Commonly prescribed small molecule drugs can have net-positive and well-understood safety profiles when prescribed individually, but unexpected consequences when taken at the same time. Detection of these drug-drug interactions (DDIs) continues to be a critical and unmet area of translational research. The Centers for Disease Control and Prevention (CDC) estimate that one third of Americans are concurrently taking two or more prescription drugs, and DDIs are estimated to be responsible for 17% of all drug adverse events. The consequences of DDIs can be relatively minor (headache, skin rash) or much more severe (bleeding, liver toxicity). At a cellular level, DDIs can occur as a result of both drugs competing for metabolism (known as pharmacokinetic interactions) or targeting the same protein target or biological pathway (pharmacodynamic interactions). Clinical trials typically focus on the effects of individual drugs, leaving DDIs to usually be discovered only after the drugs have been approved. One of the most carefully studied drug adverse events is long QT syndrome (LQTS), an unexpected change in the heart's electrical activity that can lead to a potentially fatal ventricular tachycardia known as torsades de pointes (TdP). Some patients have genetic mutations that lead to congenital forms of LQTS, while drug-induced LQTS typically occurs via block of the hERG potassium channel (KCNH2) responsible for ventricular repolarization. After a number of high profile drugs were withdrawn from the market due to discovered risk of TdP, the FDA issued guidelines so that pharmaceutical companies could anticipate and test for this side effect before a new drug is approved. These recommendations have helped prevent new QT-prolonging drugs from entering the market, but nonetheless over 180 approved drugs have been associated with drug-induced LQTS. While information on individual QT-prolonging drugs is thus readily available to clinicians, little has remained known about DDIs (QT-DDIs). There are many more commonly prescribed drugs that are safe when given individually but could increase TdP risk when administered together. This troubling situation is compounded by the fact that traditional post-market surveillance algorithms are poorly equipped to sensitively and specifically detect DDIs. Data science – the application of rigorous analytical methods to large datasets – offers an opportunity for predicting previously unknown QT-DDIs. Some biomedical datasets (such as drug-target binding affinities and experiments to determine protein-protein interactions) have been collected explicitly for research, while other valuable datasets (such as electronic health records) were initially recorded for billing purposes. Each data modality has its own important set of advantages and disadvantages, and integrative data science approaches can incorporate multiple types of data to help account for these limitations. In this thesis we develop new data sciences techniques that combine clinical, biological, chemical, and genetic data. These approaches are explicitly designed to be robust to biased and missing data. We apply these new methodologies to (1) predict new QT-DDIs, (2) validate them experimentally, and (3) investigate their molecular and genetic mechanisms. We exemplify this approach in the discovery of a previously unknown QT-DDI between ceftriaxone (cephalosporin antibiotic) and lansoprazole (proton pump inhibitor); importantly, both drugs have no cardiac indications and are safe when given individually. The clinical data mining, drug target prediction, biological network analysis, genetic ancestry prediction, and experimental validation methods described in this thesis form the basis for a comprehensive pipeline to predict QT-DDIs rapidly and robustly. They also provide an opportunity for further enriching our understanding of LQTS biology and ultimately enabling the design of safer drugs.

OBJETIVOS: Os objetivos da presente pesquisa são (i) identificar os fármacos prescritos aos pacientes idosos matriculados em ambulatório didático de geriatria; (ii) estudo da possibilidade de ocorrência de interações medicamentosas nos pacientes ambulatoriais; e (iii) proposta de modelo de rotina de intervenção preventiva para evitar interações medicamentosas prejudiciais de significância clínica antes do aviamento da receita, respeitando a rotina e os recursos disponíveis em um ambulatório de geriatria. CASUÍSTICA e MÉTODO: Ensaio aberto observacional descritivo prospectivo realizado no Ambulatório Didático de Geriatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, por meio da análise dos prontuários dos pacientes, acima de 60 anos de idade, na hora da consulta. RESULTADO: Neste Ambulatório foram feitos 380 atendimentos para 124 pacientes, prescrito 211 fármacos e 7 associações fixas, havendo a polimedicação e apenas 8 receitas continham um medicamento. Foram encontradas 65,3% receitas com interações medicamentosas e destas, 63,6% no sexo feminino e 70,1% no sexo masculino. CONCLUSÃO: Houve a identificação dos fármacos prescritos para os idosos, onde a possibilidade de ocorrência de interações medicamentosas foi alta. A proposta de modelo de rotina de intervenção para evitar interações medicamentosas foi aprovada. / OBJECTIVES: The objectives of the research are: (i) identify the drugs prescribed to the elderly enrolled in didatic ambulatory of geriatry; (ii) study of the possibility of ocorrence of drug-drug interactions in these outpatients; e (iii) propose a pattern of routine of intervention to avoid drug-drug interactions harmful of clinical significance before the prescription, respecting the routine, and the resources available in a ambulatory of geriatry. CASUISTIC and METHOD: A prospective descritive observational open assay realized in the Didatic Ambulatory of Geriatry at the Hospital of the Clinics of the Faculty of Medicine of the University of San Paul, by means of the analysis of the promptuary of the outpatients, older than 60 years of age, during the consultation. RESULTS: In these Ambulatory were done 380 attendances for 124 outpatients, prescribed 211 drugs, and 7 fixed association, having polypharmacy and just 8 recipes contained one drug. There were 65,3% recipes with drug-drug interactions, and of these, 63,6% in female, and 70,1% in male. CONCLUSION: The drugs prescribed to the outpatients were identified, and the possibility of ocorrence of drug-drug interactions was high. The purpose of pattern of routine of intervention to avoid the drug-drug interactions was approved.

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Two diverse works regarding DNA-Drug Interaction are presented here. The first portion deals with covalent interactions between compounds that are derivatives of heterocyclic aza-enediynes and DNA (conventional Watson-Crick base paired double stranded DNA) and the second is related to non-covalent interactions of these compounds with G-quadruplex DNA. The aza-enediynes have been studied for their ability to undergo aza-variants of the Bergman and Myers cyclizations, and the potential role of the ensuing diradicals in DNA cleavage chemistry. The aza-Myers-Saito cyclization of aza-enyne allenes that are derived from base-promoted isomerization of skipped aza-enediynes has been recently reported. In the first part of the dissertation, the synthesis and DNA cleavage chemistry of a series of pyridinium skipped aza-enediynes (2-alkynyl-Npropargyl pyridine salts) are reported. Efficient DNA cleavage requires the presence of the skipped aza-enediyne functionality, and optimal DNA cleavage occurs at basic pH. An optimized analog containing a p-methoxyphenyl substituent was prepared. Studies with radiolabeled DNA duplexes reveal that this analog generates nonselective frank DNA strand breaks, via deoxyribosyl 4'-hydrogen atom abstraction, and also leads to oxidation of DNA guanine bases. This is the first report of enediynelike radical-based DNA cleavage by an agent designed to undergo an alternative diradical-generating cyclization. The second part is based upon the growing evidence for G-quadruplex DNA structures in genomic DNA and the presumed need to resolve these structures for replication. A prototypical replicative helicase - SV40 large T-antigen (T-ag), a multifunctional protein with duplex DNA helicase activity is shown to also unwind G-quadruplex DNA structures. A series of G-quadruplex-interactive agents, particularly perylene diimide derivatives, is explored for inhibition of T-ag duplex and G-quadruplex DNA unwinding activities, and it is revealed that certain perylene diimides are both potent and selective inhibitors of the G-quadruplex DNA helicase activity of T-ag. Surface plasmon resonance and fluorescence spectroscopic Gquadruplex DNA binding studies of these T-ag G-quadruplex helicase inhibitors have been carried out, demonstrating the importance of attributes in addition to binding affinity for G-quadruplex DNA that may be important for inhibition. The identification of potent and selective inhibitors of the G-quadruplex helicase activity of T-ag provides tools for probing the specific role of this activity in SV40 replication.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Adelaide, Dept. of Dentistry, 1999. / Bibliography: leaves 249-260.

Thesis (M.S.)--Rochester Institute of Technology, 1990. / Includes bibliographical references, (leaves 108-110).

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 134-149).