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We have used small-angle neutron scattering (SANS) to probe the structure and interparticle interactions of lecithin-taurodeoxycholate mixed micelles. The data are fit to a core-shell model that provides the micelle composition and dimensions. The effects on the scattering spectra of electrostatic and excluded-volume interactions are explored in terms of the decoupling approximation (Kotlarchyk, M.; Chen, S.-H. J. Chem. Phys. 1983Phys. ,79, 2461 and the random phase approximation (Shimada, T.; Doi, M.; Okano, K. J. Chem. Phys. 1988,88,28 15).We found the TDC-lecithin micelles are cylindrical particles with an average cross-sectional radius of 26.7 f 0.4 A. The coreshell structure is found to be an appropriate model for the highly hydrated micelles. The micelle length increases dramatically with an increase in added electrolyte, but not with decreasing concentration as previously reported. The SANS data analysis shows that particles in 0.05 M NaCl grow by less than 15% with a 3-fold decrease in the total surfactant concentration. This is in contrast to the simple interpretation of dynamic light scattering of the same samples that shows an apparent doubling of the micelle length with the same decrease in surfactant concentration. This discrepancy is attributed to neglect of the thermodynamic and hydrodynamic interactions in the analysis of the dynamic light scattering data. Corrections for the thermodynamic interactions are determined from the static data and applied to the interpretation of dynamic light scattering measurements. The strength of hydrodynamic and entanglement interactions is also discussed in relation to existing models for both semidilute polymer solutions and spherical particles.Lecithin and bile salt are the two major cholesterol-solubilizing agents found in gallbladder bile. Lecithin is a double-tailed zwitterionic surfactant well-known for its tendency to form bilayers in solution. Bile salts are derived from cholesterol, and the four fused rings of the steroid backbone impose a "planar" structure on the surfactant. One face of the bile salt molecule is hydrophobic, while the other face is hydrophilic because of the presence of hydroxyl groups. Bile salt species differ in the number and position of hydroxyl groups and conjugation of the short hydrophilic tail with taurine or glycine. Like other surfactants, most bile salts self-associate to form either globular or cylindrical micelles.14 In gallbladder and hepatic bile, lecithin and bile salt together will form mixed aggregates (micelles or vesicles) that solubilize cholesterol.The liver continuously produces hepatic bile, which is a dilute (3 g/dL) solution of lecithin, bile salt, and cholesterol. In hepatic bile the insoluble cholesterol is carried by unilamellar, lecithinrich vesicles.s When bile is not needed for digestion, it is stored in the gallbladder for future use. Water is extracted during storage, and the resulting high concentrations of bile salt drive a microstructural transition from vesicular aggregates to mixed micelles of le...

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

Using Ic the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation.

A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log 10 copies RNA/ml for genotype 1a-and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.Hepatitis C virus (HCV) is a small, enveloped virus that contains a single-stranded, positive-sense RNA (2). The World Health Organization estimates that approximately 170 million people worldwide are infected with HCV (25). Of these, 130 million are chronic HCV carriers at risk for the development of liver cirrhosis and/or liver cancer. In the United States, HCV infection leading to liver failure is the major indication for liver transplantation (4, 12). The current standard of care, which consists of a combination of pegylated interferon and ribavirin, provides good clinical efficacy for patients infected with genotype 2 and 3 viruses but is less effective for patients infected with genotype 1 viruses. Subgenotypes 1a and 1b constitute the most commonly found isolates in the United States, Japan, and Western Europe; and thus, the development of effective treatments against genotype 1 viruses presents a pressing need.HCV nonstructural protein 5B (NS5B) encodes a viral RNA-dependent RNA polymerase, an essential enzyme responsible for the replication of the viral genome. NS5B shares very limited sequence homology with cellular polymerases; hence, it is an attractive target for the development of antiviral therapy. Several classes of inhibitors, including nucleosides, nonnucleosides, and pyrophosphate mimics, that target t...