Efficacy and safety of an intraoral electrostimulation device for xerostomia relief: a multicenter, randomized trial.

OBJECTIVE: To evaluate the efficacy and safety of an intraoral electrostimulation device, consisting of stimulating electrodes, an electronic circuit, and a power source, in treating xerostomia. The device delivers electrostimulation through the oral mucosa to the lingual nerve in order to enhance the salivary reflex. METHODS: The device was tested on a sample of patients with xerostomia due to Sjögren's syndrome and other sicca conditions in a 2-stage prospective, randomized, multicenter trial. Stage I was a double-blind, crossover stage designed to compare the effects of the electrically active device with the sham device, each used for 1 month, and stage II was a 3-month open-label stage designed to assess the long-term effects of the active device. Improvement in xerostomia severity from baseline was the primary outcome measure. RESULTS: A total of 114 patients were randomized. In stage I, the active device performed better than the sham device for patient-reported xerostomia severity (P<0.002), xerostomia frequency (P<0.05), quality of life impairment (P<0.01), and swallowing difficulty (P<0.02). At the end of stage II, statistically significant improvements were verified for patient-reported xerostomia severity (P<0.0001), xerostomia frequency (P<0.0001), oral discomfort (P<0.001), speech difficulty (P<0.02), sleeping difficulty (P<0.001), and resting salivary flow rate (P<0.01). CONCLUSION: Our findings indicate that daily use of the device alleviated oral dryness, discomfort, and some complications of xerostomia, such as speech and sleeping difficulties, and increased salivary output. The results show a cumulative positive effect of the device over the period of the study, from baseline to the end of the trial.

A Retrospective Study on Insertion Torque and Implant Stability Quotient (ISQ) as Stability Parameters for Immediate Loading of Implants in Fresh Extraction Sockets.

BACKGROUND: To date, insertion torque value (ITV) and implant stability quotient (ISQ) obtained by the Osstell instrument are common clinical methods to assess the initial stability of an implant for a predictable loading procedure. The aim of this current study is to evaluate the ITV and ISQ as stability parameters as part of the decision-making protocol in the adoption of immediate loading in fresh extraction sockets. MATERIALS AND METHODS: A total of 41 tapered implants were allocated into two groups: the test group (n = 11; 3 males and 8 females; mean age: 62.8 ± 10.7) which received 18 implants as type 1 fresh extraction sockets after teeth removal and the control group (n = 7; 4 males and 3 females; mean age: 65.4 ± 9.7) which received 23 implants placed in healed sockets for a period of at least 3 months. Both the ITV and ISQ data were recorded at the time of insertion (t 0). Since ITV (test group) and ITV/ISQ (control group) values were useful for the immediate loading protocol, a screw-retained temporary crown was immediately loaded. ISQ values were recorded after a healing period of 4 months (t 1). RESULTS: ITV mean values at t 0 in test and control groups were, respectively, 48.61 ± 15.39 and 70.47 ± 14.71, whereas ISQ mean values were 57.55 ± 1.93 and 72.86 ± 5.25, respectively, showing a statistically significant difference (p value < 0.001). ISQ mean values at t 1 in either the test or the control group were 68.68 ± 4.20 and 74.54 ± 4.17, not showing a statistical difference. The implant survival rate was 100% in both groups, and no surgical and prosthetic complications were reported during the study. CONCLUSION: In conclusion, this study remarked the presence of a residual gap that influenced the ISQ during implant insertion in fresh extraction sockets making this parameter not sufficient for a conclusive decision in the immediate loading, whereas the ITV alone showed to be the best parameter for a final substantial decision.

Evaluation of galantamine transbuccal absorption by reconstituted human oral epithelium and porcine tissue as buccal mucosa models: part I.

Over the last decade, interest in delivering drugs through buccal mucosa has increased. As a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aim of this study was to evaluate the aptitude of galantamine, useful in Alzheimer's disease, to penetrate the buccal mucosa. The evaluation of the ability of galantamine to permeate through the buccal epithelium was investigated using two permeation models. Firstly, in vitro permeation experiments were carried out using reconstituted human oral non-keratinised epithelium and Transwell diffusion cells system. Results were validated by ex vivo experiments using porcine buccal mucosa as membrane and Franz type diffusion cells as permeation model. The entity of buccal permeation was expressed in terms of drug flux (J(s)) and permeability coefficients (K(p)). Data collected by in vitro and ex vivo experiments were in agreement and suggested that buccal mucosa does not block diffusion of galantamine. The effects of drug application on histology of tissue specimens used in every experiment were also studied: no sign of flogosis and no significant cytological or architectural changes were highlighted.

Controlled delivery of naltrexone by an intraoral device: in vivo study on human subjects.

Naltrexone is widely used in the treatment of opiate addiction but its current peroral administration is characterized by low bioavailability with various side effects. The development of a long-acting transbuccal delivery device (IntelliDrug) for NLX may be useful to improve patient compliance and the therapy effectiveness. The aims of the study are (a) to test basic safety and effectiveness of controlled transbuccal drug delivery on human subjects; (b) to compare NLX bioavailability following transbuccal delivery vs per os conventional delivery; and (c) to test the hypothesis that transbuccal delivery is more efficient than the conventional route. In this randomized cross-over pilot study, 12 healthy subjects received in a different order 2 types of NLX administration, per os or transbuccal delivery, based on which group they were randomized to. For per os administration 50mg NLX tablets were used, while for transbuccal administration, a NLX-loaded prototype of the IntelliDrug device was fixed on patients' dental arch. Serial blood samples were drawn and analysed for the NLX concentration. The IntelliDrug prototype functioned properly and it did not exert any adverse side-effect. The transbuccal route resulted in administration efficiency 4-17 times higher than conventional per os route. Transbuccal delivery of NLX appears to be a more efficient drug administration route compared to peroral one. It allows to reach a given therapeutic blood level using a small drug dose.

Novel non-invasive adjunctive techniques for early oral cancer diagnosis and oral lesions examination.

Oral cancer is a potentially fatal disease with an increasing incidence and an unchanged 5-year mortality rate. Unfortunately, oral cancer is often still late diagnosed, which leads to an increase in the likelihood of functional impairment due to treatment and mortality rate. Definitive diagnosis of oral cancer must be confirmed by scalpel biopsy and histological assessment. However despite its benefits, scalpel biopsy is invasive and it is burdened by a potential morbidity. Furthermore, previous studies have suggested a high degree of intraobserver and interobserver variability regarding the histological evaluation of malignancy. As a consequence, in recent years there has been a growing and persisting demand towards developing new non-invasive, practical diagnostic tools that might facilitate the early detection of oral cancer. The most investigated non-invasive adjunctive techniques are vital staining, autofluorescence, chemiluminescence, narrow band imaging, and exfoliative cytology. Aim of the review is to critically describe these adjunctive aids and, after considering the literature data, an expert opinion on the effectiveness and the possible use of each technique will be provided.

Oral local drug delivery and new perspectives in oral drug formulation.

Modern pharmaceutical science has provided us with a wide range of substances to be administered with a wide large variety of dosage forms. Local drug delivery systems have been used for a long time; in particular, for the local therapy of diseases affecting the oral cavity. Although these diseases are often extremely responsive to local therapy, the mouth often presents various difficulties in the application of topical compounds (owing to saliva and the mouth's different functions), resulting in a short retention time of dosage forms with a consequent low therapeutic efficacy. To resolve these limitations, research today concentrates on the development of bioadhesive formulations. This review focuses on the permeability features of oral mucosa, the rationale of oral local drug delivery, and new potential bioadhesive local delivery systems. Furthermore, the most promising mucoadhesive systems proposed to locally treat oral diseases are discussed.

Oral HPV infection: current strategies for prevention and therapy.

Infection with High Risk (HR) Human Papillomaviruses (HPVs) is the main aetiological agent of Cervical Squamous Cell Carcinoma (CSCC) and also associated in a subgroup of other neoplasms, including Oropharyngeal Squamous cell Carcinoma (OPSCC). HPV infection, in genital as in oral mucosa, can also be subclinical or associated with benign proliferative lesions (common warts, condylomas, papillomas) caused mostly by infection with Low Risk (LR)-HPVs. In the last decades, extensive research has resulted in growing knowledge on HPV biology and specifically viral life cycle, biochemical properties of viral proteins and their interaction with the host proteins leading to potential new targets of prophylactic or therapeutic vaccines and therapies for HPV infection. In addition, notable progresses have been made in the field of diagnostics to detect HPV DNA or RNA. The recent epidemiological data suggest the significant changes in HPV endemic, due to the changes in sexual habits especially among young generations (i.e. early sexual debuts, multiple sexual partners, oral and anal sex); this scenario has urged on the need of adequate campaigns of primary (sexual education, vaccination programs) and secondary prevention (diagnostics of HPV-related diseases). Due to the growing interest on HPV infection and HPV related cancers, the authors made a narrative review of the literature on oral HPV infection and oral-genital transmission. After this, in view of the controversies about the strategies of therapy and prevention of HPV infection, the present review focuses on the current state of art about the available tools for the therapeutic and, if any, preventive management of oral HPV infection.

Topical therapies for oral lichen planus management and their efficacy: a narrative review.

Oral Lichen Planus (OLP) is a chronic inflammatory condition implicating T cell-mediated cytotoxicity, and involving oral mucosal surfaces. Several therapeutic regimens have been evaluated to treat OLP and pain related, but often without high level of evidence. Topical formulations are the favourite for the majority of cases; bioadhesive formulations have been considered very useful and practical for local drug delivery in oral mucosa, due to the increased residence time on the oral mucosa of the dosage forms and better therapeutic efficacy. In this narrative review, authors try to illustrate the current topical managements for OLP from the accessible literature on this topic. Steroids are very helpful in discomfort and making better quality of life: they are considered the first-line treatment even if they could cause secondary candidosis, and sometimes bad taste, nausea, dry mouth, sore throat or swollen mouth. Other substances or devices by topical administration are adopted especially when the first line approach is refractory. This is the case when retinol with its synthetic and natural analogues (retinoids), hyaluronic acid, or Aloe Vera are chosen. Recent topical applications for OLP therapy include phototherapy and low/high energy pulsing light; the treatment with extracorporeal photochemotherapy is also reasonable and promising. Finally, calcineurin inhibitors (i.e. cyclosporine, tacrolimus and pimecrolimus), antioxidant and biologics (i.e alefacept, efalizumab, basiliximab, TNF-α inhibitors - infliximab, rituximab) may be alternative approaches when OLP does not respond to the standard protocols. In this scenario, there are several studies on molecules different from glucocorticosteroids, but not sufficient or statistically adequate to justify their evidence-based use in OLP; large randomized placebo controlled trials are required to evaluate the safety and effectiveness of these non conventional therapies. In conclusion, since OLP is a chronic disease and requires long-term management, the dental/medical practitioner, who treats OLP patients, needs to know the natural history of OLP, how to monitor, and how to treat, taking in account all of the available modalities conventional and not, with pros and cons.

Mucoadhesive polymers for oral transmucosal drug delivery: a review.

The oral mucosa offers an interesting site for the application of dosage forms that release drugs within/throughout the oral mucosa, by assuring a high drug bioavailability for topic and systemic effects. However, the relative permeability of the oral mucosa and the washing effect related to the oral fluids and mechanical stresses must be considered in the formulation of oral dosage forms. Since a sustained drug release can be guaranteed only if dosage forms remain in contact with the oral site of absorption/application for a prolonged time, the development of mucoadhesive dosage forms is mandatory. The mucoadhesion is a complex phenomenon and the mucoadhesive bond consists of two different parts, the mucoadhesive polymers and the mucous substrate. In addition to factors related to the oral mucosa and oral environment features, the physical-chemical characteristics of mucoadhesive polymers must be also considered as factors influencing the mucoadhesive bonds. While it is not possible to modify the mucosal features or it is possible to modify or inhibit only in part certain mucosal processes, the knowledge of polymer properties influencing mucoadhesive bonds allows to modify or to control these properties in developing increasingly effective mucoadhesive systems. The aims of this review are to discuss the several mechanisms and factors behind the phenomenon of mucoadhesion with particular reference to the features of the oral environment, oral mucosa, and polymeric compounds influencing mucoadhesion process. Finally, a brief mention to the main mucoadhesive dosage forms designed for oral transmucosal drug delivery is made.

Medium-term culture of primary oral squamous cell carcinoma in a three- dimensional model: effects on cell survival following topical 5-fluororacile delivery by drug-loaded matrix tablets.

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of formulations for local application on malignant lesions seems to be an efficient and promising drug delivery approach. In this study, the effect of locally applied 5-FU on cell death was evaluated both in a SCC4/HEK001 model and in a newly proposed 3D outgrowth model of oral squamous cell carcinoma (OSCC). Initially, the optimal drug dose was established by delivery of solutions containing different amounts of 5-FU. The solution containing 1% (w/v) of 5-FU resulted effective in inducing cell death with complete eradication of cell colonies. Buccal tablets were designed to deliver 5-FU locoregionally to the cancer lesions of the oral cavity. Tablets were prepared using a drug loaded matrix of acrylic/methacrylic acid copolymer containing 1% (w/w) of 5-FU and applied on 3D outgrowths. The drug release from tablets appeared to be sufficient to induce cell death as confirmed by transmission electron microscopy and enzymatic assay (TUNEL). After 120 h of treatment, when about 90% of the drug had been discharged from the tablets into the culture environment, 5-FU caused loss of cell-cell communications and apoptotic cell death. After 192 h, a complete disaggregation of the 3D oral outgrowths and the death of all the cells was observed. Buccal matrix tablets could be considered a promising new approach to the locoregional treatment of OSCC. Risks of systemic toxicity are avoided since very low drug doses are delivered.

Medium-term culture of normal human oral mucosa: a novel three-dimensional model to study the effectiveness of drugs administration.

Tissue-engineered oral mucosal equivalents have been developed for in vitro studies for a few years now. However, the usefulness of currently available models is still limited by many factors, mainly the lack of a physiological extracellular matrix (ECM) and the use of cell populations that do not reflect the properly differentiated cytotypes of the mucosa of the oral cavity. For this reason, we have developed a novel three-dimensional culture model reflecting the normal architecture of the human oral mucosa, with the main aim of creating a better in vitro model where to test cellular responses to drugs administration. This novel 3D cell culture model (3D outgrowth) was set up using an artificial extracellular matrix (Matrigel™ ), allowing the interactions required for proper differentiation of the various citotypes which form the mucosal layer. Biopsies of human oral mucosa, in fragments of about 0.5 mm3, were placed onto 6.5mm Transwells, covered with Matrigel™ and grown in a specific culture medium. A gradual formation of an architectural structure similar to that of the in vivo oral mucosa was observed. Transmission electron and confocal microscopy were employed to characterize the newly developed model: the cell components (keratinocytes and fibroblasts) differentiated properly within the outgrowth and reconstituted, in vitro, the physiological structure of the human oral mucosa, including a stratified non-keratinized squamous layer composed of four different layers, a proper basal membrane and a lamina propria where fibroblasts produce ECM. Moreover, keratinocytes expressed CK5, CK13, CK19 and E-cadherin, whereas fibroblasts expressed collagen type I and IV, laminin and fibronectin. 3D outgrowths could be considered a valid alternative to animal models, and provide useful information for researchers interested in studying the responses of the human oral mucosa to locally delivered drugs or other exogenous treatments.

Intraoral electrostimulator for xerostomia relief: a long-term, multicenter, open-label, uncontrolled, clinical trial.

OBJECTIVE: A previous sham-controlled multinational study demonstrated the short-term efficacy and safety for xerostomia treatment of an intraoral device that delivers electrostimulation to the lingual nerve. The objective of this study was to test the hypothesis that those beneficial effects would be sustained over an 11-month period. STUDY DESIGN: The device was tested on a mixed sample of 94 patients with xerostomia in an open-label, uncontrolled, prospective multicenter trial. Statutory outcome assessments were done at 5th, 8th, and 11th months and analyzed by multiple comparisons. RESULTS: Improvements achieved at month 5 from baseline were sustained throughout the follow-up period for the primary outcome, xerostomia severity, and the secondary outcomes resting whole salivary flow rate, xerostomia frequency, oral discomfort, and difficulties in speech, swallowing, and sleeping. No significant side effects were detected. CONCLUSIONS: The beneficial effects of a removable intraoral electrostimulating device were sustained for an 11-month period.

Bioavailability in vivo of naltrexone following transbuccal administration by an electronically-controlled intraoral device: a trial on pigs.

Naltrexone (NLX), an opioid antagonist, is widely used in the treatment of opiate addiction, alcoholism and smoking cessation. Its current peroral administration induces various adverse side effects and has limited efficacy since bioavailability and patient compliance are poor. The development of a long-acting drug delivery system of NLX may overcome the current drawbacks and help in the improvement of treatment of addiction. The primary endpoints of this study were: a) to compare the NLX bioavailability and pharmacokinetics after delivering a single transbuccal dose, released by a prototype of intraoral device, versus an intravenous (I.V.) bolus of the same drug dose; b) to verify the functioning of a prototype of a new intraoral device in vivo; c) to evaluate the permeation enhancement effect of iontophoresis; d) to assess any histomorphological changes in the buccal mucosa after transbuccal delivery. The system was tested on 6 pigs in a cross-over trial. Venous blood samples were drawn at a fixed timetable from the beginning of drug administration and analyzed for the presence of NLX, using an LC/MS/MS method. A punch biopsy was performed for histological analysis after the final experiment. The administration of I.V. NLX induced a sharp increase in blood levels after 5 min and then a steep decrease. In contrast, transmucosal delivery resulted in a gradual increase in blood NLX levels, reaching its peak after 90 min, followed by a slow decrease. After 6h the blood levels of NLX delivered through the buccal mucosa were higher as compared to I.V. administration. No signs of flogosis or tissue damage were histologically highlighted. These results suggest that buccal delivery by an intraoral electronic device could potentially induce long-lasting, continuous and controlled blood levels of NLX, avoiding at the same time spikes of drug plasma levels typical of the I.V. administration route.

5-Fluorouracil buccal tablets for locoregional chemotherapy of oral squamous cell carcinoma: formulation, drug release and histological effects on reconstituted human oral epithelium and porcine buccal mucosa.

5-Fluorouracil (5-FU) is currently used for treatment of oral squamous cell carcinoma (OSCC). 5-FU is given by i.v. although the systemic administration is associated with severe toxic effects and no topical formulations of 5-FU for buccal drug delivery have been reported. In this study we would report the development of buccal tablets suitable for direct application of low-doses of 5-FU on cancer lesions. The topical administration could be effective on tumor area while systemic undesired side effects are avoided. Preliminarily, the limited tendency of 5-FU to cross the buccal tissue was established using reconstituted human oral epithelium (RHOE, in vitro) and porcine buccal mucosa (ex vivo) as mucosal models. The values of steady-state flux and permeability coefficient suggested the scarce aptitude of 5-FU to reach the systemic circulation. Matrix buccal tablets, were designed for 5-FU local delivery, developed and prepared. Release tests showed a highly reproducible Higuchian drug discharge. After tablet administration on buccal tissue specimens, the occurrence of histo-morphological effects of 5-FU was highlighted. Apoptotic events were registered in all samples treated while only negligible amounts of 5-FU permeated the buccal membrane and reached the simulated plasma. The results suggest that loaded matrix tablets containing 5% of 5-FU could be a useful means in topical treatment of OSCC.