In xerostomia rats, 0.4 and 0.8 mg/kg pilocarpine significantly increased parotid salivary secretion, although the salivary volume was still significantly less than in normal rats after the same dose of pilocarpine. 3. Pirenzepine (1 x 10(-6) to 1 x 10(-1) mol/L), AF-DX 116 (3 x 10(-6) to 3 x 10(-2) mol/L) and N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP; 1 x 10(-8) to 1 x 10(-2) mol/L) dose-dependently displaced radioligand binding to M(1), M(2) and M(3) receptors, respectively, in parotid membranes from both normal and irradiated rats. In each group of rats, 4-DAMP had the highest binding affinity. Pretreatment with 4-DAMP or pirenzepine dose-dependently inhibited pilocarpine-induced parotid secretion in both normal and irradiated rats, with 4-DAMP being markedly more potent than pirenzepine. 4. Normal and irradiated-rat parotid cells did not differ significantly in terms of pilocarpine-induced changes in [Ca2+](i), [K+](i) and [Cl(-)](i). Pilocarpine markedly increased the amount of AQP5 in the apical plasma membrane of parotid cells isolated from normal but not irradiated rats. 5. Thus, pilocarpine induces parotid salivary secretion mainly via the M(3) receptor subtype in both irradiated and normal rats. The reduction in this pilocarpine-induced secretion seen in irradiated rats is due not to disturbances of intracellular Ca2+ mobilization or ion transporter systems, but rather to a disturbance of AQP5 translocation, which may be involved in the pathogenesis of X-ray irradiation-induced xerostomia.

A review of the biological and clinical aspects of radiation caries.

AIM: The aim of this article is to review the clinical and biological features underlying the development and progression of radiation caries. BACKGROUND: Although radiotherapy (RT) plays an important role in the management of patients with head and neck cancer (HNC), it is also associated with several undesired side effects such as radiation caries which is a common, yet serious, complication. To review the condition, the Pubmed database was searched using the keywords "radiotherapy," "radiation," "caries," "hyposalivation," "prevention" and "management". Only studies published in the English language were selected. Cross-referencing identified additionally relevant studies. REVIEW RESULTS: RT leads to alterations in the dentition, saliva, oral microflora, and diet of patients. Consequently, irradiated patients are at increased risk for the development of a rapid, rampant carious process known as radiation caries. Motivation of patients, adequate plaque control, stimulation of salivary flow, fluoride use, and nutritional orientation are essential to reduce the incidence of radiation caries and ultimately improve the quality of life for HNC patients. CONCLUSION: Radiation caries is an aggressive side effect of RT. Dentists play an important role in the prevention of the condition via comprehensive oral healthcare before, during, and after the active cancer therapy. CLINICAL SIGNIFICANCE: Dentists should understand the clinical and biological aspects underlying radiation caries to prevent the development of lesions and provide optimal treatment when needed.

Diffusion-weighted magnetic resonance imaging to evaluate major salivary gland function before and after radiotherapy.

PURPOSE: To evaluate diffusion-weighted (DW)-MRI as a noninvasive tool to investigate major salivary gland function before and after radiotherapy (RT) for head and neck cancer (HNC). METHODS AND MATERIALS: DW-MRI was performed in 8 HNC patients before and after parotid-sparing RT (mean dose to the contralateral parotid gland <26 Gy). A DW sequence was performed once at rest and then repeated continuously during salivary stimulation. Apparent diffusion coefficient (ADC) maps for both parotid and submandibular glands were calculated. Findings were compared with salivary gland scintigraphy. RESULTS: Before RT, the mean ADC value at rest was significantly lower in the parotid than in the submandibular glands. During the first 5 min of stimulation, the ADC value of the salivary glands showed a decrease, followed by a steady increase until a peak ADC, significantly higher than the baseline value, was reached after a median of 17 min. The baseline ADC value at rest was significantly higher after RT than before RT in the nonspared salivary glands but not in the spared parotid glands. In the contralateral parotid glands, the same response was seen as before RT. This pattern was completely lost in the nonspared glands. These results corresponded with remaining or loss of salivary function, respectively, as confirmed by salivary gland scintigraphy. CONCLUSIONS: Diffusion-weighted-MRI allows noninvasive evaluation of functional changes in the major salivary glands after RT and is a promising tool for investigating radiation-induced xerostomia.