Solid polymer-drug dispersions are used to prepare and stabilize amorphous forms of poorly soluble drugs as a means of improving drug solubility, dissolution and bioavailability. Despite many reports on this subject, solid dispersion dissolution mechanisms have not been well understood. An early study was reported by Simonelli, Mehta and Higuchi (SMH) in 1969 and has served as a model for dispersion dissolution behavior. These authors proposed a dissolution model (SMH) which gave good agreement between their experimental results and model predictions for one drug and one type of PVP. Few researchers have applied this traditional approach (SMH) in a systematic fashion to solid dispersion systems. One difficulty is obtaining parameters needed for predictions such as polymer diffusion coefficient, diffusion layer thickness or other pertinent parameters. In this work, a general model has been developed based on the concepts in the traditional approach (SMH) and simulations with this model were performed to show how dispersion dissolution rates change with system variables. Such simulations showed underestimation of dissolution rates resulted when compounds had low solubility. In this work, solid dispersion dissolution behavior was studied systematically with a homologous compound series (alkyl-p-aminobenzoate esters, or PABA esters) and three polyvinylpyrrolidone (PVP) molecular weights (K15, K30 and K90). The PABA esters with varying solubility used in this study were methyl PABA (MePABA), ethyl PABA (EtPABA), propyl PABA (PrPABA) and butyl PABA (BuPABA). Six solid dispersions for each PABA ester and PVP (weight ratios of PVP:PABA ester 20:1, 10:1, 6:1, 3:1, 4:1 and 2:1) were prepared by a solvent evaporation method. Solid dispersions were obtained and their amorphous character confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Intrinsic dissolution rates for these dispersions were obtained in water with a rotating disc dissolution system. Both dissolution rate of drug (PABA ester) and carrier (PVP) were measured to obtain more information on which to evaluate the release behavior. Measuring the dissolution of the polymer (dispersion agent) and drug is unique in this work and has not been done in most other reported studies. For the more soluble PABA esters (i.e., MePABA, EtPABA and PrPABA), as drug loading increased, PABA ester dissolution rates first increased and then decreased to that of the pure drug for PVP K15 and K30 dispersions. For K90 systems, drug dissolution rates were below pure drug rates and increased steadily as drug loading increased, eventually reaching that of the pure drug. On the other hand, PVP dissolution rates decreased constantly as drug content increased for all three PVP grades. However, the decrease in polymer dissolution was more pronounced for the lower molecular weight PVPs (K15 and K30) than the higher molecular weight PVP (K90). Comparison of drug and polymer dissolution behavior indicated that congruent release of both components occurred when drug loading was low (< 15%). As drug loading increased, more deviation from congruent release behavior was observed. For BuPABA, the least soluble PABA ester, precipitated BuPABA solid accumulated on the disc surface during dissolution. PABA ester relative dissolution rates were calculated and compared with the predictions from the developed general model (based on assumptions in the traditional approach). Such predictions correlated well with experimental results at high drug loadings (i.e., >25%) but at low drug loadings (i.e.,

Volume has been suggested as a surrogate quality indicator for breast cancer surgeries by several researchers. It is crucial to understand the underlying reasons as to why there is a disparity in utilization of high volume hospitals. However, the studies that investigated the mechanism underlying the disparity in high volume hospital utilization are very limited. The objectives of this study include: 1) examine the relationship between geographic differential distance and utilization of high volume hospitals; 2) investigate other demographic, socioeconomic and clinical factors that may affect patients' utilization of high volume hospitals. Multivariate logistic regressions were used to evaluate factors that impact patients' utilization of high volume hospitals. The study results showed that geographic distance is a significant factor that impedes patients' utilization of high volume hospitals, independent of patients' clinical, demographic, and socioeconomic characteristics. It was also found that white, non-Hispanic women, patients with higher education level are more likely to be admitted in high volume hospitals compared to low volume hospitals. These factors are also significant to patients' choice of medium vs. low volume hospitals. Geographic proximity is an important factor that affects patients' choice of hospital, and directing more patients to high volume hospitals should anticipate negative effects, such as increasing the cost of seeking care at high volume hospitals. Alternative strategies need to be developed to improve surgical outcomes without increasing patients' traveling related cost, such as enhancing the network between high volume hospitals and low volume hospitals, establishing radiation centers in rural areas.

Physiologically based pharmacokinetic (PBPK) models, also known as recirculation models, consist of a series of tissue and organ blocks linked together by blood circulation, mimicking the anatomical structure of mammalian body. Each tissue is divided into vascular, interstitial, and intracellular sub-compartments. Linear system analysis (LSA)-recirculation models differ from the classical PBPK model in that they characterize each organ or tissue with a unit impulse response in the framework of input-output convolution relationship rather than systems of differential equations. Target-mediated disposition (TMD) is a phenomenon where drug disposition is influenced by capacity-limited binding to a target, resulting in dose-dependent events, such as a decrease in drug clearance with increasing dose level. Erythropoiesis stimulating agents such as recombinant human erythropoietin (EPO) and Continuous Erythropoietin Receptor Activator (C.E.R.A.) exhibit TMD where their disposition and anti-anemic activity are mediated by their interaction with EPO receptor (EPOR). The objectives of this work were: 1) to develop a minimal, receptor-based LSA-recirculation model, 2) to apply the developed model in analyzing the effect of bone marrow (BM) ablation on C.E.R.A. elimination kinetics, and comparing EPO and C.E.R.A. interaction with EPOR in vivo, 3) to investigate the efficiency of the experimental design used to achieve the previous objective for estimation of the developed model parameters, and 4) To identify the physiological conditions at which TMD-compartmental models approximate TMD-recirculation models. A literature review of LSA- recirculation models is provided in Chapter 2. In Chapter 3, receptor-based, LSA-recirculation model was mathematically formulated, and applied to analyze C.E.R.A. pharmacokinetics studied in adult sheep with normal and ablated BM using a tracer interaction method (TIM). In Chapter 4, the model developed in Chapter 3 was further applied to analyze EPO and C.E.R.A. TIM data collected in adult sheep. A comprehensive, sensitivity analysis was performed in Chapter 5. In Chapter 6, statistical moments of linearized receptor-based compartmental and recirculation models were computed; and simulation of plasma drug concentrations, and receptor profiles in both structures were presented. The developed model, together with the TIM, was able to quantitatively assess the interaction of C.E.R.A. with hematopoietic and non-hematopoietic EPOR population and provide a mechanism based explanation for C.E.R.A.'s slower elimination and greater erythropoietic activity in vivo compared to EPO, despite its lower affinity to EPOR. The TIM detected a saturable interaction between C.E.R.A. and non-hematopoietic EPOR which contradicts the behavior of EPO. The TIM experimental setting is adequate for estimation of the developed model parameters. TMD-recirculation models reduce to TMD-compartmental models under conditions of well-perfused target tissue, comparable drug initial distribution volume and target tissue extracellular volume, negligible non-receptor mediated clearance, and rapid equilibrium between venous and arterial blood drug concentrations, small extracellular volume, reduced cardiac output, low receptor pool concentration, and high drug-receptor equilibrium dissociation constant.

Cancer is a group of diseases caused by uncontrolled cellular proliferation and dissemination. After heart disease, cancer is the second most common cause of death in the United States. Main treatment approaches for cancer are surgery, radiotherapy, chemotherapy, and immunotherapy approaches. However, cancer cells have ability to develop resistance to conventional chemotherapy thus lowering the efficacy of those chemotherapeutic agents including doxorubicin (DOX). DOX has been used for the treatment of various cancers. It is usually administered via continuous intravenous infusion. Nevertheless, the use of soluble DOX is often limited by its low therapeutic index. It has been reported that DOX-induced cardiotoxicity is a life-threatening adverse effect and DOX is also a potent vesicant that can cause tissue necrosis following injections. Therefore, this dissertation investigated alternative delivery approaches for DOX including systemic and local delivery systems for enhancing antitumor efficacy while reducing the side effects of free DOX. The first part of this research aimed at developing a formulation capable of actively targeting DOX to tumors. Advances in nanotechnology have provided new ways to delivering DOX into the body and to tumor sites. Among all active targeting ligands developed to date, cRGD peptide (cyclic arginylglycylaspartic acid) occupies a unique position owing to its inherent safety, biocompatibility, and targeting ability. Thus, cRGD was used here to decorate the surface of DOX-loaded PLGA-PEG nanoparticles (NPs) using two independent crosslink reactions, EDC-NHS and thiol-maleimide reactions. The results showed that the different modification reactions yielded NPs of similar size (110-140 nm diameter). All formulations exhibited provided similar burst release phases (of DOX) over the first 12 h followed by sustained release for up to 200 h. For in vivo antitumor activity, C57BL/6J mice carrying melanoma tumors were administered with cRGD-modified DOX-loaded PLGA-PEG NPs (equivalent to 8 μg DOX) by intravenous injection once every other day for up to four doses. Tumor volumes and survival were recorded. The toxicity of this therapy was examined using serum biomarkers including bilirubin, alanine aminotransferase (ALT), and aspartate transaminase (AST). Histopathology of organs (heart, lung, spleen, liver and kidney) was evaluated using hematoxylin and eosin staining (H&E) after euthanizing the treated mice. The results indicated that the cRGD-modified DOX-loaded PLGA-PEG NPs using PLGA-PEG-maleimide polymers (cRGD-DOX-M) demonstrated higher antitumor activity as compared to other groups (p < 0.05). Finally, administration of cRGD-modified DOX-loaded PLGA-PEG NPs had no significant effect on total bilirubin, serum ALT, serum AST levels or animal weight (P > 0.05). There were no signs of tissue damage in any of the tested organs as evaluated by H&E staining. The second part of this dissertation proposed to evaluate the therapeutic effect of combining chemotherapy and immunotherapy in a murine melanoma model. In this study, DOX-loaded PLGA-PEG NPs and anti-programmed death 1 (anti-PD-1) antibodies were chosen as the model of chemotherapy and immunotherapy, respectively. Anti-PD-1 antibodies have shown a great deal of promise in the treatment of melanoma in the clinic. In this study, DOX-loaded PLGA-PEG NPs were administered IV at a dose of 8 µg of DOX/dose per mouse once every other day (total of four injections). Mice in combination treatment groups were also administered with 200 µg of anti-PD-1 solution via intraperitoneal (IP) injection every 3 days for five doses. The combination therapy demonstrated higher antitumor efficacy in vivo as compared to control, soluble DOX, monotherapy of DOX-loaded PLGA-PEG NPs or anti-PD1 solution (p<0.05). Moreover, in vivo safety studies were investigated, and the results suggested that the combination therapy was safe. Lastly, DOX-loaded PLGA-PEG millirods were successfully fabricated by a hot-melt extrusion technique and characterized for in vitro release. It was demonstrated that DOX released from the millirods could be controlled by coating with polylactide (PLA). The locally implanted uncoated DOX- loaded PLGA millirods provided significantly greater antitumor activity against melanoma tumors in mice compared to naïve group and PLA-coated DOX-loaded PLGA millirods. Antitumor activity of the millirods was related to the release profile of DOX from the millirods. PLA-coated DOX-loaded millirods exhibited slower release of DOX compared to uncoated DOX-loaded millirods which probably explains the shorter survival time of mice treated with this formulation. Moreover, skin samples from tumor-free mice were also analyzed. The results demonstrated that uncoated and PLA-coated DOX-loaded millirods could be administered peritumorally without causing local skin necrosis. In conclusion, the novel systemic delivery system and local delivery system of DOX presented here have the potential to be used as alternative approaches for cancer therapy.

In this work, aldehyde-functionalized chitosan was produced by the reaction of chitosan in the solid state with nitrogen oxide gases, generated in situ from a HNO3/H3PO4 - NaNO2 mixture. This reaction is more advantageous than the existing methods to produce aldehyde-functionalized chitosan, since the depolymerization was slower and the purification process of the products was easy and straightforward. The appearance of characteristic peaks in the Fourier transform infrared and carbon-13 nuclear magnetic resonance spectra (1733 cm-1 and 183.4 ppm, respectively) of the product confirms the presence of the aldehyde functionality in the modified chitosans. The pH-dependent 1H-NMR spectra also revealed the presence of aldehyde groups. However, as the pH increased from 2.0 to 6.0, the resonance due to the aldehyde gradually disappeared and a new resonance appeared at 8.05 ppm, which is attributable to the formation of Schiff's base between the aldehyde and the free amine groups. This aldehyde-derivative of chitosan formed a gel in situ by simply dissolving it in water at a concentration of 6% (w/w) without any added external crosslinker. This gel show potential use as drug carrier and as scaffold for vascular tissue engineering. In addition, cellulose:chitosan composites were prepared with the main purpose of obtaining a compliant hollow tube for vascular bypass application. Elastic properties of membranes made of this composite with different ratios between each polymer were determined using uniaxial tests and the ratio that yielded the less stiff membrane was chosen to prepare a small diameter hollow tube. The presence of chitosan had a favorable impact on the elasticity of the membranes, where the cellulose:chitosan 5:5 ratio showed the lowest Young's modulus. Small diameter tubular constructs were fabricated using this optimal cellulose:chitosan ratio and assessed for their suitability as coronary artery bypass grafts. The compliance of the tubes was found to be 5.91 %/mmHg x 10-2, which is higher than those of Dacron, ePTFE and saphenous vein. Burst strength tests revealed that the tubes can withstand at least 300 mmHg. Finally, the tubes showed satisfactory cell attachment property when myofibroblast cells adhered and proliferated on the lumen of the samples.

Gene therapy and immunotherapy are powerful techniques in the treatment of many life threatening diseases. The major challenge in these therapies is to seek a safe and efficient delivery carrier for gene and antigen materials. Carriers are designed to protect these molecules from degradation, improve their stability and facilitate the delivery of them to the site of action. This research study aims to develop appropriate carriers for small interferencing RNA (siRNA), DNA, antigen and ajuvant respectively. In the case of siRNA, material encompassing mannose, polyethylene glycol (PEG) and polyethylenimine (PEI) was investigated. Two structures were assembled: in one construct, mannose was conjugated to PEI directly (Mannose-PEI-PEG) whilst in a second construct; the mannose was conjugated to PEI via a PEG spacer (PEI-PEG-mannose). Confocal microscopy images suggested a faster escape and release of siRNA into the perinuclear region when siRNA was complexed with mannose-PEG-PEI. Mannosylation and PEGylation generated significant toxicity reduction compared to unmodified PEI alone. Real-time polymerase chain reaction (RT-PCR) results showed a significant decrease on mRNA knockdown when using modified PEIs. It was found that PEI-PEG-mannose was a stronger candidate for siRNA delivery because it displays lower toxicity, higher uptake efficiency and higher relative knockdown efficiencies. In the case of pDNA delivery, dextran was introduced to reduce the toxicity generated by PEI. PEI 2000 was more effective than PEI 800 in condensing DNA and inducing transfection when incorporated with dextran. The toxicity of dextran-PEI was greatly reduced when compared to unmodified PEI. Dextran-PEI was able to generate significantly higher transfection efficiencies than PEI alone in the presence of serum. An improved stability of complexes in serum by dextran-PEI was noticed along with a faster release of complexes to the perinuclear region of cells after endocytosis. These observations help to account for the higher efficiency of dextran-PEI in gene transfer. In our final study on vaccines, we utilized cationic polyamidoamine (PAMAM) dendrimer polymers to modify biodegradable particles for enhanced delivery of antigens and adjuvants. Vaccines were formulated by loading CpG oligonucleotide (CpG ODN) and ovalbumin (OVA) into biodegradable microparticles. In one group, OVA and CpG were conjugated together and then loaded into the PLGA microparticles. In other groups, CpG was loaded into the particles and OVA bound to the surface and finally particles were prepared that were loaded with OVA and surface modified with cationic PAMAM dendrimers to electrostatically bind CpG ODN. The microparticles were able to provide sustained release of antigen and adjuvants over 14 day's course. The up regulation of CD86 and H2Kb indicated strong activation of DC and therefore strong induction of CD8+ T-cells. MHC II markers were not as significantly affected. Particles loaded with OVA and surface bound CpG ODN ((OVA)-CpG) showed the highest cytotoxic CD8+ T cell response, suggesting that formulation is optimal for vaccine applications.These observations were further supported by IgG1 and IgG2a antibody levels in mice sera.

Premature infants develop anemia in their first few weeks of life. This is the result of heavy laboratory blood loss, shortened red blood cell lifespan, low plasma erythropoietin levels and inadequate erythropoiesis. As treatment for clinically significant anemia, approximately 80% of very low birth weight infants weighing less than 1.5kg at birth and 95% of extremely low birth weight infants weighing less than 1.0kg at birth receive one or more red blood cell transfusions. To reduce or eliminate red blood cell transfusions is important because they are expensive and associated with complications including infection, fluid overload, electrolyte imbalance, transfusion related acute lung injury and exposure to plasticizers, lead, and other toxins. The primary objective of this thesis is to examine erythropoietin (Epo) dosing, laboratory phlebotomy reduction and the use of restrictive red blood cell transfusion criteria to determine the potential to reduce or eliminate the need for red blood cell transfusions in preterm infants. In order to accomplish this objective, data were obtained from 27 preterm infants including: erythropoietin concentrations, phlebotomy volumes, transfusion information and multiple hematologic indices. The data were analyzed and modeled according to pharmacokinetic and pharmacodynamic principles to determine, through simulation studies, the potential for avoiding blood transfusions in preterm infants. Results from this research suggests that Epo administration, phlebotomy reductions and the use of restrictive blood transfusion criteria all have the potential to reduce the need for blood transfusions in preterm infants. Specifically, a combination of the three interventions was predicted to make blood transfusions unnecessary in all infants with a birth weight between 1.0-1.5kg, and 45% of infants with a birth weight of <1.0kg. These findings are clinically important because avoiding transfusions may lead to better clinical outcomes. The results propose strategies to utilize in future clinical trials involving preterm infants. The secondary objective of this thesis is to characterize the dynamic Epo receptor behavior in newborn sheep and determine a pharmacodynamic model which utilizes information from the Epo receptor dynamics. Results from this analysis show that the Epo receptor pool is an important predictor of red blood cell production. An Epo receptor based pharmacodynamic model is proposed that successfully predicted the red blood cell production in newborn sheep. Additionally, the optimal time for Epo administration was also determined in these newborn sheep based on the pharmacodynamic model. This optimal Epo administration time corresponded to approximately the time when the Epo receptor pool was the largest. Results from the Epo receptor based studies in newborn sheep suggest Epo clinical trials in preterm infants need to consider the dynamic Epo receptor behavior to produce the most optimal outcome.

Most solid-state kinetic principles were derived from those for homogenous phases in the past century. Rate laws describing solid-state degradation are more complex than those in homogenous phases. Solid-state kinetic reactions can be mechanistically classified as nucleation, geometrical contraction, diffusion and reaction order models. Experimentally, solid-state kinetics are studied either isothermally or nonisothermally. Many mathematical methods have been developed to interpret experimental data for both heating protocols. These methods generally fall into one of two categories: model-fitting and model-free. Historically, model-fitting methods were widely used because of their ability to directly determine the kinetic triplet (i.e., frequency factor [A], activation energy [Ea] and model). However, these methods suffer from several problems among which is their inability to uniquely determine the reaction model. This has led to the decline of these methods in favor of isoconversional (model-free) methods that evaluate kinetics without modelistic assumptions. However, isoconversional methods do not compute a frequency factor nor determine a reaction model which are needed for a complete and accurate kinetic analysis. A new approach was proposed that combines the power of isoconversional methods with model-fitting methods. It is based on using isoconversional methods instead of traditional statistical model-fitting methods to select the reaction model. Once a reaction model has been selected, the activation energy and frequency factor can be determined for that model. This approach was investigated for simulated and real experimental data for desolvation reactions of sulfameter solvates. Controversies have arisen with regard to interpreting solid-state kinetic results which include variable activation energy, calculation methods and kinetic compensation effects. The concept of variable activation energy in solid-state reaction kinetics has caused considerable debate because this behavior has been viewed by some as a violation of basic chemical kinetic principles. Activation energy variation has been detected by isoconversional or "model-free" calculation methods which generate activation energy as a function of reaction progress. The relationship between calculation methods and artifactual variation in activation energy was investigated by employing model-fitting and isoconversional methods to analyze both simulated and experimental data. The experimental data was for the sulfameter-dioxolane solvate desolvation by TGA. It was shown that variable activation energy in simple reactions could be an artifact resulting from the use of isoconversional methods; this artifactual behavior can be seen in both isothermal and nonisothermal kinetic experiments. Therefore, care should be taken when interpreting kinetic results from isoconversional methods. If the variation in activation energy is artifactual, this variation can lead to a false mechanistic conclusion about a reaction being complex while, in fact, it is not. Artifactual variation can be reduced by careful experimental design and control of experimental variables in addition to experimental replication, so that averaged kinetic parameters and their confidence intervals can be estimated. The solid-state stability of several structurally related solvates of sulfameter (5-methoxysulfadiazine) was investigated by studying the kinetics of their desolvation reaction both isothermally and nonisothermally. Calculated kinetic parameters were compared and related to the crystal structure of these solvates. A relationship was established between desolvation kinetic parameters (e.g., activation energy) and the solvent size; the larger the solvent molecule, the higher its activation energy. The solid-state reaction models selected also corresponded to the single crystal structure of the sulfameter-solvate system in which the solvent molecules were in cavities. Finally, it was found that kinetic parameters obtained isothermally and nonisothermally were not in agreement. Therefore, kinetic results from one may not be extended to the other.

No description available.

Hypertension or high blood pressure is a major cause of illness and death in the United States today.1,2 An estimated thirty-six million people suffer from this disease.3 Prolonged hypertension and its attendant strain on various organs may cause heart failure, brain stroke or kidney damage.4 Usually, a pressure of 140/90 mm Hg is taken to be the dividing line between normotension and hypertension.5,6 The hypertensive condition is generally characterized as either primary (essential) hypertension or secondary hypertension.1 A specific cause can be identified in secondary hypertensive patients, such as, pheochromocytoma or adrenal tumor. These causes can typically be corrected by surgery. Essential hypertension occurs in about 90% of the hypertensive population. The etiology of essential hypertension is unknown.1,3,6 The increase in diastolic pressure in primary hypertension may take on either a gradual (benign) or accelerated (malignant) course. The prognosis of gradual hypertension is more favorable than that of the accelerated. Blood pressure in the essential hypertensive patient can almost always be controlled by drug therapy. It is currently accepted that in most hypertensive cases the primary abnormality is due to a high peripheral resistance.7 Numerous biological feedback mechanisms interact in trying to return the body to the normotensive state.8 Some factors involved in the maintenance of homeostasis are central and peripheral sympathetic activity, renal pressor and depressor mechanisms, antidiuretic hormone, sodium balance, baroreceptors, small blood vessel resistance, blood volume and viscosity.1,4,7