Class of 2007 Abstract / Objectives: The purpose of this study was to determine if there is a difference between both graduating medical and pharmacy students in their capabilities to appropriately recognize drug-drug interactions that have led or can lead to serious toxicological consequences in humans. The hypothesis of this study was that there would be no difference between the ability of medical and pharmacy students to recognize potential drug-drug interactions. Methods: A two-page questionnaire was giving during the last semester before both the medical and pharmacy students graduate. The first page requested information about demographics, such as: gender, age, current educational program, previous education in healthcare, other degrees held, and average hours worked in healthcare per week for the past year. The second page contained 22 questions on potential drug-drug interactions. Also, there will be some questions that do not contain any drug-drug interactions. The students had four choices, in which they could answer. The choices were (1) The two drugs should not be used together (contraindicated), (2) The two drugs may be used safely together with monitoring, (3) The two drugs may be used safely together without monitoring, and (4) Not sure if the drugs can be used together. Results: Of the 168 questionnaires distributed, 51 were completed and returned. Forty-seven pharmacy students responded, while only 4 medical students responded. Pharmacy students correctly identified 38.4% + 11.7% of the interactions. The minimum correct responses was 13.6% and the maximum was 68.2% Pharmacy students without a bachelor of science (BS) performed slightly better than the students having a BS with a mean score of 40.0% + 3.0% and 37.1% + 9.0%, respectively. There was no significant difference between the groups (p = 0.42). Males had a mean score of 39.1% + 8.2%, while females had a mean score of 38.1% + 13.1%. There was no significant difference between the groups (p = 0.78). Also, there was no significant difference between the student’s age or how many hours they worked per week regarding the percent of correct responses.

Adverse Drug Reactions (ADRs) are a major cause of morbidity and mortality worldwide. Clinical trials, which are extremely costly, human labor intensive and specific to controlled human subjects, are ineffective to uncover all ADRs related to a drug. There is thus a growing need of computing-supported methods facilitating the automated detection of drugs-related ADRs from large reports data sets; especially ADRs that left undiscovered during clinical trials but later arise due to drug-drug interactions or prolonged usage. For this purpose, big data sets available through drug-surveillance programs and social media provide a wealth of longevity information and thus a huge opportunity. In this research, we thus design a system using machine learning techniques to discover severe unknown ADRs triggered by a combination of drugs, also known as drug-drug-interaction. Our proposed Multi-drug Adverse Reaction Analytics System (MARAS) adopts and adapts an association rule mining-based methodology by incorporating contextual information to detect, highlight and visualize interesting drug combinations that are strongly associated with a set of ADRs. MARAS extracts non-spurious associations that are true representations of the combination of drugs taken and reported by patients. We demonstrate the utility of MARAS via case studies from the medical literature, and the usability of the MARAS system via a user study using real world medical data extracted from the FDA Adverse Event Reporting System (FAERS).

The use of drug combinations (DCs) in cancer therapy can prevent the development of drug resistance and decrease the severity and number of side effects. Synthetic lethality (SL), a genetic interaction wherein two nonessential genes cause cell death when knocked out simultaneously, has been suggested as a method of identifying novel DCs. A combination of two drugs that mimic genetic knockout may cause cellular death through a synthetic lethal pathway. Because SL can be context-specific, it may be possible to find DCs that target SL pairs in tumours while leaving healthy cells unscathed. However, elucidating all synthetic lethal pairs in humans would take more than 200 million experiments in a single biological context – an unmanageably large search space. It is thus necessary to develop computational methods to predict human SL. In this thesis, we develop connectivity homology, a novel measure of network similarity that allows for the comparison of interspecies protein-protein interaction networks. We then use this principle to develop Species-INdependent TRAnslation (SINaTRA), an algorithm that allows us to predict SL between species using protein-protein interaction networks. We validate it by predicting SL in S. pombe from S. cerevisiae, then generate over 100 million SINaTRA scores for putative human SL pairs. We use these data to predict new areas of cancer combination therapy, and then test fifteen of these predictions across several cell lines. Finally, in order to better understand synergy, we develop DAVISS (Data-driven Assessment of Variability In Synergy Scores), a novel way to statistically evaluate the significance of a drug interaction.

Dissertation (Ph.D.)--University of Stellenbosch, 1996. / Bibliography. Also available via the Internet.

The aim of this study was to investigate the induction of CYP1A by DMSO, to determine whether DMSO induced other P450 isozymes (CYP2B) and to compare the effects of DMSO and another differentiating agent, sodium butyrate. Induction of CYP1A-dependent ethoxyresorufin-O-deethylase (EROD) was observed in the presence of increasing concentrations of DMSO. All concentration investigated (1%, 1.5% and 2%) caused induction (2-3 fold), and enhanced BA-induction of EROD. Enhancement of BA-induction was greater with 1% and 1.5% DMSO (2.5-3 fold over BA alone) than with 2% (1.8-fold). DMSO alone did not increase CYP1A1 RNA levels. Hepatocytes treated with BA and DMSO together exhibited a 1.3-fold greater increase in RNA levels than with BA alone. Western blotting indicated that CYP1A1 protein was increased by inducers (BA, DMSO and isosafrole), but that CYP1A2 was not. This indicates that the CYP1A1 isozyme is responsible for EROD activity in these cultures, and that the CYP1A2-induction mechanism is lost in rat hepatocytes cultured under the conditions of these experiments. This observation was confirmed by the lack of CYP1A2-dependent phenacetin-O-deethylase (POD) activity in culture. The substituted benzimidazole omeprazole has been shown to induce CYP1A isozymes in human hepatocyte cultures. In this study omeprazole was not effective in inducing EROD activity in rat hepatocytes or <I>in vivo</I> in the rat. This confirms that rat hepatocytes are not a good model for CYP1A induction in man. DMSO appears to be isozyme specific, since CYP2B-dependent pentoxyresorufin-O-dealkylase (PROD) activity was not increased by DMSO, and phenobarbitone (PB) induction of PROD was enhanced only slightly by DMSO on day 3 of culture (4-fold over control; 1.5-fold over PB alone). Sodium butyrate and DMSO were both shown to induce differentiation of rat hepatocyte, with maintenance of low level of γ-glutamyl transferase activity, and maintenance of a more rounded morphology.

Malaria has long affected the world both socially and economically. Annually, there are 1.5-2.7 million deaths and 300-500 million clinical infections (WHO, 1998). Several antimalarial agents (such as chloroquine, quinine, pyrimethamine, cycloguanil, sulphadoxine and others) have lost their effectiveness against this disease through drug resistance being developed by the malarial parasites (The- Wellcome-Trust, 1999). Although there is no hard-core evidence of drug resistance shown on the new antimalarial compounds (artemisinin and artesunate), induced resistant studies in animal models have demonstrated that the malarial parasites have capabilities to develop resistance to these compounds (Ittarat et al., 2003; Meshnick, 1998; Meshnick, 2002; Walker et al., 2000). Furthermore, a useful vaccine has yet to be developed due to the complicated life cycle of the malarial parasites (The- Wellcome-Trust, 1999). As such, the re-emergence of this deadly infectious disease has caused an urgent awareness to constantly look for novel targets and compounds. In this present study, Plasmodium falciparum (clone 3D7) was cultured in vitro in human red blood cells for extraction of total RNA which was later reverse transcribed into cDNA. The áI-, áII- and â-tubulin genes of the parasite were then successfully amplified and cloned into a bacterial protein expression vector, pGEX- 6P-1. The tubulin genes were then sequenced and analysed by comparison with previously published homologues. It was found that the sequenced gene of áItubulin was different at twelve bases, of which only six of these had resulted in changes in amino acid residues. áII- and â-tubulin genes demonstrated 100% sequence similarity with the published sequences of clone 3D7, but differences were observed between this clone and other strains (strains NF54 & 7G8) of â-tubulin. Nevertheless, the differences were minor in áI- and â-tubulins and there was greater than 99% homology. Subsequently, all three Plasmodium recombinant tubulin proteins were separately expressed and purified. Insoluble aggregates (inclusion bodies) of these recombinant tubulins were also refolded and have been tested positive for their structural characteristics in Western blot analysis. Both soluble and refolded recombinant tubulins of malaria were examined in a drugtubulin interaction study using sulfhydryl reactivity and fluorescence quenching techniques. Known tubulin inhibitors (colchicine, tubulozole-c and vinblastine) and novel synthetic compounds (CCWA-110, 239 and 443) were used as the drug compounds to determine the dynamics and kinetics of the interactions. In addition, mammalian tubulin was also used to determine the potential toxicity effects of these compounds. Similarities were observed with other published reports in the binding of colchicine with the recombinant tubulins, hence confirming proposed binding sites of this compound on the Plasmodium recombinant tubulins. Two synthetic compounds (CCWA-239 and 443) that have previously tested positive against P. falciparum in vitro were found to bind effectively with all three tubulin monomers, while displaying low binding interactions with the mammalian tubulin, thus indicating that these compounds have potential antimalarial activity. Therefore, this study has satisfied and fulfilled all the aims and hypotheses that have previously been stated.

Thesis (Ph. D.)--School of Chemistry and Biochemistry, Georgia Institute of Technology, 2005. Directed by Lawrence A. Bottomley. / William D. Hunt, Committee Member ; Nicholas V. Hud, Committee Member ; L. Andrew Lyon, Committee Member ; Lawrence A. Bottomley, Committee Chair ; Loren D. Williams, Committee Member. Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves 177-194).

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Class of 2008 Abstract / Objectives: The purpose of this study is to compare the critical drug-drug interaction alerting software at the Department of Veteran Affairs with Hansten and Horn's drug analysis and management (DIAM) and Micromedex®. Methods: The Department of Veterans Affairs supplied a list of drug-drug interacting (DDI) pairs. Each pair was labled as significant or critical. The critical interactions were included in the study (n=1018). Two researchers inputed the interactions into Micromedex and looked up the interactions in Hansten and Horn's drug interactions analysis and management (DIAM). A Kappa statistic was used to calculate the agreement between the 2 researchers. Results: The researchers differed in the number of interactions found to be "contraindicated" or "major" in Micromedex and "avoid" or "usually aviod" in DIAM (researcher 1= 683, 330, respectively; researcher 2= 672,176, respectively) with a Kappa of 0.9 for Micromedex and 0.57 for DIAM. Conclusions: Our study suggests that there is a difference between the VA drug interaction alerting system, Micromedex ® and DIAM in regards to the way they list interactions and their method of rating the level of severity of the interactions. Also, there may be a difference in the way each researcher interprets the information.