Abstract ! The buccal mucosal route offers several advantages but the delivery of certain drugs can be limited by low membrane permeability. This study investigated the buccal permeability properties of didanosine (ddI) and assessed the potential of Aloe vera gel (AVgel) as a novel buccal permeation enhancer. Permeation studies were performed using Franz diffusion cells, and the drug was quantified by UV spectroscopy. Histomorphological evaluations were undertaken using light and transmission electron microscopy. The permeability of ddI was concentration-dependent, and it did not have any adverse effects on the buccal mucosae. A linear relationship (R2 = 0.9557) between the concentrations and flux indicated passive diffusion as the mechanism of drug transport. AVgel at concentrations of 0.25 to 2%w/v enhanced ddI permeability with enhancement ratios from 5.09 (0.25%w/v) to 11.78 (2%w/v) but decreased permeability at 4 and 6%w/v. Ultrastructural analysis of the buccal mucosae treated with phosphate buffer saline pH 7.4 (PBS), ddI/ PBS, and ddI/PBS/AVgel 0.5%w/v showed cells with normal plasmalemma, well-developed cristae, and nuclei with regular nuclear envelopes. However, cells from 1, 2, and 6%w/v AVgel-treated mucosae showed irregular nuclear outlines, increased intercellular spacing, and plasmalemma crenulations. This study demonstrates the potential of AVgel as a buccal permeation enhancer for ddI to improve anti-HIV and AIDS therapy.

Lectins are proteins or glycoproteins of non-immune origin, capable of specific interaction with, and reversible binding to carbohydrate moieties of complex glycoconjugates. Lectins are ubiquitous in nature and are present in all living organisms. In nature lectins are implicated in cell recognition and adhesion processes, and have been described as "second generation" mucoadhesives. The aim of this project was to identify lectins that could be incorporated into dosage forms to allow their retention within the oral cavity. This would allow prolonged localised drug delivery. Initial screening studies on human buccal cells, usmg the avidin-biotincomplex/ diaminobenzidine method suggested that all the lectins tested appeared to bind to varying degrees, as visualised by a diaminobenzidine (DAB) precipitate to the oral epithelial surface. The stain intensities were analysed semi-qualitatively with E micro densitometer GN5 (Barr and Stroud). A substantial reduction in lectin binding was observed after exposing buccal cells to a series of lectin solutions pre-treated with secretor and non-secretor saliva. However when bound to the buccal cells, there was little displacement of lectins on exposure to either saliva types. Kinetic binding studies revealed the presence of the lectins from Pisum sativum and Arachis hypogaea, after only 20 s contact. There were some differences in lectin binding evident between rat oral tissue and human buccal cells, but those that bound avidly to both were selected for furthe studies. In order to allow a quantitative assessment of binding, the lectins from Canavali ensiformis, Arachis hypogaea and Triticum vulgaris were labelled with Technetium-99n (Tc-99m) using a cyclic diethylenetriamine pentaacetic acid conjugation technique. In this preliminary study it was found that 1.18 fmoles of the Canavalia ensiformis lectir 3.27 fmoles of the Arachis hypogaea lectin and 11.11 fmoles of the Triticum vulgari lectin bound per buccal cell. This was reduced when Tc-99m-labelled Canavali ensiformis lectin was inhibited by the presence of 40% w/v glucose solution. It was estimated that a therapeutic dose of a potential dosage form could be conjugated to the Triticum vulgaris lectin within the oral cavity, thus demonstrating the feasibility of using this, and possibly other lectins in a drug delivery strategy. Preliminary in vivo studies in the conscious rat model suggested that the Tc-99m-labelled Canavalia ensiformis an Triticum vulgaris lectins were present within the oral cavity, 1 hand 2 h respectively after application, with about 25% of the Canavalia ensiformis lectin being lost into the stomach through swallowing. Transmission electron microscopy studies were initiated to determine the exact sites of lectins binding to the human buccal cell. Fresh, unfixed human buccal cells were incubated in a solution containing 20 nm gold-labelled Canavalia ensiformis lectin. was found that after processing, the lectin bound to the external surface of the buccal cells, or to external mucin. No binding was observed when pre-fixed human buccal cells were used, indicating that fixation affects the glucose/ mannose-containing binding site Canavalia ensiformis lectin binding to the buccal cells was partially inhibited by the presence of glucose, the hapten sugar. It was concluded that lectins will bind to the rat oral epithelial and human buccal cell surfaces to varying degrees, and will persist, even in the presence of saliva. In particular the lectin from Triticum vulgaris was shown to have good stability in the conscious rat model for up to 2 h, and shows great promise for use in a potential lectin-containing drug delivery system.

Conventional routes of drug administration have several disadvantages. The rate and extent of absorption can vary greatly depending on the drug, its formulation, the presence or absence of food, drug interactions, and the pH of gastrointestinal fluids. Extensive first-pass metabolism can greatly reduce the absorption of many drugs. Better dosage forms or drug delivery mechanisms could minimize some of these problems. The pharmaceutical industry has recognized the need for, and has developed many new, novel drug delivery systems. Drugs that previously experienced diminished effective concentrations due to the first-pass effect may now be given by a novel route. The dosing frequency of many drugs may be reduced when administered by a novel route or site. Transmucosal drug delivery (TMDD) via the buccal mucosa is one site that is suited to rapid drug absorption and systemic delivery. Drugs selected for TMDD must have physiochemical properties that will allow them to penetrate the mucosa and produce therapeutic blood concentrations. This study utilized a buccal patch less than 1.5 cm in length to deliver albuterol and butorphanol-two drugs with dissimilar physiochemical properties. The purpose of this study was to establish pharmacokinetic parameters and the bioavailability of albuterol and butorphanol when administered intravenously and buccally. Three dogs weighing at least 20 kg were studied using a randomized crossover design, each receiving albuterol and butorphanol by buccal and intravenous administration. Blood samples were collected and analyzed using ELISA. Values for pharmacokinetic parameters were analyzed using compartmental and non-compartmental models. For albuterol, extrapolated Cmax and Co after buccal and IV administration were 10.28 ± 2.77 and 57.74 ± 9.04 ng/ml, respectively. Volume of distribution at steady state (Vss) was 2.13 ± 1.30 L/kg and Cl was 4.73 ± 3.91 ml/min/kg. A significant difference existed between the disappearance rate constant of buccal and intravenous albuterol administration. The disappearance half-lives of buccal and IV albuterol were 160.96 ± 24.19 and 364.20 ± 115.20 min, respectively. The bioavailability of buccally administered albuterol was 35%. Maximal concentration (Cmax) and Co after buccal and IV butorphanol administration were 6.66 ± 1.65 and 8.24 ± 5.55 ng/ml, respectively. Volume of distribution at steady state (Vss) was 27.58 ± 10.14 L/kg and Cl was 137.87 ± 19.55 ml/min/kg. The half-life of buccally administered butorphanol was 259.15 ± 33.12 min and the half-life of IV butorphanol was 172.12 ± 94.95 min. The bioavailability of buccally administered butorphanol was 606%. The buccal patch used in this study achieved systemic concentrations for both albuterol and butorphanol. Further studies are needed to determine if therapeutic drug concentrations can be achieved with the buccal patch and if the patch can result in clinical efficacy.

Magister Chirurgiae Dentium (MChD) / A total of 25 third molar teeth (erupted [9], as well as unerupted [16]), from subjects who had lived continuously since birth in an area where the water fluoride concentration was more than 1,8 ppm, were studied. (The range was 1,8 ppm - 2,64 ppm of F-). The subjects had no systemic fluoride supplementation. Tooth brushing with a fluoride containing dentifrice and, perhaps, occasional fluoride mouth rinsing was the only additional exposure to fluoride. The acid-etch biopsy technique was used to determine the fluoride and calcium concentrations at various depths on the enamel surface. The fluoride concentration of the buffered etch solution was determined with an adapted fluoride ion-selective electrode technique, and the amount of calcium by flame atomic absorption spectrophotometry. Six consecutive etchings were done on the mesio-buccal and mesio-lingual cusps of each tooth; the teeth were then washed in an alkali and the same procedure repeated on the disto-buccal and disto-lingual cusps. The depth of etch of each biopsy was calculated assuming that human enamel contains 37% Ca and has a density of 2,95g/ml. It was previously reported, (Grobler & Joubert, 1988), that the enamel fluoride levels of the mesio-buccal and mesio-Iingual sides did not differ from that of the disto-buccal and disto-Iingual sides. The average etch depth and fluoride concentration value as calculated from the values for the two cusps per tooth were used for statistical analysis. The mean etch depths (pm) and mean enamel fluoride concentrations of alkali-washed and unwashed enamel of both erupted and unerupted teeth were tabled, together with the standard deviations and range for each etch. Contrary to the results obtained from a low F- area, no significant difference (p>O.05) could be found in the etch depth between erupted and unerupted enamel in this study. Graphs were plotted by a line fitted to the mean enamel fluoride concentration and mean etch depths values of unwashed erupted, unwashed unerupted, alkali-washed erupted and alkali-washed unerupted third molar teeth. These graphs were compared to the graphs obtained in a comparable study done by Grobler and Kotze (1990), on erupted and unerupted third molar teeth from a low fluoride area (F- < 0,10 ppm). Results indicate that the enamel fluoride concentration in the bulk of the enamel of teeth from a high fluoride area (> 1,8 ppm), is higher than that of teeth from a low fluoride area « 0,10 ppm ). In contrast to the teeth from a low fluoride area, where there was a significant increase (p<0.05) in the fluoride concentration of the outer layer (± 4 J,lm) of erupted enamel when compared to that of the unerupted enamel, no notable increase in the F- content of the enamel was observed in the present study of teeth from a high fluoride area (p>0,05). There was, in addition, no significant (p>0.05) difference between the enamel fluoride content of alkali-washed and unwashed, erupted and unerupted teeth, which showed that very little CaF 2-like material was gained by the enamel after eruption. In both studies the subjects had brushed with a fluoride dentifrice for a period of 1 - 16 years. It was expected that this topical exposure would increase the surface enamel concentration in the high fluoride area similar to the increase found in the low fluoride area. However, this was not the case, and as all the teeth from the high fluoride area exhibited some degree of fluorosis, it was concluded that posteruptive fluoride uptake by fluorotic human enamel without severe enamel loss is limited. This is in agreement with work done by Richards, Fejerskov, Baelum and Likimani (1989).

Made available in DSpace on 2014-06-11T19:23:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-30Bitstream added on 2014-06-13T19:09:29Z : No. of bitstreams: 1 mello_pb_me_arafo.pdf: 2440580 bytes, checksum: dda996c24968844c61b4acb0db2832e7 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O corredor bucal é definido como o espaço que existe bilateralmente entre a superfície vestibular dos dentes superiores posteriores visíveis e a comissura labial durante o sorriso. Este espaço escuro também é conhecido como espaço negativo. O objetivo da presente pesquisa foi analisar o corredor bucal durante o sorriso de 150 indivíduos de 10 a 19 anos de idade, verificando se há mudança no tamanho desse espaço em diferentes idades, se há diferença entre os gêneros e se existe uma relação de proporção entre a distância inter pré-molares, a largura inter comissura e o corredor bucal. Foram realizadas fotografias digitais padronizadas em norma frontal do sorriso amplo posado que foram transferidas para um computador e os contornos das imagens dos corredores bucais e sua medida linear foram delimitados e calculados pelo programa Image Tool 3.0. Uma linha entre as comissuras labiais direita e esquerda foi definida medindo a largura inter comissura. A área inter labial do sorriso e do corredor bucal foi delimitada e calculada. As distâncias entre as cúspides vestibulares dos primeiros pré-molares superiores foram medidas em modelos de gesso comum e as mesmas foram transferidas para um computador para posteriores comparações. A análise dos dados foi realizada obtendo estimativas por intervalo de confiança, análise de variância com dois critérios de classificação, comparação múltipla de médias e coeficiente de correlação de Pearson. O corredor bucal aumentou com a idade. Os indivíduos do gênero masculino apresentam corredor bucal maior que os do gênero feminino, porém em relação ao percentual da largura inter comissura não há diferença entre os gêneros. / The buccal corridor is defined as the space that exists bilaterally between the vestibular surface of the subsequent superior teeth visible and the labial comissure during the smile. This dark space is also known as negative space. The objective of the present research is to analyze the buccal corridor during the smile of 150 individuals from 10 to 19 years of age, verifying if there is change in the size of that space in different ages and if exists a relationship of proportion among the inter premolar distance, the inter comissure width and the buccal corridor. Digital standardized pictures were accomplished in frontal norm of the posed wide smile that were transferred for a computer and the outlines of the images of the buccal corridors and linear measure were delimited and calculated by the program Image Tool 3.0. A line between the right and left comissures was defined measuring the inter comissure width. The inter labial area of the smile and buccal corridors were delimited and calculated. The distances among the vestibular cusps of the first superior premolars were measured in casts of common plaster and were transferred for a computer for subsequent comparisons. The analysis of the data was accomplished obtaining confidence intervals, analysis of variance with two classification criteria, multiple mean test and Pearson correlation coefficient to complete data. Buccal corridor increases with age. Males have bigger buccal corridor than females, but there is no difference between gender when calculated as percentage related with the inter comissure width.

Orientador: Luiz Gonzaga Gandini Júnior / Banca: Lídia Parsekian Martins / Banca: Alexandre Fortes Drummond / Resumo: O corredor bucal é definido como o espaço que existe bilateralmente entre a superfície vestibular dos dentes superiores posteriores visíveis e a comissura labial durante o sorriso. Este espaço escuro também é conhecido como espaço negativo. O objetivo da presente pesquisa foi analisar o corredor bucal durante o sorriso de 150 indivíduos de 10 a 19 anos de idade, verificando se há mudança no tamanho desse espaço em diferentes idades, se há diferença entre os gêneros e se existe uma relação de proporção entre a distância inter pré-molares, a largura inter comissura e o corredor bucal. Foram realizadas fotografias digitais padronizadas em norma frontal do sorriso amplo posado que foram transferidas para um computador e os contornos das imagens dos corredores bucais e sua medida linear foram delimitados e calculados pelo programa Image Tool 3.0. Uma linha entre as comissuras labiais direita e esquerda foi definida medindo a largura inter comissura. A área inter labial do sorriso e do corredor bucal foi delimitada e calculada. As distâncias entre as cúspides vestibulares dos primeiros pré-molares superiores foram medidas em modelos de gesso comum e as mesmas foram transferidas para um computador para posteriores comparações. A análise dos dados foi realizada obtendo estimativas por intervalo de confiança, análise de variância com dois critérios de classificação, comparação múltipla de médias e coeficiente de correlação de Pearson. O corredor bucal aumentou com a idade. Os indivíduos do gênero masculino apresentam corredor bucal maior que os do gênero feminino, porém em relação ao percentual da largura inter comissura não há diferença entre os gêneros. / Abstract: The buccal corridor is defined as the space that exists bilaterally between the vestibular surface of the subsequent superior teeth visible and the labial comissure during the smile. This dark space is also known as negative space. The objective of the present research is to analyze the buccal corridor during the smile of 150 individuals from 10 to 19 years of age, verifying if there is change in the size of that space in different ages and if exists a relationship of proportion among the inter premolar distance, the inter comissure width and the buccal corridor. Digital standardized pictures were accomplished in frontal norm of the posed wide smile that were transferred for a computer and the outlines of the images of the buccal corridors and linear measure were delimited and calculated by the program Image Tool 3.0. A line between the right and left comissures was defined measuring the inter comissure width. The inter labial area of the smile and buccal corridors were delimited and calculated. The distances among the vestibular cusps of the first superior premolars were measured in casts of common plaster and were transferred for a computer for subsequent comparisons. The analysis of the data was accomplished obtaining confidence intervals, analysis of variance with two classification criteria, multiple mean test and Pearson correlation coefficient to complete data. Buccal corridor increases with age. Males have bigger buccal corridor than females, but there is no difference between gender when calculated as percentage related with the inter comissure width. / Mestre

NANOMEDECINE DRUG DELIVERY ACROSS MUCOUS MEMBRANES By Michael G. Lancina III A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth Univeristy, 2017. Major Director: Dr. Hu Yang, Associate Professor, Chemical and Life Science Engineering Control over the distribution of therapeutic compounds is a complex and somewhat overlooked field of pharmaceutical research. When swallowing a pill or receiving an injection, it is commonly assumed that drug will spread throughout the body in a more or less uniform concentration and find its way to wherever it is needed. In truth, drug biodistribuition is highly non-uniform and dependent on a large number of factors. The development of advanced drug delivery systems to control biodistribution can produce significant advances in clinical treatments without the need to discover new therapeutic compounds. This work focuses on a number of nanostructured materials designed to improve drug delivery by direct and efficient transfer of drugs across one of the body’s external mucous membranes. Chapter 1 outlines the central concept that unites these studies: nanomaterials and cationic particles can be used to delivery therapeutic compounds across mucous membranes. Special attention is given to dendritic nanoparticles. In chapter 2, uses for dendrimers in ocular drug delivery are presented. The studies are divided into two main groups: topical and injectable formulations. Chapter 3 does not involve dendrimers but instead another cationic particle used in transmembrane drug delivery, chitosan. Next, a dendrimer based nanofiber mat was used to deliver anti-glaucoma drugs in chapter 4. A three week in vivo efficacy trial showed dendrimer nanofiber mats outperformed traditional eye drops in terms of intra-ocular pressure decrease in a normotensive rat model. Finally, we have developed a new dendrimer based anti-glaucoma drug in chapter 5. Collectively, these studies demonstrate some of the potential applications for nanotechnology to improve transmembrane drug delivery. These particles and fibers are able to readily adhere and penetrate across epithelial cell lays. Utilizing these materials to improve drug absorption through these portals has the potential to improve the clinical treatment of wide variety of diseases.

The retromolar foramen represents a little known anatomical variation in the posterior mandible of uncertain clinical importance. It has been the subject of limited study. Findings and conclusions of these studies have been placed under little scrutiny. Suggested clinical consequences associated with the presence of the retromolar foramen include local anaesthetic failure, local haemorrhage during surgery, perineural spread of infectious and invasive pathology, and loss of sensation in the normal distribution of the buccal nerve due to surgical intervention. Reports of the possibility of these complications seem to suggest that the retromolar foramen, canal and its associated neurovascular bundle are structures of great clinical importance. Case reports seem to have, however, only included reports of loss of gingival and buccal sensation as a consequence of third molar surgery in the presence of this anomaly. This study therefore aimed to report the prevalence of the retromolar foramen and canal in the South African population, describe its course and structure, and produce a clinical framework in which to approach the presence of the retromolar foramen. Comparisons between the present and existing studies were made and conclusions concerning the clinical importance of this structure were drawn. Inspection of a sample containing 946 mandibles was performed. Of these, 885 were regarded as suitable for inclusion. These mandibles were inspected for the presence of a retromolar foramen in which a 1 mm diameter needle could pass through without resistance. The distance from the last tooth in the arch to the retromolar foramen was also measured. Fifty of these mandibles were then randomly selected and scanned using microfocus computed tomography. Seventy mandibles were found to have at least one retromolar foramen (7.9% of the total sample). No statistically significant differences were found when the presence of the retromolar foramen was correlated with race, sex or age. The finding that sex and age played no significant role in the presence of the retromolar foramen is in agreement with available literature. Detected prevalence seemed to be heavily influenced by the method used to determine the presence of the retromolar foramen. The average distance between the second mandibular molar and the retromolar foramen was 16.83 ± 5.57 mm and the average distance between the third mandibular molar and the retromolar foramen was 10.47 ± 3.77 mm. These findings were found to be in agreement with most other reports. Fifty retromolar canals were selected at random and scanned using microfocus computed tomography. Analysis revealed four basic patterns. These were type A, a vertical canal between the inferior alveolar canal and the retromolar area of the mandible, type B, a curved canal taking a recurrent course between the inferior alveolar canal and the retromolar area, type C, a canal with an approximately horizontal path between the inferior alveolar canal and the retromolar area, and the temporal crest canal (TCC, not designated as type D to create a distinction between it and types A, B and C), a canal terminating on either side of the temporal crest. Type B was the most common presentation (68% of retromolar canals in the study), a finding contrary to that of other studies. The presence of the retromolar neurovascular bundle is of uncertain clinical importance and requires further anatomical and pharmacological study to determine its effect on local anaesthetic failure. A model in which the retromolar canal branches from the inferior alveolar canal does not seem to support a conclusion in which local anaesthetic failure may be directly attributable the presence of this anatomical variation alone. Classification of the retromolar canal is of limited clinical use and may require a revised scheme if clinical application is sought. Complications associated with the presence of the retromolar foramen are poorly documented and seem to be of little consequence. / Dissertation (MSc)--University of Pretoria, 2014. / tm2015 / Anatomy / MSc / Unrestricted

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