Current Pharmaceutical Design - Volume 18, Issue 34, 2012

The aim of this study was to investigate the potential for systemic administration of Methimazole (MMI) through the buccal mucosa as an alternative route for drug delivery. Considering that the most important restriction in buccal drug delivery could be the low permeability of the mucosa, the ability of MMI to cross the mucosal barrier was assessed. Permeation of MMI through porcine buccal mucosa was investigated ex vivo using Franz type diffusion cells, buffer solution simulating saliva or natural human saliva as donor phase. The collected data suggested that buccal mucosa does not hinder MMI diffusion and the drug crosses the membrane (Js = 0.068 mg cm-2 h-1 and Kp = 0.065 cm h-1). Matrix tablets, suitable for administration on buccal mucosa, were then designed and prepared by direct compression of MMI loaded matrices (70% w/w) using Eudragit® RS 100 as a matrixing, low permeable, pH-independent, mucoadhesive and insoluble agent. The matrix tablets were evaluated in vitro for dissolution; however, the drug was discharged too rapidly from tablets. To obtain drug release rate suitable to maintain constant drug levels in the central compartment the tablets were coated with lipophilic material (glycerol tristearate). In ex vivo permeation experiments, therapeutically MMI plasma levels were obtained when matrix tablets were coated with 0.10 mm thick lipophilic coating film. Coated tablets placed on buccal porcine mucosa provide optimal drug release rate. Coated buccal matrix tablets may represent a potential alternative dosage form for systemic delivery of MMI in hyperthyroidism management.

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting sideeffects, 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.

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.

Head and neck cancer refers to a group of malignancies that affects the epithelium of the upper aereodigestive tract, primarily the lip and mouth, pharynx and larynx. Head and neck cancer is strongly associated with tobacco smoking, alcohol consumption and betel nut chewing, and indeed a reduction in the exposure to these risk factors has determined a recent decrease in incidence rates in many countries. There remains, however, a significant increase in head and neck cancer rates in those regions where tobacco epidemic continues, as well as in the number of oral cancers related to HPV infection (in particular cancer of the oropharynx, tonsil, and base of the tongue), which typically affect young adults with no history of exposure to tobacco or alcohol. Treatment of head and neck cancer has significantly changed during the last few decades, and an increasing number of individuals are currently offered combined chemoradiotherapy as single treatment modality for organ preservation or in association with surgery to improve prognosis. Unfortunately, the majority of head and neck cancer patients eventually succumb to their disease, with inoperable locoregional recurrences and lack of response to chemoradiotherapy representing the main causes of death. There is an urgent need of novel molecular-targeted therapeutics that could overcome the limitations of current treatment modalities. This paper reviews the characteristics of a novel group of promising antineoplastic agents, poly (ADP-ribose) polymerases (PARP) inhibitors, which cleverly target one of the mechanisms cancer cells use to escape the toxic effect of chemoradiation, and describe the potential benefits of their addition to current limited range of head and neck cancer antineoplastic agents.

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.

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.

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.

Several drugs may have a number of adverse reactions (ADRs) involving the oro-facial region. The dose of the drug and the time required for the reaction to take place are relevant parameters; nonetheless, ADRs mechanisms are not always known and ADRs are not always predictable since aspects other than drug pharmacodynamics and/or pharmacokinetics, as well as various interacting variables contribute to the final outcome. All tissues and many functions of the oral cavity can be affected. In particular, salivary function is frequently involved and hypo-salivation is the main manifestation; several mucosal lesions with different morphology (ulcerations, vesiculobullous lesions, white lesions, pigmentations, swelling) are also possible. Taste, sensation and trigeminal function alterations have been reported and the recent evidence regarding the occurrence of jawbones osteonecrosis, especially in bisphosphonates treated patients, is increasing. Clinical management may be quite difficult due to the multiplicity of involved classes of drugs and substances (dental materials, foods), the variety of affected tissues and functions, the type of produced lesions and disturbances, the complexity of related pathogenetic mechanisms (if known), the difficulties in assessing causality and managing drug withdrawal and/or dose adjustment, as well as in establishing specific treatments, if any. In this paper the most common and significant oral ADRs, their related aspects and importance (including medico-legal implications) for health care providers will be discussed.

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.

Hyposalivation, often symptomatically manifested as xerostomia (dry mouth sensation) may indicate the presence of altered salivary gland function and places patients at a higher risk for oral complications. Diverse symptoms and consequences have been associated with hyposalivation, such as difficulties with speaking, swallowing and tasting and a significant increase in dental caries and other oral infections. Although hyposalivation may be caused by a variety of conditions (head and neck radiotherapy, Sjogren’s syndrome, medications, etc.), its hallmark symptom, xerostomia, is common to all such disorders, and varies only in intensity. Therefore, treatment is generally non-specific, and similar therapeutic approaches are used in all cases. In the present paper, available palliative oral care in the form of saliva substitutes, such as mouthwashes or gels, is detailed. Also salivary flow stimulants, such as certain pharmaceutical or gustatory preparations, acupuncture and electrostimulation are reviewed. Finally, other approaches, currently under investigation, such as biological and gene therapies, are discussed. The degree of evidence of the best known methods and their intended use are analyzed.

Probiotics are living microorganisms (e.g., bacteria) that are either the same as or similar to organisms found naturally in the human body and may be beneficial to health. Current researches have shown that the balance between beneficial and pathogenic bacteria is essential in order to maintain the oral health. Therefore, oral cavity has recently been suggested as a relevant target for probiotic applications. Dental caries can be seen as a microbial imbalance where the oral microbiota shift towards community dominance which produces acidogenic and acid-tolerant gram positive bacteria. Similarly, the accumulation of bacteria within the biofilm, facilitated by poor oral hygiene, predisposes to allogenic shifts in the microbial community, leading to the onset of periodontal inflammation. Probiotic bacteria belonging to the genus of Lactobacillus, Bifidobacterium and Streptococcus have been proven effective for preventing caries by reducing the number of cariogenic bacteria in saliva after a short period of consuming the probiotic. In contrast, the effect of probiotics on improving gingivitis and periodontitis has been less investigated. The currently available studies on the effect of probiotics on periodontal pathogens and clinical periodontal parameters showed differing results depending on the strains used and the endpoints analyzed. Many of the clinical studies are pilot in nature and with low quality, therefore, properly conducted clinical trials, using probiotic strains with in vitro proven periodontal probiotic effects, are needed. The putative beneficial effects of probiotics on oral malodour have also been evaluated, but further evidence is needed to fully explore the potential of probiotics for preventing malodour.

The use of topically applied fluoride has been widely researched as a means to reduce the risk of dental caries in conjunction with other treatment modalities (mechanical oral hygiene, dietary control, antimicrobial intervention, pit and fissure sealants). There is overwhelming evidence that reports not only the significance and importance of the use of fluoride as a caries-preventive agent, but also how safe fluoride application is when used appropriately, particularly in higher risk individuals and populations. This paper reviews the caries-protective benefits of topical fluoride application in children and adolescents, with an emphasis on the clinical efficacy and safety of the vehicles by which fluoride is topically delivered. Fluoride toothpaste represents today the most cost-effective fluoride-delivery system in the oral cavity and its use should be the centerpiece in all caries-preventive strategies. On the other hand, mouthrinses, gels and varnishes currently represent adjuncts to toothpaste use and should be targeted towards individuals and groups at high risk of caries.

Adhesive dentistry is based on the development of materials which establish an effective bond with the tooth tissues. In this context, adhesive systems have attracted considerable research interest in recent years. Successful adhesive bonding depends on the chemistry of the adhesive, on appropriate clinical handling of the material as well as on the knowledge of the morphological changes caused on dental tissue by different bonding procedures. This paper outlines the status of contemporary adhesive systems, with particular emphasis on chemical characteristics and mode of interaction of the adhesives with enamel and dentinal tissues. Dental adhesives are used for several clinical applications and they can be classified based on the clinical regimen in “etch-and-rinse adhesives” and “self-etch adhesives”. Other important considerations concern the different anatomical characteristics of enamel and dentine which are involved in the bonding procedures that have also implications for the technique used as well as for the quality of the bond. Etch-and-rinse adhesive systems generally perform better on enamel than self-etching systems which may be more suitable for bonding to dentine. In order to avoid a possible loss of the restoration, secondary caries or pulp damage due to bacteria penetration or due to cytotoxicity effects of eluted adhesive components, careful consideration of several factors is essential in selecting the suitable bonding procedure and adhesive system for the individual patient situation .

One of the goals of endodontic treatment is to achieve a complete, tridimensional, hermetic sealing of the root canal system to prevent the entry of microorganisms or their products through both the coronal and apical pathways. Gutta-percha is the most widely used material for root canal filling and despite its numerous properties, such as biocompatibility and thermoplasticity, it has however an important limit: the lack of adhesion to the canal walls. Attempts to address this problem have been made over the years by using endodontic cements capable of bonding to canal dentine but their tendency to resorption in time can compromise the quality of treatment. The first step towards a real adhesive endodontic filling4 is rather recent; in fact, it goes back to 2003 when, on the occasion of the American Dental Association (ADA) Annual Session, Resilon Research LLC introduced a new canal filling adhesive system based on a thermoplastic synthetic resin material called Resilon™. The real innovation of this system is its capacity of creating a core made of Resilon™ bonded to the cement which adheres to dentine walls previously conditioned with a selfetching primer4 so no changes in the techniques of canal preparation are required. The aim of this study was to evaluate the capacity of two filling materials (gutta-percha and Resilon) to adapt to the canal anatomy, especially on the apical third, using the continuous wave of condensation technique. Our data suggest that in the third apical the gutta-percha best shows rheological properties that are as important as the bond capability.

The use of graft materials is developed from the strong demand to support the complete bone regeneration of the empty socket and to increase the bone volume in treating the atrophies of sites already consolidated and with adverse alveolar bone conditions. A number of graft materials with different origin and mechanism of bone regeneration are available. Autologous graft materials, coming from the same patient, are defined as the gold-standard. The need of a second surgical site and the risk of morbidity and complications may make their use difficult. Human bone allografts (HBA) have been recently introduced, in order to offer an alternative to the autologous grafts. They have demonstrated to be effective in bone regeneration. Recent studies have proved the ability of HBA in bone regenerating process as they guarantee a three-dimensional structure for the re-growth of the new bone and the maintenance of inductive stimuli. In the present manuscript, Authors reviewed the evidence supporting the use of HBA in the management of the localized ridge atrophies, in the preservation of the extracted socket and in the sinus augmentation surgery, and illustrated some original case reports.

The heterogeneity of Polycystic Ovary Syndrome (PCOS) emphasizes the need for a consensual review of the data concerning its diagnosis and treatment and for determination of the relationship between the development of PCOS and the ethnic origin, the social status and the lifespan. Insulin resistance is an important characteristic in women with PCOS that aggravates features of PCOS. This review is focused in the diagnosis and treatment of insulin resistance and the risk factors for PCOS during childhood, adolescence and postmenopause. The role of endocrine disruptors and/or their interaction with PCOS have also been analyzed.

Fruits and vegetables (typically associated with the Mediterranean diet) are very rich in carotenoids, i.e. fat-soluble pigments really important in human life. Structurally, carotenoids consists of eleven (beta-carotene, zeaxanthin, lycopene) or ten (alpha-carotene, lutein) conjugated double bonds, responsible for their antioxidant capability in agreement with their substituents. Low-Density Lipoprotein (LDL) particles oxidation process is the one of the most important first steps of atherosclerotic disease and, consequentially, the first pathogenetical step of cerebro- and cardiovascular events like myocardial infarction and stroke, which are the first cause of death in industrialized countries. Reactive oxygen species (ROS) also seem to be the target of Carotenoids main action, by scavenging singlet oxygen (1O2) and free radicals. Literature data showed that ROS increase atherosclerotic individual burden. The carotenoids scavenging action could reduce atherosclerosis progression partly due to such a decrease in ROS concentrations. Many studied demonstrated such a reduction by analyzing the relationship between carotenoids and Intima-Media Thickness of common carotid artery wall (CCA-IMT), [a well established marker of atherosclerosis evolution] reduction. Aim of this review is to evaluate actual knowledge about the importance of carotenoids molecules in slowing down the starting and the progression of atherosclerotic plaque, and to consider their implementation in everyone's diet as a tool to obtain a sharp decrease of LDL oxidation and their possible effect on endothelial function.

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The use of on demand PDE5 inhibitors (-Is) for the treatment of erectile dysfunction (ED) has recently obtained approval for chronic daily dosing for the same indication. There are published data supporting the use of PDE5-Is for the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Additional reports suggest benefit by these agents in patients with chronic heart failure, pulmonary hypertension, essential hypertension, and for the treatment of ischemia. Various central nervous system disorders have been described as targets by PDE5-Is. Sildenafil may have a potential therapeutic indication as a cognitive enhancer in age-related cerebral conditions. There is preclinical evidence for further investigation of the use of PDE5A -Is to improve recovery of cerebral function in humans after stroke by enhancing angiogenesis, neurogenesis and improving neurologic function. Sildenafil delays intestinal ulceration by an increase in the secretion of mucus/fluid and a decrease in hypermotility, and has a protective effect in reducing gastric damage. Larger scale, well designed clinical trials are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5-Is in the future treatment of both urologic and non-urologic diseases. In this review, potential applications of PDE5-Is on urologic, cardiovascular, gastrointestinal, and central nervous system disorders will be updated.