PubMed · 9361848
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D Kritchevsky. 1997. Phytosterols.. https://doi.org/10.1007/978-1-4615-5967-2_24
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The ability to tailor the release profile of a drug by manipulating its formulation matrix offers important therapeutic advantages. We show here that human insulin can be cocrystallized at preselected ratios with the fully active lipophilically modified insulin derivative octanoyl-N(epsilon)-LysB29-human insulin (C8-HI). The cocrystal is analogous to the NPH (neutral protamine Hagedorn) crystalline complex formed with human insulin, which is commonly used as the long-acting insulin component of diabetes therapy. The in vitro and in vivo release rates of the cocrystal can be controlled by adjusting the relative proportions of the two insulin components. We identified a cocrystal composition comprising 75% C8-HI and 25% human insulin that exhibits near-ideal basal pharmacodynamics in somatostatin-treated beagle dogs. The dependence of release rate on cocrystal ratio provides a robust mechanism for modulating insulin pharmacodynamics. These findings show that a crystalline protein matrix may accommodate a chemical modification that alters the dissolution rate of the crystal in a therapeutically useful way, yet that is structurally innocuous enough to preserve the pharmaceutical integrity of the original microcrystalline entity and the pharmacological activity of the parent molecule.
A self-contained, microelectrochemical immunoassay on the smallest volumes reported to date (1 microL for the antigen, 1 microL for the secondary antibody-enzyme conjugate, and 200 nL for the electrochemically detected species) has been developed using mouse IgG as a model system in a sandwich-type enzyme-linked immunosorbant assay, which takes less than 30 min to both complete the assembly of immunoassay components onto the antibody-modified surface and detect enzymatically generated species (excluding time for electrochemical cleaning of electrodes). These studies demonstrate the advantage of the close proximity of electrodes to modified surfaces and their application in the analysis of small volumes. Using a 50 microm diameter x 8 microm deep cavity with individually addressable electrodes on a microfabricated chip, the primary antibody was selectively and covalently attached at a gold, recessed microdisk (RMD) at the bottom of the microcavity to the free end of SAMs of either 11-mercaptoundecanoic acid or 11-mercapto-1-undecanol using 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride. Nonspecific adsorption to the surrounding material, polyimide, of the microcavity device was eliminated. Electrochemical desorption was used to confine the immunoassay activity at the RMD. Enzymatic conversion of the substrate p-aminophenyl phosphate top-aminophenol is detectable in less than 30 s using cyclic voltammetry at a gold, tubular nanoband electrode, which is on the wall of the microcavity and immediately adjacent to the modified RMD. A third electrode, also within the region of the microcavity, served as the pseudoreference/auxiliary electrode. Calibration curves obtained for 1-microL solutions of 5-100 ng/mL of IgG and for 200 nL-solutions of 5 microM to 4 mM of PAPR gave detection limits of 4.4 nM (6.4 ng/mL) or 880 fmol (129 pg) for PAPR and 56 fM (9 pg/mL) or 56 zmol (9 fg) for IgG. It is expected that the device may be suitable for analysis with volumes down to tens of picoliters.
Ultraviolet B (UVB) radiation has been hypothesized as a potential cause of amphibian population declines and increased incidence of malformations. Realistic studies documenting UV irradiance or dose have rarely been conducted in wetlands used by amphibians. Our data indicates that 99% of UVB is attenuated in the top 5-20 cm of wetlands in our study region (northern Minnesota and Wisconsin). Furthermore, vegetation and other habitat features have substantial impacts on local UVB irradiance levels and dose. UVB attenuation in the water columns of our wetlands is controlled by the specific absorption of dissolved organic carbon (DOC), and consequently, UVB attenuation is best predicted by simple laboratory absorbance measurements such as bulk water color (absorbance at 440 nm) or wavelength-specific absorbance coefficients. Seasonal data indicate thatthe UVB absorption by early and mid-season DOC is higher than that of late summer and fall DOC, suggesting increased protection from UVB during the potentially sensitive stages of amphibian development. In addition to dissolved components, our model indicates that suspended solids play a small role in UVB attenuation in our wetlands but apparently only at high concentrations. Models predicting UV attenuation in wetlands should be used cautiously and should consider temporal variability, given the volatility and dynamic nature of water column characteristics in wetlands. Organism behavior is a critical but poorly understood phenomenon that must be addressed for development of an accurate UV exposure risk model for amphibians.