<p>Accurate and safe medication administration is an important aspect in the everyday care of the hospitalized patient. Patients put their trust and safety into the hands of those providing care and expect that care is provided in a safe and efficient manner. Nurses strive to provide high quality error free, patient care. With adult patients, medication administration accounts for 26% to 32% of hospital medication errors (Koppel, Wetterneck, Telles, &amp; Karsh, 2008). Only 2% of administration errors are corrected before reaching the patient (Dwibedi, et al., 2011). Literature supports that knowledge based medication administration programs reduce medication administration errors (Fowler, Sohler, &amp; Zarillo, 2009). The research question proposed was: What are the perceptions and beliefs of nurses using Knowledge Based Medication Administration (KBMA) bar code scanning processes in regards to patient safety? The design was a quantitative, descriptive study, using a convenience sample. The study site was west-central Illinois hospital. Data were collected and analyzed related to the perceptions and beliefs of the staff nurses using KBMA in regards to patient safety during medication administration processes. Staff nurses were surveyed using a Likert-like scale. Participants accessed the survey via My Netlearning which linked to Survey Monkey. Participation was voluntary and responses were anonymous. Future implications for quality improvement and education are considered. </p>

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The use of liposomes for the delivery of therapeutic agents to tumor sites took a major step forward with the introduction of sterically stabilized liposomes (PEG-liposomes). Several research groups reported the increased localization of PEG-liposomes at tumor sites. Once PEG-liposomes reach these sites, it can be desirable to increase the rate of release of encapsulated compound(s). The use of radiation for this purpose is attractive, because it can be delivered in a spatially and temporally selective manner. An effective strategy for the photopertubation of PEG-liposomes relies on the photoinitiated polymerization of reactive lipids in the liposomal bilayer. Previous studies indicated that the inclusion of the photoreactive 1,2-bis[10-(2' ,4'-hexadienoyloxy)decanonyl]-sn-glycero-3-phosphocholine (bis-SorbPC17,17) among the lipids of PEG-liposomes had little effect on their permeability until the PEG-liposomes were exposed to UV light. Photoexposure increased the permeability of the PEG-liposomes 200-fold. Research in this dissertation was focused upon increasing the reactivity of PEG-liposomes to UV and ionizing radiations. Additionally, the most favorable formulations were then used for the encapsulation of chemotherapeutic compounds that are currently on the market. Results in this dissertation indicate the ability to encapsulate water soluble compounds with high efficiency and subsequently release those compounds with minimal UV light exposure and with ionizing radiation doses that approach therapeutic levels.

Novel methods for synthesis of monoprotected homobifunctional polyethylene glycols and subsequent synthesis and application of heterobifunctional derivatives in protein immobilization and separation is described. In addition, modification of proteins with PEG and properties of the conjugates are presented. Heterobifunctional PEG derivatives having a chelate at one end and at the other one specific ligands for proteins have been synthesized. Metal binding constants and kinetic parameters of these bifunctional chelate polymers were found in excellent correlation with the binding affinities shown by corresponding unconjugated groups. These heterobifunctional PEG derivatives were used to characterize the partitioning behavior of several proteins in Affinity Two-Phase Partitioning, ATPP, at different conditions. Both sides of these bioaffinity chelating polymers were found to be effective in the partitioning of these model proteins. These modified heterobifunctional affinity chelating polymers were also adsorbed in aqueous media to different chelating adsorbents used in IMAC separation. In this scheme an IMA-adsorbent could be transformed to a more selective affinity separation mode, by adding an affinity-chelating ligand. The attached ligand could be removed by weakening the metal interactions between the two chelates in the system which allow the column to operate again in the original IMAC mode, if desired. The amount of these bioligands bound to the columns were a function of the type of the IMA-adsorbents, pH, salts and the metal immobilized on the gels. Trypsin and avidin were bound on columns loaded with a PAB-PEG-chelate and a biotin-PEG-chelate respectively. As a typical example, bound trypsin was eluted from the columns with the trypsin inhibitor, benzamidine, acting as a competitive ligand. The bioligands were eluted reversibly from the IMA-adsorbents, using free IDA as a competitive ligand, using low pH buffers or EDTA. PEG derivatives of 5000 daltons, were chemically fixed to non essential groups on trypsin through amidation with amino groups using two different methods. Kinetic studies were performed upon modification to determine the activity and stability of the modified biomolecule under these conditions. In both cases the modified enzyme adduct, retained their original biological activities and showed substantial changes in properties.

Topographical constraint is the most powerful approach for the design of bioactive peptides to explore the bioactive conformation of crucial side-chain pharmacophores of amino acid residues in peptide-receptor recognition and signal transduction. Novel topographically constrained amino acids β-isopropylphenylalanine and 2',6'-dimethyl-2,3-methanophenylalanine have been designed and synthesized. Incorporation of the four optically pure β-isopropylphenylalanine stereoisomers into deltorphin I produced four peptide analogues of [β-iPrPhe]Deltorphin I with differentiated bioactivities. The most potent and selective analogue, [(2S,3R)-β-iPrPhe]Deltorphin I showed an IC₅₀ nM binding affinity, and a 29000 fold selectivity for the δ-opioid receptor over the μ opioid receptor. Combined molecular modeling and NMR studies indicated that the (2S,3R)-β-iPrPhe³ residue in the analogue favors the trans rotamer, and can induce the linear peptide to form a low-energy folded conformation which was proposed as the bioactive conformation for the δ-opioid receptor. Coupling four optically pure, conformationally constrained β-methyl-2',6'-dimethyltyrosine (TMT) with L-Tic formed four dipeptide analogues of TMT-L-Tic. The most potent and selective analogue, (2S,3R)-TMT-L-Tic showed 9 nM binding affinity and 4000 fold selectivity to the δ vs μ opioid receptor. The lowest-energy conformation of (2S,3R)-TMT-L-Tic was suggested to be the bioactive one in which TMT side chain is trans and Tic side chain is in a gauche (+) conformation. Bicyclic oxytocin antagonist [dPen¹, cyclo(Glu⁴ Lys⁸)]OT (BC-OT) (pA₂ = 8.10) is an excellent template to examine further topographical ideas. Substitution of Tyr² with the topographically constrained para-methoxy-β-methyl-2',6'-dimethyltyrosine (p-MeOTMT) amino acids produced two very potent antagonists [(2S,3S)-p-MeOTMT²]BC-OT (pA₂ = 8.26) and [(2R,3R)-p-MeOTMT²]BC-OT(pA₂ = 7.80), and two inactive analogues [(2S,3R)-p-MeOTMT²]BC-OT and [(2R,3S)-p-MeOTMT²]BC-OT. These interesting results can be attributed to the biased side-chain conformation, gauche(+) and gauche(-) in (2S,3S)-p-MeOTMT and (2R,3R)-p-MeOTMT respectively, and trans in both (2S,3R)-p-MeOTMT and (2R,3S)-p-MeOTMT residues. Rational design of non-peptide mimetics from peptide leads is still elusive. Based on the δ-opioid selective lead [(2S,3R)-TMT¹]DPDPE and SAR of δ-opioid selective ligands, the first generation of non-peptide mimetics have been designed and synthesized. The new lead SL-3111 showed binding affinity IC₅₀ = 8 nM, and over 2000 fold selectivity for the δ-opioid receptor over the μ receptor.

The synthesis of a series of N-9-fluorenylmethoxycarbonyl (N-FMOC) protected amino acid glycosides is reported. These (1-2)-trans glycosides came directly from Koenigs-Knorr type glycosylations under Hanessian's silver triflate conditions, except for the synthesis of N-acetylgalactosamine FMOC amino acid in which silver perchlorate conditions were used to promote α-glycoside formation. The effect of D-amino acid aglycones was investigated under glucosylation conditions, and a yield dependence on amino protection was seen in the enantiomers of threonine. Due to this match vs. mismatch dichotomy, both O'Donnell Schiff bases and FMOC-amino aglycones were used in the subsequent glycosylation reactions. Glycosides were made using the monosaccharides xylose, mannose, glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, and disaccharides lactose [galactose-β-(1-4)-glucose], cellobiose [glucose-β-(1-4)-glucose] and melibiose [galactose-α-(1-6)-glucose]. All glycosides were converted to their respective FMOC-amino acid forms for direct use in solid-phase glycopeptide synthesis (SPGPS) using established methodology. A strategy into the synthesis of an FMOC-amino acid trisaccharide of Lewis ˣ (Leˣ) was also investigated in an effort to expand on the established glycoside methodology. Preliminary work with D-glucosamine and L-fucose is reported. Our synthetic rationale was based on retaining the peptide pharmacophore or message sequence constant as DCDCE (D-cys²ʼ⁵-enkephalin) with a serine-glycine tether, and making changes only in the environment of the amino-acid glycoside. Changes in amino acid, amino acid chirality, and in the sugar moiety itself would provide a stereochemical investigation into the requisite orientation and electronics for optimum blood-brain barrier (BBB) penetration, opiate receptor binding, and analgesia. Several glycopeptides were synthesized, and all were purified in both reduced and oxidized forms (if containing cysteine). A highly optimized glycopeptide synthetic strategy has been developed and will be presented and critiqued. Pharmacological analysis involving serum stability studies, BBB-penetration studies, GPI/MVD physicochemical studies and mu/delta-opiate receptor studies were completed on all glycopeptides. SAM-1095, the most potent of the glycopeptides synthesized, was resynthesized on a large scale, and this compound was assessed for in vivo pharmacology, along with the non-glycosylated version SAM-995. Preliminary results demonstrate an analgesic effect similar to that of the narcotic morphine. Assessment of all pharmacology will afford a platform for future SAR-based glycopeptide investigations.

Values for the melting points, total enthalpies of melting, and total entropies of melting of organic compounds are required in order to accurately estimate properties such as aqueous solubility and vapor pressure. These measurements, therefore, are critical to predicting how a chemical will behave both in the body and in the environment. Despite their importance, relatively few methods are available for predicting these properties from chemical structure. One reason for the lack of available methods is that these properties are easily obtained experimentally. The major reason, however, is that the development of general models for their prediction is extraordinarily challenging. This study first develops a model for estimating the melting points of organic compounds. The model incorporates additive functional group descriptors as well as non-additive descriptors of molecular geometry. The model is trained on the melting points of nearly 3000 compounds, has an R² value of 0.873 and an average error of 29.8 Kelvin degrees. The melting point model is then used to estimate the total enthalpy of melting through the incorporation of an additional geometric descriptor of molecular eccentricity, ε. Eccentricity is a measure of the extent to which the structure of a molecule deviates from a sphere. The total enthalpy model is trained on data for 191 compounds. The model has an R² value of 0.910 and an average error of 3812 J/mol. The total entropy of melting is then estimated from the predicted enthalpy value by incorporating an additional parameter in the model, τ, as a measure of molecular flexibility. The total entropy model is trained on data for the same 191 compounds as the enthalpy model. It has an R² value of 0.928 and an average error of 9.8 J/Kmol. The total enthalpy and entropy models have average absolute errors that are similar to those obtained using existing techniques that are more complex. The melting point method, however, is significantly more accurate and widely applicable than the additive models that are currently available.

A number of alpha-melanotropin (α-MSH) analogues have been designed de novo, synthesized and bioassayed at different melanocortin receptors from frog skins, mice and humans. These ligands were designed from two scaffolds, Somatostatin and Deltorphin-II, by two new hybrid approaches, one of which utilizes the modified cyclic structure (H-DPhe-Cys---Cys-Thr-NH₂) of a Somatostatin analogue--Sandostatin®, while the other incorporates the hydrophobic tail of Deltorphin-II (Glu-Val-Val-Gly-NH₂). Some of the ligands designed, H-DPhe-c [XXX-YYY-ZZZ-Arg-Trp-AAA]-Thr-NH₂ [XXX and AAA = Cys, DCys, Pen, DPen; YYY = His, His(1-Me), His(3-Me); ZZZ = Phe and side chain halogen substituted Phe, DPhe, DNal(1') and DNal(2 ')] and c[XXX-YYY-ZZZ-Arg-Trp-Glu]-Val-Val-Gly-NH₂ [XXX = nothing, Gly, β-Ala, γ-Abu, 6-Ahx; YYY = His, His(3-Bom), (S)-cyclopentylglycine (CPG); ZZZ = Phe, DPhe; DNal(2')], show unique selectivity and potency among the receptors tested. In particular, one of the ligands, Delt-38B--c[Gly-CPG-DNal(2')Arg-Trp-Glu]-Val-Val-Gly-NH₂, is a human melanocortin receptor (hMC1R) antagonist (IC₅₀ = 12 nM) the first potent hMC1R antagonist discovered. These results provide strong evidence supporting our hypothesis that ligand scaffolds for different G-protein coupled receptors (GPCRs) can be used to design ligands for other GPCRs. In addition, the structures of some of the ligands have been analyzed by high field solution NMR and their conformation evaluated by modeling with MacroModel. The conformations obtained from these methods help us better understand the structural basis the selectivities and ligand-receptor interactions.

New methods of analyzing pharmaceuticals by high performance thin-layer chromatography and microplate imaging were investigated using array imaging technology. Both techniques provide high sample throughput over more traditional analytical techniques for the analysis of pharmaceuticals. HPTLC provides high sample throughput by performing separations in parallel using a planar stationary phase. Imaging the entire plate with a single exposure performs quantitation of the analytes in the chromatographic medium. Fluorescence and fluorescence quenching detection modes are presented by employing tetracyclines, famotidine, and several over the counter drugs as model compounds. Studies conducted include sensitivity, separation efficiency and reproducibility of the system. Microplate imaging allows for the quantitation of numerous analytes in parallel. In this technique, solutions containing the analyte of interest are deposited into numerous self-contained wells on microplates, also known as 96-wellplates or ELISA plates. Light is passed through the wells of the plate allowing for absorption, fluorescence, or fluorescence quenching. Imaging with an array detector enables the researcher to simultaneously quantitate each well in parallel. The reaction between primary amines, ampicillin and amoxicillin, and fluorescamine was investigated. Microplate imaging was also tested for quantitating analytes in the low UV region (254 nm).

Based on the efficient substrate for p60ᶜ⁻ˢʳᶜ protein tyrosine kinase (PTK) YIYGSFK (1) (K(m) = 55 μM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors for this enzyme. The inhibitors showed IC₅₀ values in low micromolar range (0.1-3 μM). A "rotamer scan" was performed by introducing four stereoisomers of β-Me(2')Nal in the postulated interaction site of peptide inhibitor (23) Y-c[D-Pen-(2')Nal-GSFC]KR-NH₂ (IC₅₀ = 1.6 μM). We found that the χ¹ space constraints imposed by the specialized amino acids, introduced at position 3 of peptide 23, were not as important as the configuration of the Cᵅ of that residue to recognize the active site of Src and Lck PTK, as reflected on the observed selectivity ratios. Cocrystallization studies between Lck and two of our inhibitors are in progress, in a collaboration with Dr. X. Zhu (Kinetix, Pharmaceuticals, Inc.). The results obtained may serve as the basis for the design of Lck and/or Src inhibitors, either peptide or nonpeptide. SL-3111 is a high affinity (IC₅₀ = 8.4 nM) and selective (μ/δ = 2020) δ-opioid receptor peptidomimetic ligand developed in Dr. Hruby's laboratory, as the result of extensive structure-activity relationship (SAR) studies based on peptide leads. However, bioassays (GPI and MVD) and in-vivo antinociception studies on the racemic mixture and both enantiomers of this compound, have shown particular problems such as low potency and toxicity. We have shown the importance of the piperazine ring in this molecule for binding toward the δ-opioid receptor. Thus, maintaining such scaffold we have studied a series of solution and solid-phase approaches toward the synthesis of SL-3111 analogues, which explore wider functional diversity at this heterocyclic ring. Compounds 64-67 were synthesized by solution methods. Analysis of the biological data and molecular modeling studies of these compounds, revealed an interesting trend in terms of the effects of the substituent at position two of the piperazine scaffold. Three different solid-phase protocols were explored toward the development of a combinatorial library of this type of compounds, which may facilitate future SAR studies.