Research on prosodic structure, the underlying structure organising the prosodic grouping of spoken utterances, has shown that it consists of hierarchically organised prosodic constituents. The present thesis explores the nature of this constituency, in particular the question of whether prosodic structure is comprised of a given set of qualitatively distinct domains, or of a set of domains of the same type varying only gradiently in "strength", or a possible mixture of both types of relations across prosodic levels. This question is addressed by testing how prosodic constituency (mirrored on boundary strength manipulations) is signalled acoustically via pre- and post-boundary durations, intonation contours, and two sandhi processes, namely vowel hiatus resolution and post-nasal stop voicing in Modern Greek. Results show that the phonetic signalling of boundary strength provides support for a mixture of both differences of type and strength across prosodic levels, with some levels only differing in terms of their strength. Pre-boundary durations and resolution of vowel hiatus are gradiently affected by boundary strength with shorter to longer durations from lower to higher domains, and less instances of vowel deletion higher in the hierarchy. Post-nasal stop voicing is qualitatively affected by boundary strength with almost all voicing instances occurring in the lowest constituent of the structure in the way a qualitative view of prosodic constituency would predict, and in line with research on prosodic phonology. Finally, both the alignment and scaling of intonation contours at the edges of domains is found to distinguish qualitatively the lowest domain from the higher ones. All higher phrasal domains align with respect to the boundary and their peak scaling varies consistently gradiently across speakers. When combining those two findings, support is provided for the existence of differences of strength and type within the same process. Taken together the results from these four phenomena support the postulation of an underlying prosodic structure with a limited number of qualitatively distinct domains, within which at the same time some type of recursivity or structured variability must be allowed for. It is shown that there are structural properties of speech, like the length of the utterance, influencing the organisation of utterances in a principled gradient manner, supporting the existence of differences of strength within domain types. These findings bear significance for theories of prosodic structure that have assumed either the view of solely qualitative differences, or sole boundary strength differences, as well as for future proposals on prosodic constituency. Finally, the use of Modern Greek in this thesis adds to the existing literature on a language that has been extensively used by researchers working in views supporting the existence of qualitative distinctions of type across prosodic domains, and provides the first in depth experimental analysis of post-nasal stop voicing.

Die akustische Rhinometrie ist in der Humanmedizin eine etablierte, nicht-invasive Methode zur Bestimmung von Nasenhöhlenvolumina und definierten Querschnittsflächen in nasalen Atemwegen beim Menschen. Sie basiert auf dem Vergleich beziehungsweise der Analyse der Amplituden von Schallwellen (definiert über die Querschnittsflächen) als Funktion der Zeit (definiert durch den Abstand in die Nasenhöhle), die durch Reflexionen einer Ausgangs-schallwelle in der Nasenhöhle entstehen. Das Ziel dieser Studie war es, erstmals den Nutzen der akustischen Rhinometrie für die klinische Veterinärmedizin bei Hunden zu überprüfen. Die Hauptschwerpunkte lagen in der Quantifizierung des geometrischen Aufbaus der Nasenhöhle von gesunden (n=15) und kranken (n=32) Hunden über die Auswertung der Flächenabstandskurven, der Definition von minimalen Querschnittsflächen (MCA1, MCA2) und Zuordnung zu anatomischen Landmarken auf CT-Schnittbildern. Für die Messungen wurde das Rhinometer SRE 2000 (RhinoMetrics, Dänemark) verwendet. Voruntersuchungen zu Wiederholbarkeit und Genauigkeit der Messmethode erfolgten an zylindrischen Stufenmodellen (n=3). Für jeden Beagle konnte eine deutliche Korrelation der ersten minimalen Querschnittsflächen zur Spitze der Concha nasalis ventralis nachgewiesen werden. Die zweite minimale Querschnittsfläche ließ sich keiner anatomischen Landmarke zuordnen. Es bestand kein statistisch signifikanter Unterschied in Nasenhöhlenvolumina, Auftreten der MCA1 und MCA2 und ihrer entsprechenden Dimension der jeweils rechten und linken Nasenhöhle im Gruppenvergleich. Nach lokaler Applikation von Xylometazolin lag die Größenzunahme des Volumens der rechten Nasen-höhle bei 19,4% [3,9-24,7%] (n=13) und der Linken bei 23,7% [15,4-36,4%] (n=12). Von insgesamt 32 untersuchten Hunden zeigten acht Hunde eindeutig einseitige Veränderungen (25%) in den CT-Schnittbildern. Anhand der Kurvensymmetrie ließ sich die pathologisch veränderte Nasenhöhlenseite nur in vier von acht Fällen zweifellos zuordnen. Besonders bei Erkrankungen mit Rhinorrhoe oder Ansammlungen von Sekret innerhalb der Nasenhöhle kam zu Fehlinterpretationen der Flächenabstandskurven. Oszillationen traten bei 22% der Patienten auf. Die Ergebnisse lassen Rückschlüsse zu, dass sich die akustische Rhinometrie aufgrund einer guten Wiederholbarkeit und einfachen Anwendung für wissenschaftliche Studien eignet, bei denen der Schwerpunkt auf intraindividuellen Vergleichen liegt. Obwohl die Daten objektiv ermittelt werden, ist die Anwendung dieser Methode in der klinischen Veterinärmedizin bei Hunden nur in Kombination mit anderen Untersuchungsmodalitäten sinnvoll. Fehlmessungen treten bereits bei einfach strukturierten Modellen auf; am caninen Patienten nehmen sie durch die ansteigende Diskrepanz zum idealen theoretischen Modell weiter zu. Primäre pathologische Veränderungen in der Nasenhöhlengeometrie werden nicht erkannt oder durch sekundäre Veränderungen maskiert. Verschiedene Krankheitsbilder weisen gleiche oder ähnliche strukturelle Veränderungen in der Nasenhöhle auf und können durch Messungen mit akustischen Schallwellen nicht unterschieden werden. Die Interpretation von Absolutwer-ten ist kritisch. Die Quantifizierung einer intranasalen Stenose ist nicht möglich.

Approximately 350 million people worldwide suffer from diabetes mellitus (DM) and this number increases yearly. Since the discovery and clinical application of insulin in 1921, subcutaneous injections have been the standard treatment for DM. Because insulin is hydrophilic and has a high molecular weight and low bioavailability, this molecule is poorly absorbed if administered orally. The aim of this study is to evaluate nasal delivery systems for insulin, using Sprague Dawley rats as the nasal absorption model. Pheroid technology and N-trimethyl chitosan chloride (TMC) with different dosages of insulin (4, 8 and 12 IU/kg bodyweight insulin) was administered in the left nostril of the rat by using a micropipette. Pheroid technology is a patented (North-West University) carrier system consisting of a unique oil/water emulsion that actively transports drug actives through various physiological barriers. These formulations were administered nasally to rats in a volume of 100 p/kg bodyweight in different types of Pheroids (vesicles, with a size of 1.7 1 - 1.94 pm and microsponges, with a size of 5.7 1 - 8.25 pm). The systemic absorption of insulin was monitored by measuring arterial blood glucose levels over a period of 3 hours. The TMC formulation with 4 IU/kg insulin produced clinically relevant levels of insulin in the blood and as a result also the maximal hypoglycaemic effect. TMC is a quaternary derivative of chitosan and is able to enhance the absorption of various peptide drugs by opening tight junctions between epithelial cells. Pheroid formulations were also effective in lowering blood glucose levels but only at higher doses (8 and 12 IU/kg) of insulin. This study indicated that Pheroid rnicrosponges had a faster onset of action and a slightly better absorption of insulin when compared to Pheroid vesicles, but many more studies are needed in this field. Although the results of this study with absorption enhancers are encouraging, nasal insulin bioavailability is still very low, and the Pheroid formulations and long-term safety of nasal insulin therapy have yet to be investigated. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Advances in biotechnology and recombinant technologies have lead to the production of several classes of new drugs such as peptide and protein drugs. These compounds are mostly indicated for chronic use but their inherent characteristics such as size, polarity and stability prevent them from incorporation in novel dosage forms. The bioavailability of nearly all peptide drugs is very low due to poor absorption from the administration site. Several challenges confront the pharmaceutical scientist in developing effective and innovative dosage forms for these classes of drugs. A lot of attention has been given to the nasal route of drug administration for delivery of peptide drugs. The availability of several promising classes of absorption enhancers and new drug delivery technologies has also prompt scientists to develop new delivery systems for nasal administration of peptide drugs. It has been shown in recent years that N-trimethyl chitosan chloride (TMC), a quaternary derivative of chitosan, is effective in enhancing the absorption of several peptide drugs, both in the peroral route and in the nasal route of drug administration. Early indications are that new drug delivery technologies such as Pheroid technology will also be able to enhance peptide drug absorption in the nasal route. The aim of this study was to evaluate and compare the absorption enhancing abilities of TMC and Pheroid technology in the nasal delivery of calcitonin, a peptide hormone with low bioavailability. Pheroid vesicles and Pheroid microsponges were prepared and characterized for their morphology and size distribution. Calcitonin was entrapped into these vesicles and microsponges and TMC and TMO solutions (0.5 % w/v), containing calcitonin, was also prepared. These formulations were administered nasally to rats in a volume of 100 μl/kg body-weight to obtain a final concentration of 10 IU/kg body-weight of calcitonin. Plasma calcitonin and calcium levels were determined over a period of 3 hours. The results of this study clearly indicated that both Pheroid formulations and the TMC formulation increase the nasal absorption of calcitonin with a resulting decrease in plasma calcium levels, indicating an increased absorption of calcitonin. The highest increase in calcitonin absorption was obtained with the TMC formulation and this was explained by the difference in the mechanism of action in enhancing peptide absorption between TMC and Pheroid technology. It was concluded that Pheroid technology is also a potent system to enhance peptide drug delivery and that the exact mechanism of action should be investigated further. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Over the past couple of years there has been rapid progress in the development and design of safe and effective delivery systems for the administration of protein and peptide drugs. The effective delivery of these type of drugs are not always as simple as one may think, due to various inherent characteristics of these compounds. Due to the hydrophilic nature and molecular size of peptide and protein drugs, such as recombinant human growth hormone, they are poorly absorbed across mucosal epithelia, both transcellularly and paracellularly. This problem can be overcome by the inclusion of absorption enhancers in peptide and protein drug formulations but this is not necessarily the best method to follow. This investigation focussed specifically on the evaluation of the ability of the PheroidTM carrier system to transport recombinant human growth hormone across mucosal epithelia especially when administered via the nasal cavity. The PheroidTM delivery system is a patented system consisting of a unique submicron emulsion type formulation. The PheroidTM delivery system, based on PheroidTM technology, will for ease of reading be called Pheroid(s) only throughout the rest of this dissertation. The Pheroid carrier system is a unique microcolloidal drug delivery system. A Pheroid is a stable structure within a novel therapeutic system which can be manipulated in terms of morphology, structure, size and function. Pheroids consist mainly of plant and essential fatty acids and can entrap, transport and deliver pharmacologically active compounds and other useful substances to the desired site of action. The specific objectives of this study can be summarised as follows: a literature study on Pheroid technology; a literature study on chitosan and N-trimethyl chitosan chloride; a literature study on recombinant human growth hormone (somatropin); a literature study on nasal drug administration; formulation of a suitable Pheroid carrier; entrapment of somatropin in the Pheroid carrier, and in vivo evaluation of nasal absorption of somatropin in Sprague-Dawley rats. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

The present thesis explores the relationship between occupational rhinitis and occupational asthma under the postulates of the "united airways disease" concept that refers to the multiple links observed between rhinitis and asthma. Accordingly, the main objective of this thesis is to demonstrate the concomitant expression of significant changes in nasal patency and bronchial calibre following exposure to occupational agents during specific inhalation challenges, complementing the assessment with the investigation of changes in markers of airways inflammation in nasal lavage. To achieve the objectives, we set up a protocol to diagnose occupational rhinitis and conducted a study from January 2005 to January 2007 at Hopital du Sacre-Coeur de Montreal in subjects undergoing investigation for occupational asthma. The reliability of the main research tools---acoustic rhinometry and nasal lavage---used to investigate occupational rhinitis was tested by analyzing the reproducibility of the methods. Both methods proved sufficiently reproducible to be included in our investigative protocol. The results presented in this thesis demonstrate a joint reaction of the nose and the lungs in a group of study subjects after performing specific inhalation challenge. This supports the concept of a "united airways disease" and its applicability to rhinitis and asthma of occupational origin. However, the results also show that although occupational rhinitis frequently coexists with occupational asthma it can also be present without occupational asthma. The assessment of upper airways inflammation in a subgroup of study subjects by the nasal lavage method allows us to observe significant changes in eosinophils counts after the challenge that correlates with the decrease in nasal patency observed in the same subjects.

The wide variation in infant maxillary morphology and cleft size of children with unilateral cleft lip and palate (UCLP) and isolated cleft palate (CP) raise concerns about their possible influences on treatment outcome. The studies in this thesis aimed to investigate the relation between cleft size in infancy and crossbite at 5 years of age (Paper I); the impact of primary surgery on cleft size and maxillary arch dimensions from infancy to 5 years of age (Paper II); associations between cleft size, maxillary arch dimensions and facial growth in both UCLP and CP children (Paper III); and, to evaluate the relation between infant cleft size and nasal airway size and function in adults treated for UCLP (Paper IV). In homogenously treated groups of children with UCLP and CP, dental casts were used to measure cleft size and maxillary arch dimensions from infancy up to 5 years of age, and for crossbite recording at 5 years. Serial lateral cephalometric radiographs taken between 5 and 19 years of age in the same groups were used to study facial growth. Nasal airway size and function were evaluated by acoustic rhinometry, rhinomanometry, peak nasal inspiratory flow and odour test in a group of adults treated for UCLP. The main findings were: crossbite was a frequent malocclusion at 5 years of age in children with UCLP and large cleft widths at the level of the cuspid points in infancy were associated with less anterior and posterior crossbite in this group (Paper I). Cleft widths decreased after lip closure and/or soft palate closure in both UCLP and CP children. Initially, UCLP children had wider maxillary arch dimensions, but after hard palate closure, the transverse growth was reduced, and at 5 years, they had smaller maxillary arch widths than CP children had (Paper II). Maxillary arch depths and cleft widths in infancy were correlated with maxillary protrusion and sagittal jaw relationships in both UCLP and CP children (Paper III), but cleft width in infancy was not correlated with nasal airway size and function in adults treated for UCLP (Paper IV).

The development of peptides as therapeutic agents has been hampered by their poor enzymatic stability and bioavailability. Many strategies, such as chemical modification, synthesis of peptidomimetics and formulation, have been employed to overcome these issues. For central nervous system (CNS) active peptides, the blood brain barrier is an added hurdle. Nasal delivery is believed to provide a direct access to the brain via the olfactory nerve, which would bypass the blood brain barrier. This route of administration, however, is dependant on the size and physico-chemical properties of the administered drug. For these reasons, three CNS active peptides were chosen as models. Leu-enkephalin, endomorphin-1 and a-conotoxin MII are three peptides that differ in their size, amino acid sequence and conformation. Using chemical modifications to improve their stability and ability to cross biological membranes, in vitro assessments of derivatives of these peptides were performed and in vivo nasal delivery was attempted on the most promising candidates. The chemical modifications consisted in the addition of lipids and/or sugars to the N- or C-terminus of the peptides. Assessment of the in vivo bioavailability after nasal administration, however, proved to be challenging. The initial method chosen for this purpose was the use of tritiated acetic anhydride which would radiolabel the peptide via acetylation at the N-terminus of the peptide derivatives. Consequently, in vitro stability and permeability of each acetylated derivatives was also studied. Acetylation of the lipidic derivatives, which formed an amide bond, proved to be beneficial for the stability of the lipidic peptides. In contrast, acetylation of the Nterminus sugar derivatives, which formed an ester bond at one or several positions of the sugar, was an unstable modification. Thus, an extraction method for the tested peptides from rat tissues was developed, and LC-MS/MS analyses were conducted to measure the level of peptide in the olfactory bulbs, brain and blood. Leu-enkephalin derivatives were all amide derivatives at the C-terminus of the peptide. The most successful Leu-enkephalinamide derivatives were C8-LeuEnk (2), C12- LeuEnk (3) and Lac-LeuEnk (8), which are the Leu-enphelinamide peptide modified with a C8 lipoamino acid, a C12 lipoamino acid and a lactose moiety respectively. They all exhibited improved permeability across Caco-2 monolayers and stability in Caco-2 cell homogenate and/or plasma. Problems of solubility encountered with C12-LeuEnk (3), however, hampered its testing in vivo after nasal administration. C8-LeuEnk (2) and Lac-LeuEnk (8) were administered intranasally to male Sprague-Dawley rats. Both peptides were found in the olfactory bulbs after 10 minutes administration (2: 49.2 ± 15.6 nM; 8: 40.6 ± 14.6 nM) while blood concentration remained low, showing that the peptide reached the olfactory bulbs directly from the nasal cavity via the olfactory nerve. Brain concentrations were 13.5 ± 10.1 nM for C8-LeuEnk (2) and 13.6 ± 6.9 nM for Lac-LeuEnk (8). These two peptides brain concentrations seemed to be high enough to exhibit analgesic effect when compared to their binding affinity in vitro. This was not statistically significant, however, due to the high standard deviations observed (Kiμ C8-LeuEnk (2) = 7.74 ± 1.15 nM; Kiμ Lac-LeuEnk (8) = 6.69 ± 1.81 nM). Endomorphin-1 was only modified at the N-terminus as previous results have shown that the activity of the peptide is strongly decreased by C-terminus modifications. The most successful modification, regarding permeability across Caco-2 monolayers and water solubility, was shown to be the addition of a lactose moiety to the N-terminus of the peptide. Lac-Endo1 (16) exhibited a permeability of 1.91 ± 0.76 x 10-6 cm/s and was soluble at the concentration used for in vivo nasal administration (2 mg/Kg, 50 μL administration). After 10 minutes administration, Lac-Endo1 (16) was found in the olfactory bulbs (418 ± 410 nM), in the brain (4.01 ± 4.61 nM) and in the blood (1.58 ± 1.85 nM). The large standard deviations observed reflect the difficulties encountered with the extraction process of this peptide. A direct transport for the nasal cavity to the olfactory bulb was observed as illustrated by the low blood concentrations. Brain concentrations, however, were too low to expect a strong analgesic effect from this compound after nasal administration (Kiμ Lac-Endo1 (16) = 11.3 ± 1.2 nM). a-Conotoxin MII is a 16 amino acid long peptide containing two disulfide bonds. The formation of these two disulfide bonds leads to low yields in the synthesis of the derivatives of this peptide. Addition of a lipidic moiety to the peptide did not seem to improve its permeability through biological membranes. This modification resulted in highly lipophilic peptides with dissolution issues in water based media such as those used in the permeability experiments. The most successful a-conotoxin MII derivative was GS-Ctx (25) which exhibited a permeability of 4.22 ± 0.53 x 10-7 cm/s across Caco-2 monolayers. This permeability, however, was too low to consider in vivo administration. In conclusion, we successfully synthesised a series of derivatives of Leu-enkephalin, endomorphin-1 and a-conotoxin MII and screened them through Caco-2 monolayers for permeability and Caco-2 cell homogenates and human plasma for stability. Three derivatives (C8-LeuEnk (2), Lac-LeuEnk (8) and Lac-Endo1 (16)) were intranasally administered and found in the olfactory bulbs 10 minutes after administration. The low blood concentrations observed show that a direct transport from the nasal cavity to the brain occurs. Thus, nasal administration could be an option for delivering to the brain low molecular weight peptides exhibiting increased stability and permeability in vitro.

The development of peptides as therapeutic agents has been hampered by their poor enzymatic stability and bioavailability. Many strategies, such as chemical modification, synthesis of peptidomimetics and formulation, have been employed to overcome these issues. For central nervous system (CNS) active peptides, the blood brain barrier is an added hurdle. Nasal delivery is believed to provide a direct access to the brain via the olfactory nerve, which would bypass the blood brain barrier. This route of administration, however, is dependant on the size and physico-chemical properties of the administered drug. For these reasons, three CNS active peptides were chosen as models. Leu-enkephalin, endomorphin-1 and a-conotoxin MII are three peptides that differ in their size, amino acid sequence and conformation. Using chemical modifications to improve their stability and ability to cross biological membranes, in vitro assessments of derivatives of these peptides were performed and in vivo nasal delivery was attempted on the most promising candidates. The chemical modifications consisted in the addition of lipids and/or sugars to the N- or C-terminus of the peptides. Assessment of the in vivo bioavailability after nasal administration, however, proved to be challenging. The initial method chosen for this purpose was the use of tritiated acetic anhydride which would radiolabel the peptide via acetylation at the N-terminus of the peptide derivatives. Consequently, in vitro stability and permeability of each acetylated derivatives was also studied. Acetylation of the lipidic derivatives, which formed an amide bond, proved to be beneficial for the stability of the lipidic peptides. In contrast, acetylation of the Nterminus sugar derivatives, which formed an ester bond at one or several positions of the sugar, was an unstable modification. Thus, an extraction method for the tested peptides from rat tissues was developed, and LC-MS/MS analyses were conducted to measure the level of peptide in the olfactory bulbs, brain and blood. Leu-enkephalin derivatives were all amide derivatives at the C-terminus of the peptide. The most successful Leu-enkephalinamide derivatives were C8-LeuEnk (2), C12- LeuEnk (3) and Lac-LeuEnk (8), which are the Leu-enphelinamide peptide modified with a C8 lipoamino acid, a C12 lipoamino acid and a lactose moiety respectively. They all exhibited improved permeability across Caco-2 monolayers and stability in Caco-2 cell homogenate and/or plasma. Problems of solubility encountered with C12-LeuEnk (3), however, hampered its testing in vivo after nasal administration. C8-LeuEnk (2) and Lac-LeuEnk (8) were administered intranasally to male Sprague-Dawley rats. Both peptides were found in the olfactory bulbs after 10 minutes administration (2: 49.2 ± 15.6 nM; 8: 40.6 ± 14.6 nM) while blood concentration remained low, showing that the peptide reached the olfactory bulbs directly from the nasal cavity via the olfactory nerve. Brain concentrations were 13.5 ± 10.1 nM for C8-LeuEnk (2) and 13.6 ± 6.9 nM for Lac-LeuEnk (8). These two peptides brain concentrations seemed to be high enough to exhibit analgesic effect when compared to their binding affinity in vitro. This was not statistically significant, however, due to the high standard deviations observed (Kiμ C8-LeuEnk (2) = 7.74 ± 1.15 nM; Kiμ Lac-LeuEnk (8) = 6.69 ± 1.81 nM). Endomorphin-1 was only modified at the N-terminus as previous results have shown that the activity of the peptide is strongly decreased by C-terminus modifications. The most successful modification, regarding permeability across Caco-2 monolayers and water solubility, was shown to be the addition of a lactose moiety to the N-terminus of the peptide. Lac-Endo1 (16) exhibited a permeability of 1.91 ± 0.76 x 10-6 cm/s and was soluble at the concentration used for in vivo nasal administration (2 mg/Kg, 50 μL administration). After 10 minutes administration, Lac-Endo1 (16) was found in the olfactory bulbs (418 ± 410 nM), in the brain (4.01 ± 4.61 nM) and in the blood (1.58 ± 1.85 nM). The large standard deviations observed reflect the difficulties encountered with the extraction process of this peptide. A direct transport for the nasal cavity to the olfactory bulb was observed as illustrated by the low blood concentrations. Brain concentrations, however, were too low to expect a strong analgesic effect from this compound after nasal administration (Kiμ Lac-Endo1 (16) = 11.3 ± 1.2 nM). a-Conotoxin MII is a 16 amino acid long peptide containing two disulfide bonds. The formation of these two disulfide bonds leads to low yields in the synthesis of the derivatives of this peptide. Addition of a lipidic moiety to the peptide did not seem to improve its permeability through biological membranes. This modification resulted in highly lipophilic peptides with dissolution issues in water based media such as those used in the permeability experiments. The most successful a-conotoxin MII derivative was GS-Ctx (25) which exhibited a permeability of 4.22 ± 0.53 x 10-7 cm/s across Caco-2 monolayers. This permeability, however, was too low to consider in vivo administration. In conclusion, we successfully synthesised a series of derivatives of Leu-enkephalin, endomorphin-1 and a-conotoxin MII and screened them through Caco-2 monolayers for permeability and Caco-2 cell homogenates and human plasma for stability. Three derivatives (C8-LeuEnk (2), Lac-LeuEnk (8) and Lac-Endo1 (16)) were intranasally administered and found in the olfactory bulbs 10 minutes after administration. The low blood concentrations observed show that a direct transport from the nasal cavity to the brain occurs. Thus, nasal administration could be an option for delivering to the brain low molecular weight peptides exhibiting increased stability and permeability in vitro.

The effect of absorbable packing on the healing of nasal respiratory epthelium after endoscopic sinus surgery (ESS) was examined in a diseased sheep model. Full thickness injuries were created on the lateral nasal wall of sheep infested with Oestrus ovi. Sites of injury were packed on one side with hyaluronic acid (HA) packing or hyaluronic acid packing impregnated with insulin-like growth factor- 1 (HA+IGF1) in a randomized fashion. The opposite side was left unpacked as a control. Biopsies were obtained for light microscopy, scanning electron microscopy, and ciliary beat frequency (CBF) analysis over a period of 16 weeks. Statistical analysis of results was performed in order to determine if any intervention had any impact on healing and to determine if there was any correlation between extent of regeneration as assessed by electron microscopy and CBF. Furthermore assessment of the effect of isotonic and hypertonic saline on ciliary beat frequency was performed in healthy human volunteers. Reepithelialization was increased in the HA+IGF1 group compared to the HA group and controls at eight weeks after injury but not at later time points. Cilial regeneration was improved in the HA+IGF1 group compared to the HA group and controls at 16 weeks. CBF was noted to be worse at the eight week time point with the HA+IGF1 group compared to the HA group and controls, but no other statistically significant effects on CBF were noted. This most likely represents a spurious finding. Wide distributions of CBF results were noted, reflecting numerous missing data points due to methodological difficulties. There was a trend noted toward increased CBF with improved grades of reciliation, although this correlation was not statistically significant. However this trend was supported by the finding of statistically significant differences between individual and combined grades of reciliation. Hypertonic saline was found to have a ciliostimulatory effect when compared to normal saline at 5 minutes after administration in healthy human subjects. This effect had disappeared by 60 minutes after administration. It is suggested that the presence of insulin-like growth factor- 1 at the time of mucosal injury improves epithelial regeneration in the short term, but is not sufficient for this effect to be sustained. This improved early epithelial regeneration forms a foundation for cilial regeneration, as is reflected in an improved grade of reciliation at 16 weeks. Our interventions had no effect on CBF, and various experimental problems made it difficult to provide further comment on CBF results. There is evidence that CBF improves as the grade of cilial regeneration improves following ESS. Furthermore, hypertonic saline appears to also have a positive impact on CBF, which is likely to reflect changes in the rheological properties of mucous. A number of possible avenues of enquiry are delineated and recommendations for future research are outlined. / Thesis (M.S.)--Department of Surgery, 2005.