EO9 (Apaziquone): from the clinic to the laboratory and back again

EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9’s poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that ‘the EO9 story’ has for the development of other loco-regional therapies

Synthesis and Performance of Stimuli-Responsive Polymeric Biomaterials for Immunological and Therapeutic Application

Macromolecular platforms for delivery of therapeutics have long been a desirable strategy for treatment of various pathologies. While improving the bioavailability and efficacy of certain therapeutics, these methods have historically been limited due to systemic toxicity or irregular and uncontrolled release profiles. This has led to substantial interest in the design and application of biomaterials which can modulate activity or exhibit precise delivery of therapeutic agents to the disease site in response to certain physiochemical triggers. Such “stimuli-responsive biomaterials” can respond to their environment to allow for specified treatment tailored for spatial and temporal accuracy. This dissertation discusses the development of various stimuli-responsive platforms for therapeutic treatment including temperature responsive polymeric vaccine adjuvants and pH-responsive copolymers for controlled payload release. This is achieved by incorporating rationally designed therapeutic agents or chemical functionalities into polymeric architectures with comonomers to yield macromolecular biomaterials which can be tailored toward a desired clinical benefit. This modular approach allows for a variety of therapeutic strategies together with the performance benefits of macromolecular scaffolds towards the chosen application. Specifically, the development of novel thermoresponsive vaccine adjuvants demonstrates modulation of proinflammatory immune response inversely related to increasing temperature. The combination of rationally designed glycolipid adjuvants with the thermoresponsive material polyN-isopropyl acrylamide affords an adjuvant wherein potency itself is manipulated in response to temperature. Additionally, translation of established acid-labile phorsphoramidate linker chemistry to hydrophilic polymeric carriers has successfully imparted their selective release profiles to macromolecular systems, expanding the repertoire of delivery strategies for anti-cancer therapeutics with efforts to improve circulation times and availability of traditionally hydrophobic chemotherapeutics. As stimuli-responsive biomaterials continue to progress, their capacity to reshape immunotherapy and therapeutic administration holds immense prospects, restructuring the landscape of treatment methodologies and auguring heightened prognoses for patients

An Electromyographic and Motion Analysis of Forward and Backward Walking

Backward walking is a common intervention in the rehabilitation of lower extremity injuries. Despite its popularity, there is limited research available on the EMG activity during backward walking at an incline when compared to forward walking. In this study, we recorded EMG activity in four muscles of the lower extremity and utilized motion analysis to evaluate the knee range of motion when walking forward and backward on a treadmill at 0 and 15 percent grade inclines. Overall, our results indicated a greater increase in muscle activity during backward walking than forward walking. Walking backward at a 15 percent grade incline showed the largest increase in muscle activity with the vastus lateralis showing increase of 609%, vastus medialis increasing 339%, semitendinosus increasing 189%, and biceps femoris increasing 172% when compared with forward walking at a 0 percent grade. Our results showed the degree of knee flexion to be the greatest during backward walking at a 15 percent grade (70.2 degrees of knee flexion), followed by forward walking at a 15 percent grade (68.4 degrees of knee flexion), forward walking at 0 percent grade (67.4 degrees of knee flexion) and finally backward walking at 0 percent grade (57.5 degrees of knee flexion). We conclude that both backward and forward walking at an incline can be beneficial for lower extremity rehabilitation

Demonstratives and determiner-phrase structure in Hidatsa narrative discourse: a morphological, syntactic, and semantic analysis

The general morphology of Hidatsa has been studied extensively by a handful of scholars (Matthews, W. 1874; Robinett 1955; Matthews, G. H. 1965; Jones 1979, 1992; Boyle 2007, 2011; Gebhardt & Boyle 2012; Park 2012), but little work has been done on the structure of narrative discourse. This thesis examined the morphology, syntax, and semantics of how Hidatsa utilizes four demonstratives, -he, hirí, hiróo, and šéʔ, in narrative texts. By examining seven traditional Hidatsa narratives collected over the past 80 years by various scholars (Lowie 1939; Parks, Jones, & Hollow 1978; Wicker 1978; Boyle 2007), I uncovered specific functions of the four morphemes and identified syntactic-semantic patterns for each function to provide insight into how Hidatsa utilizes demonstratives and other functional elements for referent tracking and the general flow of information. I found that there is a hierarchy in the syntax and that demonstratives are more versatile than scholars have previously thought. I found that Hidatsa demonstratives project their own functional level (i.e., demonstrative phrase) and are both internal and external to determiner phrases. I demonstrated that -he functions as head of the determiner phrase and that hirí, hiróo, and šéʔ are always predicative whether functioning adnominally, pronominally, or as locatives. The results from this analysis have expanded our knowledge of functional elements, the structural characteristics of determiner phrases, and the complex interaction of elements within Hidatsa syntax. They have also contributed to clearing up any controversy regarding the functions, distributions, and semantic roles of a subset of demonstratives in Hidatsa, and in general

Measurement of limiting activity coefficients using a differential dew point technique

Thesis (B.S.) in Chemical Engineering -- University of Illinois at Urbana-Champaign, 1989.Includes bibliographical references (leaf 19)Microfiche of typescript. [Urbana, Ill.]: Photographic Services, University of Illinois, U of I Library, [1989]. 1 microfiche (37 frames): negative.s 1989 ilu n

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples