This Dissertation presents a number of projects and novel ideas related to pharmaceutical solution chemistry, including: combination solubilization and formulation techniques, predictive modeling methods, and experimentally demonstrated complexation theory. Chapter 1 presents both the underlying theory and experimental results of a formulation project for a novel anticancer drug which resulted in an 8,000-fold increase in solubility. Chapter 2 presents an extensive computer and literature-based predictive model for the estimation of cosolvent solubilization. Finally, Chapter 3 presents an exhaustive theoretical derivation with experimental validation of a novel method to determine complexation stability constants in mixed stoichiometric systems of cyclodextrin complexes.

Currently, the National Cancer Institute is investigating RH1 for its potential use as an anti-tumor agent. A parenteral formulation is desired but the drug is highly unstable in aqueous solutions. Various effects on the stability of RH1 are investigated. All the reactions of RH1 follow first-order kinetics. The maximum shelf-life, obtained in neutral conditions, is about one week. The pH-rate profile shows slopes of approximately -1 in acidic conditions and +1 in basic conditions indicating that the degradation of RH1 is specific acid-base catalyzed. The energies of activation at pH's 6.0 and 7.0, and 8.0 confirm a difference in the mechanisms of decomposition in acid and base. No significant effect of light or anti-oxidants is seen in either acidic or basic solutions, however, the chelating agent (EDTA) significantly slows the degradation of RH1. Use of pure ethanol increased the stability four times that over the buffered solution at pH 7.33 resulting in a shelf-life of approximately one month. Four major degradation products are observed in acid pH. The results of LC-MS suggests that the degradation of RH1 involves hydrolysis of the aziridine rings to form the mono-ethanolamine derivative (degradation product I). The second reaction involves nucleophilic substitution of the aziridine ring(s) by hydroxyl groups to form mono-hydroxy derivatives. Depending upon which aziridine ring is hydrolyzed, two additional degradation product (II and III) can be formed. Two isomers are possible for the three proposed decomposition products. The absence of any degradation products with molecular masses expected from the reaction of both the aziridines suggests that one of the isomers is preferentially formed. This is most likely due to the fact that the C2 aziridine nitrogen can form a hydrogen bond with the neighboring methyl hyroxy group, making it less reactive. A freeze-dried formulation buffered at pH 7.0 containing 5% hydroxypropyl-beta-cyclodextrin that can be reconstituted with a buffer (pH 7.0) is recommended for parenteral use. A prodrug, 2,5-diaziridinyl-3,6-dihydroxymethyl-1,4-benzoquinone, is proposed based upon the fact that two hydrogen bonds between the hydroxymethyl groups and aziridine nitrogens will be possible that may lead to improved stability of the drug.

Congestive heart failure (CHF) represents the end-stage of all heart disease. The current incidence of CHF in the US is 550,000 cases per year and is expected to increase in the future. Therapy with β-blockers, ACE inhibitors, and digoxin has been associated with a decreased risk of all-cause hospitalization and CHF-related hospitalization in randomized clinical trials. The purpose of this study was to evaluate the effect of beta-blocker, ACE inhibitor, and digoxin therapy on these outcomes and total direct medical costs among patients with CHF enrolled in a managed care plan. Neither therapies were associated with a statistically significant reduction in CHF-related hospitalizations. ACE inhibitor therapy (180 days) was associated with a significant decrease (34.7 percent, p < 0.0001) in the risk of all-cause hospitalization and lower total direct medical costs ($2135, p < 0.001) over a one year period. The results suggest increased use of ACE inhibitors is warranted.

Plan for the investigation of pharmacokinetics of amphotericin B (AmB) in rats. The disposition kinetics of AmB as a function of dose was characterized in this research project to improve the therapeutic usage of this drug. Male Sprague-Dawley rats were randomly divided into three different dose groups, receiving high, medium and low dose of AmB. Serum samples and urine samples were collected and assayed by HPLC. There are no significant differences for half-life, volume of distribution or systemic clearance as a function of dose. However, renal clearance decreases when the total infused dose increases. Creatinine clearance decreases significantly in the high dose group, suggesting the occurrence of nephrotoxicity. We conclude that volume of distribution and systemic clearance are linear over the dose range studied. The dose-dependent renal clearance may be due to either the nephrotoxicity associated with AmB or saturable secretion.

Antibiotic misuse and overuse increase health care costs while promoting antibiotic resistance. The identification of physician characteristics predictive of poor antibiotic prescribing could enable targeted educational interventions before physicians' entry into practice. / The objective of this study was to assess whether physicians' medical school training, licensure examination scores, and time in practice could predict antibiotic prescribing behaviour. / A historical cohort consisting of 912 physicians who obtained certification in 1990--1993 and subsequently entered fee-for-service practice in Quebec, and the 4,258,362 patients they saw during 1990--1998 was used. Multivariate logistic regression analyses for clustered data were performed. / Foreign medical graduates were more likely to prescribe antibiotics for viral respiratory infections (RRadjusted 1.78, 95%CI 1.30, 2.44). Physicians who scored higher on the Medical Council of Canada Qualifying Examination were more likely to prescribe newly marketed antibiotics (RRadjusted 1.19, 95%CI 1.07, 1.33). The likelihood of unnecessary and inappropriate antibiotic prescribing increased with practice experience.

<p> The pace of globalization continues to accelerate, which is demanding new approaches to leadership. One area where global mergers, acquisitions, alliances, and partnerships have become commonplace is in the pharmaceutical industry. This growing globalization has made it significantly more important to understand how culture impacts and influences effective leadership. Outstanding global leadership will continue to be a business imperative for the future. </p><p> This study used a mixed-method approach to identify the characteristics and behaviors that contribute to outstanding global leadership and to recommend methods for developing these characteristics. For the quantitative portion of the study, the GLOBE Research Survey was administered to mid-level leaders in a global pharmaceutical company. The qualitative portion of the study included semi-structured interviews with a smaller set of participants from the original sample group. </p><p> The quantitative survey indicated that the characteristics of integrity, performance-oriented, inspirational, visionary, and decisive strongly contribute to outstanding global leadership. The qualitative interviews supported these findings and offered recommendations on how to develop these characteristics, including the implementation of role models, feedback, coaching, learning environments, and culturally diverse opportunities. </p><p> This study provides preliminary evidence that there are specific characteristics that contribute to outstanding global leadership. The results of this study may be used to contribute to the success of global corporations, specifically in the pharmaceutical industry.</p>

Poly(propylene fumarate) (PPF) was developed as a scaffold to guide bone regeneration. Synthesis of this material via refined reaction pathways led to increased purity and higher molecular weights of this unsaturated, linear polyester. Due to its unsaturated nature, PPF can be formulated as an injectable composite through the incorporation of a vinyl monomer (N-vinyl pyrrolidinone), a leachable porogen (sodium chloride), and a particulate phase ($\beta$-tricalcium phosphate). Variations in this formulation led to the development of a material that can cure in situ at body temperature, resulting in a scaffold with mechanical properties equivalent to human trabecular bone. The composite formulation was altered to determine its effect on the time course of degradation under both in vitro and in vivo conditions. Inflammatory response upon subcutaneous implantation was monitored during in vivo degradation, with all composite formulations eliciting a mild initial inflammatory response followed by thin fibrous encapsulation. Marrow stromal cells were used to develop a model for in vitro bone formation. Osteogenic supplements were added early in the culture time frame to optimize the proliferation of these cells, as well as their differentiation into osteoblasts. PPF/$\beta$-tricalcium phosphate composites provided an osteoconductive surface for the proliferation and differentiation of marrow-derived cells. Additionally, delivery of growth factors to induce bone regeneration was investigated by incorporating transforming growth factor beta-1 into biodegradable microspheres. Increased proliferation and osteoblastic differentiation of marrow-derived cells was observed when they were maintained in the presence of the growth factor-loaded microparticles.

P H A R M E T I C S dispensary is a prototype retail facility developed by combining one drugstore chain conglomerate and one international cosmetic company. The dispensary is sited as an operational component in commerce, utilizing economic and regulatory systems, marketing strategies, and cultural identification conditions as means to investigate and articulate a physical retail environment. Strategic cross-industry exchange results in innovative hybrid products and services, while expanding the categorical particularities of practice.

<p> <b>Background:</b> Commonly used response scales in patient-reported outcome (PRO) measures include the visual analogue scale, 11-point numeric rating scale, 5-point numeric rating scale, 5-point verbal rating scale, and 5-point verbal-numeric rating scale. Although prior studies have explored the interpretation of response scale labels and compared scores resulting from the response scale, many questions remain.</p><p> <b>Purpose:</b> To identify sets of verbal descriptors interpreted with the least variation and to explore whether the response scales provide interval level data and whether the scales are interchangeable.</p><p> <b>Methods:</b> Subject recruitment and screening was through an online drug-drug interaction service (MediGuard.org). Via an online survey platform, subjects used a scale (0 = lowest possible and 10=highest possible) to assign interpretation scores to verbal descriptors. Repeated measures analysis of variance informed the test interval data between scores. Subjects also completed repeated administrations of four symptom-specific item stems with different response scales.</p><p> Ordinal regression informed the analysis of scores assigned to verbal descriptors, comparison of probabilities of responding in given categories across scales, and prediction of response category on one scale conditional on observed response on another scale. Cut-points informed tests for interval level data.</p><p> <b>Results:</b> The sample (n=350) comprised 223 females and 127 males with a mean (SD) age of 56.9 (12.1) years. Number of health conditions per subject ranged from 1 to 12 (median = 5). Age, sex, level of education, and number of health conditions were associated with the interpretation of verbal descriptors. Scores assigned to "poor," "fair," "good," "very good," "excellent," "somewhat," "sometimes," and "quite a bit," had the largest variation. The probability of responding in the same categories on the different response scales was significantly different across scales before and after collapsing categories. No scale yielded interval level data. The 11-NRS data tended more towards interval level than the data from other scales.</p><p> <b>Conclusions:</b> Using different response scales with verbal descriptors in non-randomized studies may introduce bias. Differential item functioning and subgroup analyses should be investigated in the development and use of these response scales. The scales are not interchangeable. Compared with other scales the 11-NRS produced data approaching interval level. Collapsing categories entails significant probabilities of misclassification.</p>

A novel magnetic Polylactic acid microsphere was developed and produced. Various magnetic materials like Iron, Nickel and Magnetite were introduced into the microspheres, at concentrations of 5 to 10% by weight. The resulting microspheres were characterized for their magnetic responsiveness with a continuous flow apparatus which simulated the vascular system. The effect of specific experimental parameters on the rate of magnetic retention were evaluated using factorial and fractional factorial designs. The observed parameters were the flow tube diameter, test fluid flow rate, magnetic field strength and the mass of added microspheres. The effect of magnetic material type and concentration, microsphere size and test fluid viscosity were also observed. The magnetic retention profiles were photographically recorded and characterized. Computer simulations of various characteristics were completed to interpret several underlying phenomenas of the retention process.