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You searched for +publisher:"Purdue University" +contributor:("Gregory Knipp"). Showing records 1 – 3 of 3 total matches.

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1. Kulczar, Christopher Dale. The development of preclinical strategies for facilitation of lead candidate selection.

Degree: PhD, Industrial and Physical Pharmacy, 2016, Purdue University

Chapter 1 details a background of techniques used for modeling the blood-brain barrier (BBB). The BBB represents a diffusive barrier to both paracellular and transcellular movement of many compounds in and out of the brain. The main rate- limiting barriers of the BBB include exclusive tight junctions that prevent the movement of hydrophilic molecules through intercellular gaps, and efflux proteins in the membrane which pump many hydrophobic molecules back into the blood. In addition, the BBB contains metabolizing enzymes, including Cytochrome P450s. This barrier acts to protect the vulnerable tissues of the brain from harmful xenobiotics, but also can serve as a restrictive barrier for potential therapeutic compounds for the growing number of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, stroke, depression, brain cancers, and many others. A number of in vitro cell screens have been established to mimic the BBB for permeation testing. Principally, the best model should include primary human brain microvessel endothelial cells (BMECs), however, due to the growing interest in BBB permeation and lack of tissues, the supply is limited. As an alternative method, many groups have investigated the use of primary animal BMECs, usually of murine, porcine, or bovine source. These models prove effective at restricting paracellular movement; however, one must question the effects of animal isoforms on modeling uptake, efflux, and metabolism of transcellular markers. This proves important as in vivo most, if not all, therapeutic compounds will cross the BBB transellularly. Consequently, much work has been done to establish immortalized human BMECs. These immortalized cell lines alleviate the high cost and lack of supply found with primary human cells, but potentially may serve as a better model for transcellular permeation over animal cell lines. Currently, the most widely characterized immortalized human BMEC cell line is the human cerebral microvessel endothelial cell line (hCMEC/D3). These cells express tight junction proteins, efflux proteins, cyp450 enzymes, and are conducive to in vitro testing. However, while these cells express tight junctions, their function is less than ideal and leads to a leaky monolayer which may allow faster permeation through the paracellular route or paracellular permeation of compounds that move transcellularly in vivo leading to poor prediction of BBB permeability. One method of investigating the reason behind these leaky tight junctions was to take a closer look at the BBB itself. Chapters 2 and 3 discuss the optimization and establishment of a direct contact coculture in vitro model in which both endothelial cells and astrocytes are plated on the apical side of the Transwell® allowing for more physiologically relevant signaling between the cells. Early results suggest decreased paracellular permeation in this configuration compared to endothelial monocultures and indirect cocultures. In addition, this… Advisors/Committee Members: Gregory Knipp, Gregory Knipp, David Engers, Steven Byrn, Elizabeth Topp.

Subjects/Keywords: Health and environmental sciences; Blood-brain barrier; Coculture; Drug delivery; Formulation; Human serum albumin; Permeability; Pharmacy and Pharmaceutical Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Kulczar, C. D. (2016). The development of preclinical strategies for facilitation of lead candidate selection. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/961

Chicago Manual of Style (16th Edition):

Kulczar, Christopher Dale. “The development of preclinical strategies for facilitation of lead candidate selection.” 2016. Doctoral Dissertation, Purdue University. Accessed December 05, 2019. https://docs.lib.purdue.edu/open_access_dissertations/961.

MLA Handbook (7th Edition):

Kulczar, Christopher Dale. “The development of preclinical strategies for facilitation of lead candidate selection.” 2016. Web. 05 Dec 2019.

Vancouver:

Kulczar CD. The development of preclinical strategies for facilitation of lead candidate selection. [Internet] [Doctoral dissertation]. Purdue University; 2016. [cited 2019 Dec 05]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/961.

Council of Science Editors:

Kulczar CD. The development of preclinical strategies for facilitation of lead candidate selection. [Doctoral Dissertation]. Purdue University; 2016. Available from: https://docs.lib.purdue.edu/open_access_dissertations/961


Purdue University

2. Beck, Daniel Edward. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.

Degree: PhD, Medicinal Chemistry and Molecular Pharmacology, 2015, Purdue University

The research in this thesis is focused on the design, synthesis, and biological evaluation of indenoisoquinolines that inhibit the human topoisomerase IB enzyme (Top1). At present, there are only two FDA-approved cancer chemotherapeutic drugs that target this enzyme. These agents bind to a covalent Top1-DNA cleavage complex intermediate that is formed when Top1 relaxes supercoiled DNA. The effect of this stabilization is that a DNA replication fork can “collide” with the cleavage complex, which produces cytotoxic DNA damage products. Although the present arsenal of Top1 inhibitors is effective in the treatment of solid tumors, their common camptothecin-based structure is plagued by physicochemical and pharmacological issues. For these reasons, alternative structures with Top1 inhibitory activity are currently needed. The objectives of this research were to: (1) establish new and improved synthetic routes to three clinically studied Top1 inhibitors that are based on an indenoisoquinoline scaffold; (2) investigate the structure-activity relationships (S.A.R.) of indenoisoquinolines substituted with carbohydrate-derived and carbohydrate-mimetic moieties; (3) seek out bioisosteric replacements for the nitro group in the highly active 3-nitroindenoisoquinoline Top1 inhibitor series; and (4) design and test dimeric indenoisoquinolines that could Advisors/Committee Members: Mark Cushman, Casey Krusemark, Markus Lill, Gregory Knipp.

Subjects/Keywords: indenoisoquinoline; medicinal; synthesis; topoisomerase I

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Beck, D. E. (2015). DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/1166

Chicago Manual of Style (16th Edition):

Beck, Daniel Edward. “DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.” 2015. Doctoral Dissertation, Purdue University. Accessed December 05, 2019. https://docs.lib.purdue.edu/open_access_dissertations/1166.

MLA Handbook (7th Edition):

Beck, Daniel Edward. “DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS.” 2015. Web. 05 Dec 2019.

Vancouver:

Beck DE. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. [Internet] [Doctoral dissertation]. Purdue University; 2015. [cited 2019 Dec 05]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1166.

Council of Science Editors:

Beck DE. DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL INDENOISOQUINOLINES AS POTENTIAL ANTICANCER AGENTS. [Doctoral Dissertation]. Purdue University; 2015. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1166


Purdue University

3. Mitra, Biplob K. The impact of stress history of deformable dry granules on the mechanical properties of tablets.

Degree: PhD, Pharmacy Practice, 2015, Purdue University

A mechanistic understanding of the relationship among the granule composition, individual granule property, downstream robust processing, and the final tablet attributes is critical for rational development of a quality tablet. However, in the dry granulation literature, milled granules that are polydisperse in solid fraction, size, and shape are extensively used for compaction studies. Thus, the effect of an individual granule property or an individual component on the compaction properties of dry granules was not adequately separated. To advance the mechanistic understanding of the effect of dry granulation on tensile strength of tablets, individual granule properties such as size, solid fraction, and granule composition need to be decoupled, precisely controlled, and independently varied. To accomplish this, in this thesis, small cylindrical biconvex compacts of powder were used as model dry granules for compaction studies, which have the advantage of being monodisperse in both size and solid fraction. In addition, size and solid fraction of monodisperse granules and their composition were independently varied and precisely controlled. The novel use of monodisperse granules brings a new perspective on understanding the compaction properties of deformable dry granules. The effect of granule size and solid fraction on tensile strength of tablets was deconvoluted using monodisperse granules as well as milled granules of microcrystalline cellulose (MCC). A strong linear relationship (with negative slope) exists between the tablet tensile strength and granule solid fraction. In contrary to popular perception, granule size has no statistical impact on the tablet tensile strength. A smooth or rough fracture surface of tablets prepared from low or high solid fraction granules, respectively indicates differences in fracture of the tablets. ^ Subsequently, a novel method was developed to map the fracture surfaces of tablets. The proportion of intra-granular versus extra-granular fracture of tablets was quantified by image analysis. Low solid fraction granules deform extensively, neighboring granule surfaces intermingle closely, and produce homogeneous tablet matrices. At a high deformation potential (defined as, tablet solid fraction - initial solid fraction of the packed granule bed), tablets fracture indiscriminately both intra-granularly (fracture of individual granules) and extra-granularly (separation of neighboring granules). In contrast, at a low deformation potential, tablets preferentially fracture extra-granularly. The proportion of intra-granular fracture is a function of the deformation potential only. Tensile strength of tablets increase nearly linearly with the deformation potential and the slope of the linear relationship is larger for higher tablet solid fraction. At or below the critical deformation potential the tablet structure is not coherent and it does not fracture intragranularly. ^ Calibration of the Drucker Prager Cap (DPC) model parameters provides a means for a deeper understanding of the… Advisors/Committee Members: James D. Litster, James D. Litster, Gregory Knipp, Jon Hilden, Carl Wassgren.

Subjects/Keywords: Medicinal Chemistry and Pharmaceutics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Mitra, B. K. (2015). The impact of stress history of deformable dry granules on the mechanical properties of tablets. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/519

Chicago Manual of Style (16th Edition):

Mitra, Biplob K. “The impact of stress history of deformable dry granules on the mechanical properties of tablets.” 2015. Doctoral Dissertation, Purdue University. Accessed December 05, 2019. https://docs.lib.purdue.edu/open_access_dissertations/519.

MLA Handbook (7th Edition):

Mitra, Biplob K. “The impact of stress history of deformable dry granules on the mechanical properties of tablets.” 2015. Web. 05 Dec 2019.

Vancouver:

Mitra BK. The impact of stress history of deformable dry granules on the mechanical properties of tablets. [Internet] [Doctoral dissertation]. Purdue University; 2015. [cited 2019 Dec 05]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/519.

Council of Science Editors:

Mitra BK. The impact of stress history of deformable dry granules on the mechanical properties of tablets. [Doctoral Dissertation]. Purdue University; 2015. Available from: https://docs.lib.purdue.edu/open_access_dissertations/519

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