Jeanette C. Roberts

Acute effects of novel selenazolidines on murine chemoprotective enzymes.

Novel selenazolidines, designed as l-selenocysteine prodrugs and potential cancer chemopreventive agents, were examined for their ability to affect the transcription of murine hepatic chemoprotective enzymes. Compounds investigated were selenazolidine-4(R)-carboxylic acid (SCA) and six 2-substituted derivatives that cover a C log P range of -0.512 to -3.062. Their biological effects were compared with those of L-selenocystine. Gene transcripts were examined 24 h after a single dose, administered i.p. and i.g., and covered a range of chemoprotective enzymes; alpha, mu and pi class glutathione transferases (Gsts), UDP-glucuronosyltransferases (Ugts) 1a1, 1a6, 1a9, and 2b5, glutathione peroxidase 1 (Gpx), thioredoxin reductase (Tr), NAD(P)H-quinone oxidoreductase 1 (Nqo), and microsomal epoxide hydrolase (Meh). When given i.g., 2-butyl SCA (BSCA) resulted in elevations in alpha, mu and pi class Gsts, Ugt1a6, Tr, and Gpx, and 2-phenyl SCA (PhSCA) elevated GstP, Ugt1a9, Tr, Gpx (3 kb), and Meh. Other derivatives with C log P values both lower [2-(2-hydroxy)phenyl SCA (PhOHSCA) and 2-methyl SCA (MSCA)] and higher [2-cyclohexyl SCA (ChSCA) and 2-oxo SCA (OSCA)] than BSCA and PhSCA elevated far fewer transcripts; PhOHSCA (Ugt1a1, Gpx), MSCA (Ugt1a1, Meh), ChSCA (Ugt1a1, Ugt1a9), and OSCA (Ugt1a6, Ugt1a9, GstM). When given i.p., the most pervasive transcript changes were parallel increases in Nqo and Tr transcripts which occurred with BSCA, PhSCA, MSCA, and OSCA. PhSCA also increased GstP, and PhOHSCA increased Ugt1a1 and Ugt1a6 levels. Unique among the compounds, PhSCA reduced the transcript levels of GstA, and the 1.6 kb transcript of Gpx although only when given i.p. Neither l-selenocystine nor SCA affected the level of any transcript and no compound altered the amount of Ugt2b5 mRNA. Despite chemical similarity and common ability to potentially serve as a source of l-selenocysteine, each selenazolidine compound appeared to elicit a unique pattern of mRNA responses and by either route of administration, there was no correlation between the magnitude of response of any gene and the calculated C log P values of the organoselenium compounds.

Are We Producing Innovators and Leaders or Change Resisters and Followers

Education seems to be in America the only commodity of which the customer tries to get as little he can for his money. (1) The Scottish social philosopher Adam Smith, who gave us the concept of the invisible hand as a force in society, is often credited with articulating the importance of the unintended consequences of actions, especially those taken on a societal scale. History is replete with examples of public policy that, while intended to address a societal need, has given rise to long-term, unanticipated negative consequences. For example, the generous donation of clothing to certain regions of Africa has decimated the local textile industry, exacerbating rather than relieving poverty. (2) In the healthcare arena, 1 of the commonly cited unintended consequences of our educational and practice efforts is the lack of innovation in health care and healthcare delivery. The Institute of Medicine Roundtable on Value & Science-Driven Health Care, whose purpose is the development of a learning healthcare system that is designed ... to drive the process of discovery as a natural outgrowth of patient care; and to ensure innovation, quality, safety, and value in health care, has noted that although medical care in the United States has the capability to be the worlds best, it currently falls short. Far too often, care that is important is not delivered, and care that is delivered is not important. (3) The Roundtable was referring to health care in general, but we believe that their concerns are especially applicable to pharmacy practice and education. Over the past 2 decades, pharmacy education has undergone a major transformation with the shift to a doctor of pharmacy degree for entry-level practice. This change was made because of the prevailing belief at the time that pharmacy practice and pharmaceutical science were advancing to the point where additional education was required to ensure that the pharmacy profession maintained its leadership role in medication therapy management and ensuring the safety of drug therapy. (4) The result of this educational shift was a number of changes in how we recruit, educate, and place our students. While each measure enacted has been intended to advance our education of new professionals, it is legitimate to ask if these well-intentioned actions are giving rise to inadvertent negative consequences. In particular, we suggest that pharmacy educational programs are at risk of producing not the leaders and innovators needed to change health care but rather followers who will inappropriately tend to preserve the status quo in health care and pharmacy practice. We believe there are several trends promoting this concern. These are widespread and affect our key processes: admissions/recruitment, curricular design, programmatic evaluation, and preparation/advising for career placement. Our concerns begin with how we select students for admission to our programs. There is significant research published on the various admission processes used in colleges and schools of pharmacy. The research indicates that our quantitative measures (eg, Pharmacy College Admissions Test scores, prepharmacy grade-point average [GPA], math/science grades) are good predictors of academic success, defined as professional program GPA, graduation rates, and success on national board examinations. (5-9) Although most schools use these measures as key predictors for admittance, there appears to be little research on how good these measures are at predicting applicants future leadership potential or their likelihood of becoming change agents for the profession. Fortunately, the requirement of the Accreditation Council for Pharmacy Education (ACPE) that all potential enrollees be interviewed enables us to combine these quantitative criteria with qualitative assessments. Interview approaches appear to vary widely and the ability of these approaches to predict students academic performance or, more importantly, their potential for leadership or innovation is not clear. …

Maintaining pharmacy education's research focus as the academy expands.

In 2006, dean William H. Campbell made the following observations: For academic programs to provide quality professional instruction, full-time faculty must be actively engaged in research in the pharmaceutical sciences...Faculty who cannot participate in expanding the body of knowledge required by practice and science cannot be expected to provide mastery level instruction to pharmacy students. Demonstration of active engagement in the pharmaceutical sciences must include extramural support, scholarly publication, scientific presentations, and supervision of graduate (masters, PhD, postdoctoral) students... (1) The authors agree with this assessment. Indeed, in crafting Standards 2007, (2) the Accreditation Council for Pharmacy Education (ACPE), through stakeholder feedback, listed scholarship and research as one of 12 areas that were emphasized in the revision process. There are different forms of scholarship, (3) with research (or the scholarship of discovery) being just one. In Standards 2007, the relevant section is Standard 25 (Faculty and Staff), guideline 8, which reads: Faculty should generate and disseminate knowledge through scholarship. Scholarship by faculty members, including the scholarship of teaching, must be evident and demonstrated by productive research and other scholarly activities, such as contributions to the scientific, professional, and educational literature; publication of books and review articles; and successes in securing extramural funding to support research and other scholarly activities. Although the standard may seem straightforward, it could be interpreted in different ways: from non-research forms of scholarship (eg, review papers); to alternate forms of scholarship not necessarily associated with publication, such as the scholarship of application (ie, clinical practice) or the scholarship of engagement (ie, public service); to the traditional currency of research in colleges and schools of pharmacy, with benchmarks such as competitive federal funding and subsequent peer-reviewed publications of original work in visible, high-impact journals. The authors do not wish to minimize the importance of scholarship, broadly defined (3); all forms of scholarly contribution within colleges and schools of pharmacy are clearly important. Nevertheless, what we are most concerned with, and is the subject of this statement, is the latter form of scholarship, defined by Boyer (3) as the scholarship of discovery. The report of the 2003-2004 American Association of Colleges of Pharmacy (AACP) Research and Graduate Affairs Committee (4) noted an increasing concern about the potential diminution of the academys collective scholarship, particularly in the area of the scholarship of discovery, because of the increasing numbers of new pharmacy programs at institutions with an unknown culture of scholarship. Eight years after that report, it is now possible to objectively describe the cohort of newer colleges with regard to their emphasis on research and to preliminarily discern if this committees concerns were well founded. For the purposes of this paper, we compared the new colleges and schools of pharmacy (those that admitted students during or after the year 2000) and the older colleges from the AACP Web site (5) list of members with respect to their research focus. There are 45 colleges and schools of pharmacy that first admitted students during or after the year 2000 and 79 colleges in the pre-2000 group. Of the newer colleges and schools, 10 of the 45 have research as a stated part of their mission (though many more mention scholarship). Most are not associated with academic health centers, (6) which are great sources of interdisciplinary education and also provide access to patients for research, non-pharmacy collaborators, and a culture of translational research and discovery. …