Class of 2005 Abstract / Objectives: To explore the factors that motivate current pharmacy students to enter the field of pharmacy, and compare these motivational factors to currently registered and practicing pharmacists. Methods: Identical questionnaires were distributed to the student and pharmacist populations. The questionnaire collected ratings on how influences such as job security, earnings potential, community service, and family obligation affected decisions to enter the profession of pharmacy. Other data regarding salary information, satisfaction with the profession, first career choices, and basic demographics were also collected. Results: Questionnaires were completed and returned by 214 students and 84 practitioners. Statistically significant differences were found between groups for all demographic descriptors (p<0.001). Differences were also seen amongst rating scores applied to most of the various motivational factors listed. However, when put in ranking order, the top 4 motivating influences for choosing pharmacy were consistent across all survey groups. The factor with the least influence on study participants was also consistent amongst all groups. Implications: People that are choosing pharmacy as a profession today differ demographically from experienced pharmacists; however the influences on selecting pharmacy as a profession are similar.

The objective of this investigation was to evaluate the USP dissolution apparatus. The test drug products used were two brands of chlorpromazine HC1 tablets which had been previously evaluated clinically. On the basis of the dissolution characteristics obtained with these and several other products, it was concluded that (a) simulated gastric fluid was the media of choice for tablets containing chlorpromazine HC1, (b) the geometry of the dissolution vessel had no significant effect on dissolution characteristics, (c) a ten mesh basket be substituted for the 40 mesh basket now specified by the USP, (d) the depth of the basket in the media should be 3 cm. rather than the 2 cm. now specified, (e) the pH effect of the media should be studied carefully before setting specifications for a drug product, (f) that the basket should be inserted into the media while rotating in order to prevent variations in dissolution characteristics, (g) the method is reproducible under standardized conditions, and (h) the method is as good or better than three other dissolution methods described in the literature. This abstract represents the true contents of the thesis submitted. / Pharmaceutical Sciences, Faculty of / Graduate

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Potential Pharm.D. students and graduate students -- lots of choices! This session targeted by Pharm.D. and graduate admissions stake-holders will describe how understanding career-decision-making processes can assist colleges and schools in developing and implementing interventions to foster Pharm.D. and graduate student recruitment. Attendees will explore mechanisms through which Pharm.D. and graduate programs can collaborate to promote evidence- and experience-informed career decisions among potential matriculants.

Increasing emphasis has been placed on improving clinician resilience and well-being due to concerning rates of burnout, depression, and suicide in healthcare professionals. Session participants will learn how multiple instiutions have created initiatives that promote a culture of health and well-being for students, staff, and faculty. Particpants will learn about practical strategies for performing an environmental scan of current culture and incorporating assessment tools, educational programs, and workplace wellness into their own organizational initiatives.

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The poor aqueous-solubility of many anticancer drugs limits their use as therapeutic agents. PacIitaxel, for example, is extremely useful for many refractory cancers yet its poor aqueous-solubility «1IJg/mL) requires solubilisation in Cremophor® EL, the latter which presents many clinical side-effects. To overcome such issues, micellar vehicles constructed from generally regarded as safe (GRAS) surfactants, such as poloxamer P105, that can not only solubilise but enhance the action of chemotherapeutic agents due to their inherent P-glycoprotein (Pgp) inhibitory activity has been investigated. Whilst poloxamer surfactants form thermodynamically stable hydrophilic micelles at high concentrations, they are prone to dissociation upon dilution especially in the case of intravenous injections. Micelles were stabilised to prevent premature drug release via three methods (i) cross-linking di-acetylene bonds in tricosadiynoic acid which was initiated by UV irradiation in the presence of classical micelles formed from sodium dodecyl sulphate (SOS), (ii) generation of an interpenetrating polymer network within and around poloxamer P105 micelles by free radical generation using N,N-diethylacrylamide (NNOEA), and (iii) physical adsorption of a pre-formed, hydrophilic polymer, .polyacrylamíde (10kOa) onto poloxamer P105, P103, L64 and F127 micelles: This final method of stabilisation produced superior results with respect to control over particle size, formulation homogeneity, and shelf-life stability hence, drug release from the stabilised system was further investigated. Thermal differential scanning calorimetry (OSC) analysis suggested that a blend of poloxamer P105 and polyacrylamide were miscible resulting in a change in glass transition (Tg) from -71°C to -30°C. Photon correlation spectroscopy (PCS) also confirmed an interaction as particulate size increased from 18nm ± 0.62nm (non-coated micelles) to 22nm ± 1.36nm (after coating; P<0.05) with low sample polydispersity values. The physlco-chemtcal stability of coated micelles containing poorly water-soluble molecule, dye Oil Red O (ORO) or anticancer drug, methotrexate, demonstrated an inverse relationship with polyacrylamide coating with respect to drug release. Thus, an inCrease in the coating level reduced methotrexate/dye release, which suggested overall formulation intactness. Chemosensitivity studies (via MTT assay) on breast cancer cell lines showed that MCF-7 cells were far more sensitive to free methotrexate (lCso of 23nM ± 3nM) than drug resistant MCF-7/AOR cells (ICso>200nM) at 48h. In the presence of poloxamer P105 and methotrexate, MCF-7/AOR cells became sensitised, attaining a significantly lower ICso of 85nM ± 12nM (P<0.05) at 48h, while exposure of poloxamer alone at concentrations up to 15001JM, which is well above the critical micelle concentration (CMC) of,P105 demonstrated little to no signs of cell toxicity at 48h. These results demonstrate Pgp inhibitory activity bought about by poloxamer P105. Further investigations led to comparison of in vitro data obtained for poloxamer P105 in contrast to other poloxamers which were either reported to exhibit Pgp activity (poloxamer L64), to have unknown Pgp activity (poloxamer P103) or no Pgp activity (poloxamer F127). Results demonstrated that all the poloxamers tested exhibited Pgp inhibitory activity since a decrease in IC50 values were recorded between free methotrexate and poloxamer in the presence of methotrexate. However, while the resistant cells showed little sensitivity to P105 exposure alone at high concentrations all the other polexamera indicated cell sensitivity at concentrations just above their CMC values. Stabilised, coated poloxamer P105 micellar formulations containing methotrexate show great potential in the treatment of refractory tumours as developed by this study.

A high proportion of prostate cancers have been shown to be androgen-dependent. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17[alpha]-hydroxylase/17, 20-lyase (P450[sub]17[alpha]), which is responsible for the conversion of C[sub]21 steroids (for example pregnenolone and progesterone) to the androgens (for example dehydroepiandrosterone and androstenedione respectively). The inhibition of this enzyme would therefore lead to the overall reduction in the level of androgens and thus result in an overall decrease in the stimulation of androgen-dependent cancer cells. The compounds synthesised within the current study were designed such that the compounds were able to donate a lone pair of electrons to the Fe atom within the haem group of the active site of P450[sub]17[alpha]. As such, compounds based on benzyl imidazole backbone were synthesised as the major range of compounds with a small number of phenyl alkyl imidazole based compounds synthesised in an effort to evaluate physicochemical factors such as hydrophobicity. In general, the results of the study show that of the benzyl imidazole-based compounds were weak inhibitors of P450[sub]17[alpha] in comparison to the standard compound, namely ketoconazole (3) (IC[sub]50=1.66[plus or minus]0.15[mu]M against 17,20-lyase and IC[sub]50=3.76[plus or minus]0.01[mu]M against 17[alpha]-hydroxylase). The most potent benzyl imidazole-based compounds synthesised were: 4- iodobenzyl imidazole (224) (IC[sub]50=1.58[plus or minus]0.17[mu]M against 17,20-lyase and IC[sub]50=10.06[plus or minus]0.96[mu]M against 17[alpha]-OHase); 1-(3,4-dichloro-benzyl)-1H-imidazole (215) (IC[sub]50=2.07[plus or minus]0.07[mu]M against 17,20-lyase and IC[sub]50=12.22[plus or minus]0.88[mu]M against 17[alpha]-hydroxylase); 1-(3,5-dichloro-benzyl)-1H-imidazole (216) (IC[sub]50=3.34[plus or minus]0.11[mu]M against 17,20-lyase and IC[sub]50=22.56[plus or minus]0.34[mu]M against 17[alpha]-hydroxylase); 1-(3,5-dibromo-benzyl)-1H-imidazole (221) (IC[sub]50=3.16[plus or minus]0.11[mu]M against 17,20-lyase and IC[sub]50=25.95[plus or minus]0.91[mu]M against 17[alpha]-hydroxylase). The phenyl alkyl imidazole based compounds were found to be more potent than the benzyl imidazole-based compounds and 3 and included: phenylheptyl imidazole (318) (IC[sub]50=0.10[plus or minus]0.02[mu]M against 17,20-lyase and IC[sub]50=0.32[plus or minus]0.05[mu]M against 17[alpha]-hydroxylase); phenyloctyl imidazole (321) (IC[sub]50=0.21[plus or minus]0.02[mu]M against 17,20-lyase and IC[sub]50=0.25[plus or minus]0.01[mu]M against 17[alpha]-hydroxylase); and phenylnonyl imidazole (324) (IC[sub]50=0.35[plus or minus]0.01[mu]M against 17,20-lyase and IC[sub]50=1.06[plus or minus]0.03[mu]M against 17[alpha]-hydroxylase). Consideration of the structure-activity relationship determination and the molecular modeling of the synthesised compounds using the substrate-haem complex (SHC) approach shows that the disubstituted derivatives of benzyl imidazole were able to utilise both hydrogen bonding groups which are presumed to exist at the active site of P450[sub]17[alpha]. These compounds were found to be considerably more potent than the mono-substituted derivatives, as such, it suggests that the increase in the number of interactions between the inhibitor and the enzyme is the key feature which results in the increase in potency. The inhibitory data obtained for the phenyl alkyl imidazole-based compounds show that hydrophobicity (logP) of the inhibitor plays a major role in determining the overall inhibitory activity of these compounds. As such, the study suggests that in the design of further novel inhibitors of this enzyme, the interaction with the active site and logP are two factors which would allow for the synthesis of highly potent inhibitors of this enzyme.

The Dimroth rearrangement in ring-fused 1,2,4-triazoles has been reviewed in detail in Part I and the synthesis of all known triazolo-triazines is described in Part II. Experimental investigations concerned the establishinent of the skeletal arrangement of a variety of triazolotriazines formed by several synthetic routes. Interaction of 3-amino-5-hydrazino-12,4-triazole and benzilafforded 2-amino-6, 7-diphenyl-1, 2,4-triazolo[ 5, 1-c-]-1,2,4-triazine,whereas cyclization of 5,6-diphenyl-3-hydrazino-1,2,4-triazine withcyanogen bromide resulted in the isomeric 3-amino-6,7-diphenyl,-1,2,4-triazolo [4, 3-b]-1,2,4-triazine: both amines were deaminated with amyl nitrite in boiling tetrahydrofuran without rearrangement of the heterocyclic skeleton. 6,7-Diphenyl-1,2,4-triazolo[5,1-cJ-1,2.4-triazine, synthesized from 3-hydrazino-1,2,4-triazole and benzil, formed a covalent hydrate which could be detected spectroscopically in solution, and a covalemt methanolate and ethanolate which could be isolated. A new route to 3-amino-5-hydrazino-pyrazole is described and cyclization to 7-amino-3,4-diphenyl-pyrazolo[ 5,1-.c]-1,2,4-triazine was achieved with benzil. The diazonium nitrate of 3-amino-1,2,4-triazole coupled with ethyl cyanoacetate to yield a mixture of two geometrical isomers of ethyl 2-(2H-1,2,4-triazol-3-ylhydrazono) cyanoacetate. Recrystallization of the crude coupling mixture from aqueous ethanol gave a single hydra-zone which cyclized predominantly to ethyl 7-amino-1,2,4-triazolo[5,1-c]-1,2,4-triazine-6-carboxylate in acid conditions and 6-cyano-1,2,4-triazolo[ 5,1-c]-1,2,4~triazin-7(4H)-one under basic conditions. The nature of the cyclizing medium also controlled the cyclization of .the (pyrazol-ylhydrazono) cyanoacetate hut the corresponding (tetrazol- ylhydrazono) cyanoacetate gave only ethyl 7-aminotetrazolo[ 5,1-cJ-1,2,4- -triazine-6-carboxylate. 2-( 2H-1,2,4-Triazol-3-:ylhydrazono) malonitrile cyclized unambiguously to 7-amino-6-cyano-1,2,4-triazolo-[ 5,1-c]-1,2,4- triazine. Drastic hydrolysis of ethyl 2-(2H-1,2,4-triazol-3-yllhydrazono)-cyanoacetate, ethyl 7-amino-1, 2,4-triazolo[ 5,1-c]-1,2,4-triazine-6-carboxylate, 6-cyano-1,2,4-triazolo[ 5,1-c]-1,2,4-triazin-7{ 4H)-one and 7-amino-6- cyano-1,2,4-triazolo[5,1-c]-1,2,4-triazine gave a hydrate of 1,2,4-triazo1o[5,1-c ]-1,2,4-triazin-7(4H)-one. Mass spectral fragmentations of 7-aminoazolo-[5,1-c]-1,2,4-triazinesconfirm that the azole ring is more stable than the 1,2,4-triazine ring on electron impact.