Syntheses and biological evaluation of potentially active sydnone analogues

Dunkley, Christopher S University of the Sciences in Philadelphia 2005 해외박사(DDOD)

A series of mesoionic compounds (sydnones) were synthesized and evaluated for anticancer and anti-inflammatory activities. The first series of sydnones was designed as potential anti-cancer drugs based on two lead compounds developed by Grynberg et al. Another series of sydnones was designed as potential anti-inflammatory agents based on structural similarities between sydnones and rofecoxib and celecoxib. All compounds were evaluated for anti-cancer activity at the National Cancer Institute (NCI).

Effect of higher prescription co-payments on clinical outcomes in patients with hypercholesterolemia in a managed care organization

Al-Zakwani, Ibrahim S University of the Sciences in Philadelphia 2005 해외박사(DDOD)

Prescription cost-sharing mechanisms have been demonstrated to reduce prescription utilization and expenditures. However, the literature evaluating the impact of prescription cost-control on actual clinical outcomes is largely unexplored. The aim of this research was to evaluate the effect of higher prescription co-payments on clinical outcomes in patients with hypercholesterolemia in a managed care organization. A retrospective, observational cohort analysis was conducted of pharmacy, medical, and laboratory claims database from a southeastern US health plan. Patients were included if they began statin therapy between 7/1/1999 and 6/30/2001, had no dyslipidemic therapy in the previous 6 months, had continuous health plan enrollment 6 months pre-index and 12 months post-index, and had both pre- and post-index lipid measurements. Patients were stratified into higher (≥$20) and lower (<$20) prescription co-payment cohorts. The primary endpoints were mean percent change in each of the lipid fractions (total cholesterol [TC], LDL-cholesterol [LDL-C], HDL-cholesterol [HDL-C], and triglycerides [TG]), NCEP-ATP-III (National Cholesterol Education Program) LDL-C goal attainment, and time to development of major adverse cardiac event (MACE). Statistical analyses were conducted using ordinary least squares, logistic, and Cox proportional hazard regression. A total of 5,476 patients were identified (<$20 = 3,157; ≥$20 = 2,319). The higher prescription co-payment cohort was associated with a significantly greater adjusted mean percent reduction in LDL-C (-26.2% vs. -25.2%; p = 0.022) and a significantly greater adjusted mean percent increase in HDL-C (1.6% vs. 0.7%; p = 0.039) when compared to the lower prescription co-payment group. There were no significant differences in mean percent change in TC and TG as well as NCEP-ATP-III LDL-C goal attainment rates between the groups. However, patients in the higher prescription co-payment cohort were associated with higher MACE events compared to those in the lower prescription co-payment group (HR 1.37; 95% CI: 1.02 to 1.85; p = 0.36). These findings indicate an association between prescription cost-sharing and the most important outcome measure of all, actual cardiac events. However, the non-significant and counterintuitive findings of the intermediate lipid laboratory outcomes as well as the potential limitations, call for substantial further research into the relationship between prescription co-payment and MACE before any definitive conclusions are made.

Characterization of blended PLGA:PEG scaffolds for bone regeneration applications

Forcino, Rachel Graves University of the Sciences in Philadelphia 2007 해외공개박사

Biodegradable PLGAs have been widely investigated for use as tissue engineering devices, however, limitations include: insufficient porosity, low mechanical strength, immunogenicity, heterogeneous degradation, and low cell affinity. This research investigated the potential advantages of fabricating scaffolds by blending PLGA with PEG to deliver rhBMP-2 for bone regeneration applications. The manufacturing process was found to be the most significant factor influencing the thermo-mechanical properties of the scaffolds regardless of the concentration and molecular weight of PEG used. Blended PLGA:PEG scaffolds fabricated using compression, heat-molding, and high molecular weight PEGs (10 and 20 kDa) had sufficient mechanical strength for bone scaffolding applications as shown by a compressive modulus comparable to trabecular bone. Thermal properties of the scaffolds showed that amorphous solid-state miscibility was not responsible for changes in mechanical strength, however changes in melting temperatures was dependent on fabrication method. We demonstrated the ability to use blending and fabrication processes to design biodegradable scaffolds for a range of biomedical applications. Combinations of initial processes were used to design strong and uniform devices that demonstrated minimal in vitro immune response. With high moduli and plastic deformation the modified, compressed scaffolds showed significant promise for use as bone regenerating devices. The adhesion of macrophages to PLGA scaffolds was dependent upon method of fabrication as well as blending with PEG. The presence of PEG in the polymeric scaffolds reduced macrophage attachment in all blends compared to PLGA controls. We established that the modified compression method produced scaffolds demonstrating mechanical strength similar to bone as well as reduced macrophage attachment. To further characterize the modified compression method, in vitro degradation as well as preosteoblast attachment and differentiation in the presence of rhBMP-2-containing scaffolds was studied. The degradation rate of PLGA scaffolds was slowed significantly during weeks 1 and 2 by blending PLGA with PEG, attributable to reduced acid-catalyzed degradation. Upon incubation with preosteoblasts, the PLGA:BMP formulation was the only scaffold to demonstrate increased ALP activity. We showed that PEG and rhBMP-2 inclusion in PLGA scaffolds was able to alter degradation rate, thermo-mechanical properties, preosteoblast attachment, and preosteoblast ALP production.

Chiral separation of pharmaceutical compounds by capillary electrophoresis using cyclodextrins

Goel, Thanh V University of the Sciences in Philadelphia 2005 해외박사(DDOD)

Capillary electrophoresis (CE) has proven to be an invaluable tool for chiral separations. Since the introduction of the first commercial CE instrument a decade ago, its applications have become widespread. Today, CE is a versatile analytical technique which is successfully used for the separation of small ions, neutral molecules as well as large biomolecules. The advantages of this method over high-performance liquid chromatography (HPLC), gas chromatography (GC), and gel electrophoresis include high efficiency and fast separations, relatively inexpensive and long lasting capillary columns, small sample size requirements, and low reagent consumption. Herein, the chiral resolution of various model pharmaceutical compounds was investigated using various single-isomer cyclodextrins. The successful coupling of CE to tandem mass spectrometric detection was also explored. Furthermore, the solid-phase extraction of representative compounds was examined in biological matrices. Chapter 2 reports the use of cyclodextrins as a chiral additive for the enantiomeric separation of model pharmaceutical compounds. Importantly, the impact of derivatized cyclodextrins (CDs) in the background electrolyte (BGE) was critically evaluated. Chapter 3 investigates the effects of coupling capillary electrophoresis to mass spectrometry (CE-MS). Compatibility factors as well as different interfaces were explored. The combination of these two powerful analytical techniques is especially amenable to the analysis of analytes with limited sample quantities which is frequently important when analyzing biological matrices. Chapter 4 examines the chiral separation of labetalol with multiple stereogenic centers. Data illustrating the effects of capillary length and cyclodextrin concentration on the separation are presented. The optimized method was applied to the analysis of human control plasma containing labetalol utilizing solid-phase extraction (SPE) in the 96-well format. Similarly, Chapter 5 investigates the use of single-isomer cyclodextrins on the chiral separation of timolol enantiomers in biological matrices by CE-MS. Finally, in Chapter 6 a library representing chiral separations of model pharmaceutical compounds are reported. The results illustrate the complete profile of selectivity and sensitivity for each compound in the various cyclodextrin BGEs and at various concentrations and pH ranges. The single-isomer CD chiral selectors, heptakis-(2,3-dihydroxy-6-sulfato)-beta-CD (HS-beta-CD), heptakis-(2,3-diacetyl-6-sulfato)-beta-CD (HDAS-beta-CD), and heptakis-(2,3-dimethyl-6-sulfato)-beta-CD (HDMS-beta-CD) all proved to be applicable towards the chiral separation of representative acids, bases, and neutrals. (Abstract shortened by UMI.).

The application of coarse particle ethylcellulose and high molecular weight polyethylene oxide in the production of beads by extrusion-spheronization

Mallipeddi, Rama University of the Sciences in Philadelphia 2009 해외공개박사

The present investigation evaluated the potential of coarse particle ethylcellulose (CPEC) and high molecular weight polyethylene oxide (PEO) in the production of beads by an extrusion-spheronization technique. CPEC was investigated as a diluent and PEO as an extrusion aid and a binder. Beads containing CPEC, PEO, and microcrystalline cellulose (MCC) with caffeine as a model drug were manufactured. To compare the effects of particle size of ethylcellulose on properties of the beads, CPEC was substituted with fine particle ethylcellulose (FPEC) in the formulation. Release studies were conducted, and the bead size, shape, yield, and friability were determined. The effects of formulation and process variables and their interactions were studied by a sequential experimental design based on a response surface method. In the initial stage, a two-level, half-fractional factorial design was employed as a screening design, which was subsequently augmented to a central composite design (CCD). Statistical analysis indicated that formulation variables including PEO, MCC, and water content, and two process variables, namely spheronizer speed and spheronization time, significantly affected the properties of the beads. Interactions between two factors have significant effects on several of the measured responses. Simultaneous optimization of the responses was conducted and validated by performing experiments at the optimal conditions. Use of either particle size resulted in beads with acceptable properties. However, CPEC formulations required less water to form a wetted mass suitable for extrusion and showed better tolerance to changes in the water content when compared to FPEC formulations. The friability of the beads produced was less than 2% in either case, although FPEC beads had slightly lower friability values when compared to CPEC beads. Alteration in the drug load from 10% to 70% in the formulation still yielded acceptable product, indicating the suitability of the formulation for a wide range of drug levels. Release profiles showed that there was immediate release of the drug from the beads. Keywords. Ethylcellulose, polyethylene oxide, extrusion, spheronization, beads, factorial design, response surface method, central composite design, optimization.