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Directly compressed sustained release pellets were prepared from material consisting of a molecule of 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) covalently linked via carbonate moieties to two molecules of 5-flourouracil (5FU) to form a novel THS-BIS-5FU codrug for the treatment of angiogenesis. Dissolution and drug release was tested in vitro in 0.1M phosphate buffer (pH 7.4), human serum, and vitreous humor. The results suggest that neat THS-BIS-5FU codrug pellets are useful for sustained release ocular delivery of the parent compounds, and that the unique physicochemical properties of the codrug allow slow dissolution and rapid release of the two parent drugs. This codrug formulation is regarded as a "chemical delivery" system that involves dissolution of the codrug as the rate-limiting step followed by rapid hydrolysis of the carbonate ester linkages to release the parent drugs via sustained delivery.

We consider the thermally driven motion of a microcantilever in a fluid environment near a wall, a configuration characteristic of the atomic force microscope. A theoretical model is presented which accounts for hydrodynamic interactions between the cantilever and wall over a wide range of frequencies and which exploits the fluctuation-dissipation theorem to capture the Brownian dynamics of the coupled fluid-cantilever system. Model predictions are tested against experimental thermal spectra for a cantilever in air and water. The model shows how, in a liquid environment, the effects of non-delta-correlated Brownian forcing appear in the power spectrum, particularly at low frequencies. The model also predicts accurately changes in the spectrum in liquid arising through hydrodynamic wall effects, which we show are strongly mediated by the angle at which the cantilever is tilted relative to the wall.

Intraocular neovascularization is a complication in a variety of eye diseases, and is a leading cause of visual loss. The purpose of this study was to design and synthesize three novel codrugs of the antiangiostatic steroid, 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) with the cytotoxic agent 5-fluorouracil (5FU) which incorporates either one or two molecules of 5FU attached through carbonate ester linkages at positions O(3), and/or O(21) of the THS molecule. Furthermore, a kinetic study of the O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyL) 17alpha-hydroxy-5beta-pregnan-20-one (THS-BIS-5FU) codrug was carried out. The overall goal of this codrug strategy was to improve sustained drug delivery of both compounds by overcoming their individual solubility problems, and to thus enhance their bioavailability. The codrug was found to be optimal with superior angiostatic activity using the CAM assay compared to the activity of the parent compounds alone. In the hydrolysis studies 5FU was released at a faster rate than THS with an unknown intermediate observed by HPLC, a rationale and proposed structure and mechanism of the unknown THS derivative is provided.

A morphological interpretation is presented for data collected during growth of a filamentous organism, using a focused beam reflectance measurement (FBRM) system. The morphology of the organism was also obtained using conventional semiautomatic image analysis to support the interpretation of the FBRM data. The model organism employed is the filamentous soil-borne actinomycete Streptomyces natalensis, which produces the antifungal agent pimaricin. The organism was cultivated both in shake flasks and in a bench-scale stirred tank bioreactor. It was found that FBRM could be used to track changes in the morphology of the organism throughout the course of its growth on both scales. These changes were highlighted using both the median chord length and length-weighted mean chord length obtained from the chord length distribution measured with the FBRM probe. The ability of the FBRM probe to respond to changes in both the size and morphology of mycelial aggregates was supported by standard image analysis parameters, including equivalent diameter, convex area, and compactness.