Uptake and transport of orally-deliverable drugs across caco-2 cell monolayers:the effect of lipid formulations

The aim of this thesis is to investigate the physicochemical parameters which can influence drug loading within liposomes and to characterise the effect such formulations have on drug uptake and transport across in vitro epithelial barrier models. Liposomes composed of phosphatidylcholine (PC) or distearoyl phosphatidylcholine (DSPC) and cholesterol (0, 4, 8, 16 µM) were prepared and optimised in terms of drug loading using the hand-shaking method (Bangham et al., 1965). Subsequently, liposomes composed of 16 µM PC or DSPC and cholesterol (4 µM) were used to monitor hydroxybenzoate release and transport from Iiposomes. The MIT (3[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) and crystal violet assays were employed to determine toxicity of the Iiposome. formulations towards the Caco-2 cell line, employed to model the epithelial barrier in vitro. Uptake and transport of mannitol, propranolol, glutamine and digoxin was measured in the presence and absence of Iiposome formulations to establish changes in absorption resulting from the presence of lipid formulations. Incorporation of the four hydroxybenzoates was shown to be influenced by a number of factors, including liposome composition and drug conformation. Methyl hydroxybenzo.ate (MP) was incorporated into the bilayer most effectively with percentage incorporation of 68% compared to 45% for butyl hydroxybenzoate (BP), despite its increased Iipophilicity. This was attributed to the decreased packing ability of BP within the hydrocarbon core of the lipid bilayer compared to MP. Release studies also suggested that the smaller MP was more strongly incorporated within the lipid bilayer with only 8% of the incorporated solute being released after 48-hours compared to 17% in the case of BP. Model transport studies were seen to reflect drug release profiles from the liposome bilayers with significantly (p < 0.01) higher amounts of BP partitioning from the liposome compared to MP, Caco-2 cell viability was maintained above 86% in the presence of all Iiposome formulations tested indicating the liposome formulations are non-toxic towards Caco-2 cells. Paracellular (apical-to-basolateral) transport of mannitol was significantly increased in the presence of DSPC, PC / DSPC:Cholesterol (16:4 µM; 1000 µg). Glutamine uptake and transport via the carrier-mediated route was Significantly (p < 0.01) increased in the presence of PC I DSPC:Cholesterol (16:0; 16:4 µM). Digoxin apical-to-basolateral transport was significantly increased (p < 0,01) in the presence of PC / DSPC:Cholesterol (16:0; 16:4 µM); thus reducing digoxin efflux via P-glycoprotein. In contrast, PC:ChoJesterol (16:0; 16:4 µM) significantly (p < 0.01) decreased propranolol uptake via the passive transcellular route. Bi-directional transport of propranolol was significantly (p < 0,01) decreased in the presence of PC/DSPC:Cholesterol (16:0; 16:4 µM). The structure of a solute is an important determinant for the incorporation and release of a solute from liposome formulations. PC, DSPC and cholesterol liposome formulations are nontoxic towards Caco-2 cell monolayers and improved uptake and transport of mannitol, glutamine. and digoxin across Caco-2 cell monolayers; thus providing a potential alternative delivery vehicle.

Gold mineralisation in the Caledonides of the British Isles with special reference to the Dolgellau Gold-belt, North Wales and the Southern Uplands, Scotland. Available in 2 volumes.

Two aspects of gold mineralisation in the Caledonides of the British Isles have been investigated: gold-telluride mineralisation at Clogau Mine, North Wales; and placer gold mineralisation in the Southern Uplands, Scotland. The primary ore assemblage at Clogau Mine is pyrite, arsenopyrite, cobaltite, pyrrhotine, chalcopyrite, galena, tellurbismuth, tetradymite, altaite, hessite, native gold, wehrlite, hedleyite, native bismuth, bismuthunite and various sulphosalts. The generalised paragenesis is early Fe, Co, Cu, As and S species, and later minerals of Pb, Bi, Ag, Au, Te, Sb. Electron probe micro-analysis (EPMA) of complex telluride-sulphide intergrowths suggests that these intergrowths formed by co-crystallisation/replacement processes and not exsolution. Minor element chemical variation, in the sulphides and tellurides, indicates that antimony and cadmium are preferentially partitioned into telluride minerals. Mineral stability diagrams suggest that during gold deposition log bf aTe2 was between -7.9 and -9.7 and log bf aS2 between -12.4 and -13.8. Co-existing mineral assemblages indicate that the final stages of telluride mineralisation were between c. 250 - 275oC. It is suggested that the high-grade telluride ore shoot was the result of remobilisation of Au, Bi, Ag and Te from low grade mineralisation elsewhere within the vein system, and that gold deposition was brought about by destabilisation of gold chloride complexes by interaction with graphite, sulphides and tellurbismuth. Scanning electron microscopy of planer gold grains from the Southern Uplands, Scotland, indicates that detailed studies on the morphology of placer gold can be used to elucidate the history of gold in the placer environment. In total 18 different morphological characteristics were identified. These were divided on an empirical basis, using the relative degree of mechanical attrition, into proximal and distal characteristics. One morphological characteristic (a porous/spongy surface at high magnification) is considered to be chemical in origin and represent the growth of `new' gold in the placer environment. The geographical distribution of morphological characteristics has been examined and suggests that proximal placer gold is spatially associated with the Loch Doon, Cairsphairn and Fleet granitoids. Quantitative EPMA of the placer gold reveals two compositional populations of placer gold. Examination of the geographical distribution of fineness suggests a loose spatial association between granitoids and low fineness placer gold. Also identified was chemically heterogeneous placer gold. EPMA studies of these heterogeneities allowed estimation of annealing history limits, which suggest that the heterogeneities formed between 150 and 235oC. It is concluded, on the basis of relationships between morphology and composition, that there are two types of placer gold in the Southern Uplands: (i) placer gold which is directly inherited from a hypogene source probably spatially associated with granitoids; and (ii) placer gold that has formed during supergene processes.

Highly sensitive, localized surface plasmon resonance fiber device for environmental sensing, based upon a structured bi-metal array of nano-wires

We demonstrate a bi-metal coated (platinum and gold or silver), localized surface plasmon resonance fiber sensor with an index sensitivity exceeding 11,900 nm/RIU, yielding an index resolution of 2 × 10-5 in the aqueous index regime. This is one of the highest index sensitivities achieved with an optical fiber sensor. The coatings consist of arrays of bi-metal nano-wires (typically 36 nm in radius and 20 μm in length), supported by a silicon dioxide thin film on a thin substrate of germanium, the nano-wires being perpendicular to the longitudinal axis of the D-shaped fiber.

Presbyopic LASIK using hybrid bi-aspheric micro-monovision ablation profile for presbyopic corneal treatments

Purpose: To evaluate distance and near image quality after hybrid bi-aspheric multifocal central presbyLASIK treatments. Design: Consecutive case series. Methods: Sixty-four eyes of 32 patients consecutively treated with central presbyLASIK were assessed. The mean age of the patients was 51 ± 3 years with a mean spherical equivalent refraction of-1.08 ± 2.62 diopters (D) and mean astigmatism of 0.52 ± 0.42 D. Monocular corrected distance visual acuity (CDVA), corrected near visual acuity (CNVA), and distance corrected near visual acuity (DCNVA) of nondominant eyes; binocular uncorrected distance visual acuity (UDVA); uncorrected intermediate visual acuity (UIVA); distance corrected intermediate visual acuity (DCIVA); and uncorrected near visual acuity (UNVA) were assessed pre- and postoperatively. Subjective quality of vision and near vision was assessed using the 10-item Rasch-scaled Quality of Vision and Near Activity Visual Questionnaire, respectively. Results: At 1 year postoperatively, 93% of patients achieved 20/20 or better binocular UDVA; 90% and 97% of patients had J2 or better UNVA and UIVA, respectively; 7% lost 2 Snellen lines of CDVA; Strehl ratio reduced by ~-4% ± 14%. Defocus curves revealed a loss of half a Snellen line at best focus, with no change for intermediate vergence (-1.25 D) and a mean gain of 2 lines for near vergence (-3 D). Conclusions: Presbyopic treatment using a hybrid bi-aspheric micro-monovision ablation profile is safe and efficacious. The postoperative outcomes indicate improvements in binocular vision at far, intermediate, and near distances with improved contrast sensitivity. A 19% retreatment rate should be considered to increase satisfaction levels, besides a 3% reversal rate.