Thesis (M.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Masters Abstracts International, Volume: 46-03, page: 1501. Adviser: Jimmy L. Perkins. Includes bibliographical references.

I692: Project in Bioinformatics August 2005 / Objective: Literature review to evaluate the extent to which Bioinformatics has facilitated the drug discovery and development process from an economic perspective Problem: A plethora of genomic and proteomic information was uncovered by the U.S Human Genome Project (HGP). Despite the projected impact that Bioinformatics and Pharmacogenomics were projected to have in the drug discovery and development process, the challenges facing the pharmaceutical companies – in this regard, still persist. Design: An extensive integrated literature review of library resources such as MEDLINE, ERIC, PsychInfo, EconLit, Social Services Abstracts, ABI/INFORM and LISA (all 1990 – Present). These electronic databases were researched because of their focuses on the healthcare sector, medical and scientific innovations, economic modeling and analysis, bioinformatics and computational biology, applied social research and technology applications. Semi-structured interviews of Bioinformatics professionals were also conducted to complement the literature review. Also, Internet-based databases from reliable resources were also researched resulting in serendipitous discoveries. Sample: Published English language reports of studies and research carried out worldwide from 1990 to 2004, relating to drug discovery and development. Selection criteria: Primary focus was on research publications and journals that identify and discuss the practice of Bioinformatics, especially in the area of drug discovery and development. Premium was placed on articles and publications that discussed the economic impacts of Bioinformatics in the drug discovery process. Results: Though the goals of Bioinformatics have been clearly defined, and the discipline is widely practiced in the pharmaceutical industry, this study has not found any definite attempts to evaluate its economic and regulatory impact specifically in facilitating the drug discovery and development process, and the delivery of personalized drugs. Discussion: Bioinformatics and Pharmacogenomics are the new facets of the ever-evolving drug discovery and development process. It may still be a while before their full impact and potential is attained.

No description available.

Informed consent for pharmacogenomic testing in people with a learning disability Background Advances in genomic healthcare will enable medication to be tailored to each individual’s needs, based on subtle genetic variations. This will result in individuals being asked to consent to genetic testing for this purpose. The recent political agenda for social change has emphasised the right of people with learning disabilities to have more autonomy and make their own decisions. There have also been significant changes in the way healthcare practitioners relate to their patients, with a shift away from paternalism towards shared decision-making. Research Aim The aims of the study were (1) to explore the information needs of people with mild to moderate learning disabilities with respect to pharmacogenomic tests and (2) to identify ways of facilitating informed consent. Methods An integrative literature review was conducted to identify research on informed consent to healthcare interventions in people with learning disabilities (Phase 1). Subsequent phases (Phases 2-4) of the study were conducted using an ethnographic approach. Phase 2 involved observation of six participants with learning disabilities undergoing a routine blood test consultation in general practice. This was followed by Phase 3, in which semi-structured interviews with 14 participants with learning disabilities were conducted. In Phase 4, three different methods were used: focus groups with carers (four paid carers, five family carers), an on-line bulletin board for healthcare professionals (five participants) and interviews with six key informants from the field of learning disability. Findings The data showed consent procedures were often inadequate and there was inconsistent knowledge of mental capacity law amongst health professionals. Provision of information to patients prior to a blood test was variable, but interviews with people with learning disabilities revealed the fact that this information may not be wanted by them. People with learning disabilities viewed pharmacogenomic tests as similar to other blood tests and would want access to them. The attitudes of paid carers and family carers differed in terms of decision-making opportunities for people with learning disabilities. Conclusions Healthcare practitioners, carers and people with learning disability need to be familiar with the principles of the Mental Capacity Act to facilitate valid consent in the healthcare context. Healthcare practitioners also need to be made aware of developments in pharmacogenomics if it is to become part of routine health care. Finally, this study demonstrated the value of qualitative research in exploring the knowledge and attitudes of people with learning disability.

Class of 2009 Abstract / This study was partially funded by the Centers for Disease Control Grant No. 1U38GD000070 OBJECTIVES The purpose of this study was to assess the level of pharmacogenetics and pharmacogenomics instruction and of faculty and curriculum development in schools and colleges of pharmacy (here after colleges of pharmacy) in the United States based on the current AACP policy. METHODS: A revised questionnaire based on a previous study by Latif and McKay and 2008 House of Delegates of the American Association of Colleges of Pharmacy (AACP) was sent via email to 90 contacts identified by their respective deans at colleges of pharmacy in the United States. RESULTS: Of the 90 questionnaires sent, seventy-five (83.3% ) usable questionnaires were returned to the investigators. Coverages in the curriculum and its level of importance to the responder were assessed based on the guidelines outlined by AACP. Ninety-one percent of the colleges of pharmacy are currently including pharmacogenetics and pharmacogenomics at the PharmD level, a significant increase (p = 0.0134) from Latif and McKay, with the majority of the instruction as a required didactic course. Less than half (46.7%) of the colleges of pharmacy are planning to increase their course work of pharmacogenetic/pharmacogenomic over the next three years, at the same time as 54.7% have no plans to follow the AACP policy for faculty development. CONCLUSIONS: The genetic basis of disease core competency is being covered and considered important in pharmacogenetic/pharmacogenomic curriculum. Ethical, social and economic implications are also considered an equally important competency in this curriculum; however, it is not being adequately covered. Although pharmacogenetic/pharmacogenomic is currently in the curriculum, the majority of colleges of pharmacy are not adequately prepared to comply with the AACP policy regarding faculty development.

Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance. This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. A constructed interactome suggested that there is cross-talk at the Nrf-2 oxidative stress pathway between genes associated with resistance to doxorubicin and paclitaxel. This unique GWA approach serves as a proof-of-principle study and systematically investigates targets responsible for variable response to chemotherapy in breast tumor cells and possibly the tumors of breast cancer patients. Overall, the model discovered novel candidate genes that have not been previously associated with doxorubicin and paclitaxel cytotoxicity. Future studies will be directed at illustrating a causative relationship between the observed genomic changes and drug resistance in breast cancer patients undergoing doxorubicin and paclitaxel chemotherapy.

Η φαρμοκογονιδιωματική είναι η μελέτη του πως οι γενετικές διαφορές επηρεάζουν τις ποικίλες αποκρίσεις των ασθενών σε φάρμακα. Τα τελευταία χρόνια, έχουν γίνει πολλές μελέτες για την επιλογή φαρμακογονιδιωματικών δεικτών σε διάφορους πληθυσμούς της Ευρώπης, αλλά και παγκοσμίως. Εξετάσαμε και συγκρίναμε τη δο-μή του γονιδιώματος του ελληνικού πληθυσμού όσον αφορά τους φαρμακογονιδι-ωματικούς δείκτες και τη συχνότητα εμφάνισης τους σε αυτόν σε σχέση με τους κεντροευρωπαίους (CEU),όπως έχουν μελετηθεί και καταταχθεί από το πρόγραμμα HapMap. Μια γενική μελέτη 1936 φαρμακογονιδιωματικών δεικτών σε 225 γονίδια με φαρμακογονιδιωματικό ενδιαφέρον διεξήχθη σε 50 υγιείς Έλληνες εθελοντές, χρησιμοποιώντας την DMET+ μικροσυστοιχίες (Affymetrix, Santa Clara,CA,USA). Η στατιστική ανάλυση αποκάλυψε 46 φαρμακογονιδιωματικούς δείκτες που παρου-σιάζουν σημαντική στατιστική διαφορά ανάμεσα στους δύο πληθυσμούς (p<0.05). Η μελέτη μας επεκτάθηκε σε συνολικά 10 πληθυσμούς, οι οποίοι χωρίστηκαν σε υποομάδες σύμφωνα με ιστορικά και γεωγραφικά κριτήρια, δηλαδή, Βαλκάνια (Ελ-λάδα, Κροατία, Σερβία, Σλοβενία), Κεντρική Ευρώπη (Ουγγαρία, Σλοβενία, Πολωνία, Τσεχία, Γερμανία), Νότια Ευρώπη (Ελλάδα, Μάλτα, Τουρκία). Σε αυτή την περίπτω-ση εστιάσαμε το ενδιαφέρον μας στη σύγκριση φαρμακογονιδιωματικών δεικτών που δεν εμφανίζονται ούτε πολύ σπάνια, αλλά ούτε και πολύ συχνά σε αυτές τις πληθυσμιακές ομάδες, δηλαδή σε ποσοστό εμφάνιση από 20% έως και 50%. Τελι-κά, αποδείχθηκε ότι 123 σημαντικοί φαρμακογονιδιωματικοί δείκτες στην υποομάδα της Νότιας Ευρώπης, 103 στην υποομάδα των Βαλκανίων και 106 στην υποομάδα της Κεντρικής Ευρώπης συγκλίνουν ως προς τις συχνότητες εμφάνισης τους. Συ-νεπώς, η κύρια και μελλοντική συνεισφορά αυτής της μελέτης είναι η συμβολή της στον εξορθολογισμό της φαρμακευτικής αγωγής σε αυτές τις χώρες με πιθανή μεί-ωση των ιατροφαρμακευτικών εξόδων. Ένα επιπρόσθετο (προαιρετικό) βήμα είναι η ανάπτυξη της DruGeVar (http://drugevar.genomicmedicinealliance.org), μιας βάσης δεδομένων τριγωνισμού φαρμάκων, γονιδίων και φαρμακογονιδιωματικών δεικτών, σε μια προσπάθεια κα-τασκευής μιας κατανοητής βάσης δεδομένων που θα μπορούσε να εξυπηρετεί την κλινική εφαρμογή της φαρμακογονιδιωματικής. Συνεπώς, ένα απλό και προγνωστικό προφίλ φαρμακευτικής απόκρισης, το οποίο θα παρέχει πληροφορίες για την πιθανότητα αποτελεσματικότητας και ασφάλειας ενός φαρμάκου για συγκεκριμένο ασθενή, θα αλλάξει την πρακτική και την οικονομία της ιατρικής. / Pharmacogenomics is the study of how genetic differences influence the variability in patients’ responses to drugs. In recent years there have been many studies on the selection of pharmacogenomic biomarkers, in different populations in Europe and worldwide. We examined and compared the genome structure of the Greek population in regards to pharmacogenomic biomarkers and their incidence in that population to HapMap CEU population. A general study of 1936 pharmacogenomic biomarkers in 235 genes with pharmacogenomic interest was conducted in 50 healthy Greek individuals by using DMET+ microarray (Affymetrix, Santa Clara,CA,USA). Statistical analysis revealed 46 pharmacogenomic biomarkers showing statistical significance among those two populations (p<0.05). We expanded our study to ten European populations dividing them into subgroups according to the history and geography standards, i.e. the Balkans (Greece, Croatia, Serbia, and Slovenia), Central (Hungary, Slovenia, Poland, Czech Republic and Germany) and Southern Europe (Greece, Malta, Turkey). In that case our interest was channeled in the comparison of pharmacogenomic biomarkers among 20%-50% frequency of appearance. Finally, i) 123 important pharmacogenomic biomarkers in the subgroup of South Europe, ii) 103 in the subgroup of Balkans and iii) 106 in the sub-group of Central Europe were posing vast convergence among these countries.So with this study we expect to contribute to the rationalization of medication in these countries with possible reductions in medical costs. An additional step was the development of DruGeVar (http://drugevar.genomicmedicinealliance.org), an online database triangulating drugs with genes and pharmacogenomics biomarkers in an effort to build a comprehensive database that could serve clinical pharmacogenomics. The medical significance and economic value of a simple, predictive medicine response profile, which will provide information on the likelihood of efficacy and safety of a drug for an individual patient, will change the practice and economics of medicine.

Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance. This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. A constructed interactome suggested that there is cross-talk at the Nrf-2 oxidative stress pathway between genes associated with resistance to doxorubicin and paclitaxel. This unique GWA approach serves as a proof-of-principle study and systematically investigates targets responsible for variable response to chemotherapy in breast tumor cells and possibly the tumors of breast cancer patients. Overall, the model discovered novel candidate genes that have not been previously associated with doxorubicin and paclitaxel cytotoxicity. Future studies will be directed at illustrating a causative relationship between the observed genomic changes and drug resistance in breast cancer patients undergoing doxorubicin and paclitaxel chemotherapy.

Warfarin, the most commonly prescribed anticoagulant, is principally metabolized by cytochrome P450 2C9 which functions by inhibiting the Vitamin K epoxide reductase. Genes CYP2C9 and VKORC1 code for these two proteins, respectively. CYP2C9 and VKORC1 exhibit genetic polymorphisms that have been shown to affect warfarin response and favorably facilitate warfarin dosing and improve clinical outcomes. However, none of these studies have involved populations from sub-Saharan Africa where the potential benefit of optimal dosing and reduced complications is greatest. Therefore, the thesis describes a study designed to investigate the role of genetic variations in CYP2C9 and VKORC1 on the time taken to reach a stable therapeutic international normalized ratio (INR) and warfarin dose required to maintain a therapeutic INR. This was a cross-sectional study of patients on warfarin to determine the relationship between genetic polymorphism in CYP2C9 and VKORC1 amongst black and mixed ancestry South Africans and clinical surrogates of warfarin metabolism. Medical records were accessed to determine time to INR and warfarin doses. DNA was extracted from blood samples, and genotyping for polymorphism in CYP2C9 (*2,*3,*8,*11) and VKORC1 (1173C>T, 1639G>A, 3730G>A) was accomplished by PCR-RFLP, Sanger sequencing and iPlex Mass Sequencing. Our results show that the genetic profile of CYP2C9 and VKORC1 differs between Black Africans (BA) and their Mixed Ancestry (MA) counterparts. VKORC1-1639AA genotype was observed at frequencies of 0.11 and 0.01 in the MA and BA, respectively. Time to stable INR was not influenced by CYP2C9 and VKORC1. Furthermore, compared to known genetic polymorphisms in these genes from population out of Africa, both qualitative and quantitative differences were observed. Finally, we found that VKORC1 genetic variation significantly affected the doses of warfarin in MA but had no effect in BA. These results suggest that further research in this area is warranted, and that it will be important to include populations from sub-Saharan Africa in future if the potential to develop personalized algorithms which integrate pharmacogenomics to assist with effective warfarin dosing and prevention of warfarin related complications is to be realized.

Conclusion: The majority of independent community pharmacists are interested in incorporating personalized medicine services into their practices, but they require further education before this is possible. Future initiatives should focus on the development of comprehensive education programs to further train pharmacists for provision of these services.Objectives: To evaluate the perceptions of independent community pharmacists within a regional independent community pharmacy cooperative on implementing personalized medicine services at their pharmacies and to gauge the pharmacists' self-reported knowledge of pharmacogenomic principles.Design: Descriptive, exploratory, nonexperimental study.Setting: American Pharmacy Services Corporation (APSC), 2011-12.Participants: Pharmacists (n = 101) affiliated with the independent pharmacies of APSC.Intervention: Single-mode surveyMain outcome measures: Independent community pharmacists' interest in implementing personalized medicine services, perceived readiness to provide such services, and perceived barriers to implementation.Results: 101 completed surveys were returned for data analysis. The majority of pharmacists surveyed (75%) expressed interest in offering personalized medicine services. When asked to describe their knowledge of pharmacogenomics and readiness to implement such services, more than 50% said they were not knowledgeable on the subject and would not currently be comfortable making drug therapy recommendations to physicians or confident counseling patients based on results of genetic screenings without further training and education. Respondents identified cost of providing the service, reimbursement issues, current knowledge of pharmacogenomics, and time to devote to the program as the greatest barriers to implementing personalized medicine services.