The Phamacologist March 2016

the

A Publication by The American Society for Pharmacology and Experimental Therapeutics

Pharmacologist Vol. 58 • Number 1 • March 2016

Inside: Election Results Award Winners Annual Meeting Program

Ivermectin and River Blindness

The Pharmacologist is published and distributed by the American Society for Pharmacology and Experimental Therapeutics.

Contents 1 Message from the President 3 Global Pharmacology Partnerships 4 Election Results 5 Award Winners 13 Feature Story: Ivermectin and River Blindness: The Chip Shot Heard Around the World

26 ASPET Annual Meeting at EB2016 39 Science Policy News 43 Education News 44 Journals News 46 Membership News 54 Members in the News 58 Division News 63 Chapter News 64 Crossword: ASPET History

THE PHARMACOLOGIST PRODUCTION TEAM Rich Dodenhoff Catherine L. Fry, PhD Dana Kauffman Judith A. Siuciak, PhD Suzie Thompson COUNCIL President Kenneth E. Thummel, PhD President-Elect David R. Sibley, PhD Past President Annette E. Fleckenstein, PhD Secretary/Treasurer Dennis C. Marshall, PhD Secretary/Treasurer-Elect Charles P. France, PhD Past Secretary/Treasurer Paul A. Insel, PhD Councilors Wayne Backes, PhD John D. Schuetz, PhD Margaret E. Gnegy, PhD Chair, Board of Publications Trustees Mary E. Vore, PhD Chair, Program Committee Scott Waldman, MD, PhD FASEB Board Representative Brian M. Cox, PhD Executive Officer Judith A. Siuciak, PhD The Pharmacologist (ISSN 0031-7004) is published quarterly in March, June, September, and December by the American Society for Pharmacology and Experimental Therapeutics, 9650 Rockville Pike, Bethesda, MD 20814-3995. Annual subscription rates: $25.00 for ASPET members; $50.00 for U.S. nonmembers and institutions; $75.00 for nonmembers and institutions outside the U.S. Single copy: $25.00. Copyright Š 2016 by the American Society for Pharmacology and Experimental Therapeutics Inc. All rights reserved.

Periodicals postage paid at Bethesda, MD. GST number for Canadian subscribers: BN:13489 2330 RT. ASPET assumes no responsibility for the statements and opinions advanced by contributors to The Pharmacologist.

Postmaster: Send address changes to: The Pharmacologist, ASPET, 9650 Rockville Pike, Bethesda, MD 20814-3995.

Cover image reprinted with permission from Merck

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Message from

The President With the start of the New Year, I hope that, like me, you are looking forward to attending EB2016 in San Diego (April 2-6) for a level of invigorating intellectual discourse that only a gathering of national and international pharmacologists and other biological scientists can bring. The ASPET component of the Experimental Biology program promises to be memorable, with significant breadth and depth in topics of traditional interest, as well as presentations of emerging innovations and discoveries that may transform therapeutics interventions in the prevention and treatment of disease.

This includes lectures from some of our 2016 scientific achievement award winners – Jing Yang, Bryan L. Roth, Masahiko Negishi, Travis Thompson, and Mark T. Nelson. ASPET will acknowledge the achievements of these and other ASPET scientific achievement award winners at its business meeting on Saturday, April 2nd.

The ASPET program at EB is also filled with multiple opportunities for young scientists to network and obtain research and career development advice from some of the finest members of our society. Notable events include the Undergraduate Networking and Career Development Luncheon, a symposium on “Undergraduate Research: Cultivating the Next Generation of Researchers through SURF and Beyond” and the Student/Postdoc Poster Competition, with expanded outreach to undergraduates (supported by an increased number of travel awards) that ASPET leadership plans to grow in future years. This year’s Graduate Student/Postdoctoral Colloquium will feature a presentation and discussion from Rick McGee, Associate Dean for Faculty Recruitment and Professional Development at the Northwestern Feinberg School of Medicine, on “Mentoring Your Mentor: Key Skills for Effective Mentoring Relationships with Shared Responsibility”. The theme of mentoring will be also be emphasized throughout the inaugural programming of the ASPET Mentoring Network led by Susan Ingram, Lynn Wecker, and other members of the ASPET Committee on Mentoring and Career Development, with critical support from our Education Manager, Catherine Fry, and special mentor training from Rick McGee. Funded through the BIG IDEAS initiative, the Mentoring Network matches mid- to late-career scientists with senior-level graduate students and postdoctoral fellows to help guide them in their development and career advancement by deconstructing the skills needed to succeed scientifically, professionally, psychologically, and socially.

Of course, a significant attraction of the EB meeting is the chance to attend symposia sponsored by the collective of participating societies. Your registration fee gives you free access to those events and exposure to an incredible diversity of research that, through an exchange of knowledge and perspectives, can foster new avenues of inquiry that are essential to the long-term health of ASPET. Community service during EB is also important to ASPET. For a third year, the Division for Behavioral Pharmacology is hosting Give a Day of Service at the Vincent de Paul Village in San Diego. All are invited to help provide assistance to San Diegans (contact Charles France, france@uthscsa.edu).

The election of ASPET Council and Division officers was recently completed, and I am pleased to announce that John Schuetz (john.schuetz@stjude.org), John Tesmer (tesmerjj@umich.edu), and Carol Beck (carol.beck@jefferson.edu) will be joining the senior leadership of ASPET as your president-elect, secretary/treasurer-elect and councilor, respectively.

Also, the names of our newly elected divisional officers can be found starting on page 58. Please join me in congratulating all of them and thanking all those that graciously agreed to stand for election–their service to the society is essential to its health and deserving of our utmost appreciation.

On a more somber note, it is with deepest sadness that I acknowledge the recent passing of Dr. Alfred G. Gilman.

He was a pioneer in the field of receptor pharmacology, winning the Nobel Prize in Physiology or Medicine in 1994 for his discovery of G proteins. A special tribute to Dr. Gilman, highlighting his lifetime achievements, can be found on page 49.

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2 Finally, I want to take this opportunity to announce two new additions to the ASPET office staff: Dave Chalker, Webmaster and Dana Kauffman, Marketing Communications Coordinator. They bring several years of experience in their respective areas of expertise and a level of enthusiasm that we know will enhance the ability of the ASPET office and elected leadership to serve you, the members of the society, and the educational, industrial, regulatory, and advocacy organizations that you represent.

Cheers – and I look forward to seeing you in San Diego for EB2016!

Kenneth E. Thummel ASPET President

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Global Pharmacology Partnerships An important element of the ASPET mission is to advocate for the discipline of pharmacology and its associated research and educational enterprises. While we have the benefit of a dedicated and accomplished membership and administrative staff that work tirelessly to advance the mission of ASPET, there are also clear benefits to be gained by partnering with societies of pharmacology from other countries. To that end, ASPET has recently engaged with the British Pharmacological Society (BPS), the Japanese Pharmacological Society (JPS), and the Chinese Pharmacological Society (CNPHARS), as well as other international pharmacological societies, to foster an exchange of scientific knowledge and best educational practices that we hope will help address the health problems of the world.

Some examples planned for 2016 include an invited JPS-ASPET lecture at the 89th annual meeting of the JPS in Kyoto, Japan (March 9-11) by P. Jeffrey Conn (Vanderbilt University, USA), who will speak on “Allosteric modulators of GPCRs as a novel approach for treatment of CNS disorders.” Later this year, ASPET will sponsor a scientific symposium at the annual meeting of the BPS in London (December 13-15). CNPHAR will also be present at the 2016 BPS meeting, sponsoring their own scientific symposium and creating a remarkable opportunity for cultural and scientific exchange by three great societies.

Reciprocal arrangements for future ASPET meetings are under consideration.

On the horizon, the next meeting of the IUPHAR sponsored 18th World Congress of Basic and Clinical Pharmacology will be held in Kyoto, July 1-5, 2018.

While this may seem far off, the World Congress organizers have already reached out to the international community of pharmacologists and have invited proposals for the scientific program. Visit the meeting website at www.wcp2018.org.

I encourage all members of ASPET to consider contributing to and attending these and other international meetings of pharmacologists. Our future depends on the widest exchange of ideas, expertise, and discoveries.

P. Jeffrey Conn will be speaking on “Allosteric modulators of GPCRs as a novel approach for treatment of CNS disorders” at 10:30AM on March 10, 2016 during the 89th Annual Meeting of the Japanese Pharmacological Society. Be sure to check out the June 2016 issue of The Pharmacologist for more information by Dr. Conn.

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Election Results The 2016 ASPET election closed on January 15, 2016 with a great turnout. 19% of our regular, postdoctoral, and retired members participated in the election to vote for the Society’s new leadership.

Congratulations to newly elected Council members Dr. John D. Schuetz, Dr. John J.G. Tesmer, and Dr. Carol L. Beck who will begin their terms on July 1, 2016.

President-Elect

Secretary/Treasurer-Elect

Councilor

John D. Schuetz, PhD Member & Vice Chair, Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital

John J.G. Tesmer, PhD Professor of Pharmacology & Biological Sciences, Life Sciences Institute, University of Michigan

Carol L. Beck, PharmD, PhD Assistant Professor, Department of Pharmacology & Experimental Therapeutics, Sidney Kimmel Medical College; Assistant Dean for Curriculum, Jefferson College of Biomedical Sciences, Thomas Jefferson University

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Award Winners ASPET presents several major awards on either an annual or a biennial basis. These awards are given to recognize accomplishments either in specific areas of pharmacology or contributions to the discipline in general. We are pleased to announce our 2016 Scientific Achievement Award winners.

ASPET will present these awards on Saturday, April 2, 2016 at 6:00PM at the Business Meeting and Awards Presentation at the ASPET Annual Meeting at Experimental Biology 2016 at the San Diego Convention Center in Room 16AB.

John J. Abel Award in Pharmacology The John J. Abel Award in Pharmacology, presented annually, is named after the founder of ASPET. It was established in 1946 to stimulate fundamental research in pharmacology and experimental therapeutics by young investigators.

Jing Yang, PhD University of California, San Diego Dr. Jing Yang has been named the 2016 recipient of the John J. Abel Award in Pharmacology. Nominated by Paul Insel from the University of California, San Diego (UCSD), Dr. Yang is being recognized for her significant research achievements and ground breaking investigations in the field of pharmacology.

Dr. Yang is currently an associate professor of pharmacology and pediatrics at UCSD. As a postdoctoral fellow, Dr. Yang discovered that the transcription factor Twist1 and the epithelialmesenchymal transition (EMT) program play essential roles in tumor metastasis (Yang et al., Cell, 2004).

This study is considered ground breaking by demonstrating that tumor cells reactivate the latent EMT morphogenesis program to acquire the ability to invade and metastasize.

Dr. Yang obtained her PhD in molecular cancer biology from Duke University’s Graduate Program

in Cell and Molecular Biology, Department of Pharmacology and Cancer Biology in 1999. She then became a Damon Runyon Cancer Research Foundation postdoctoral fellow with Dr. Robert Weinberg at the Whitehead Institute. Dr. Yang joined the Department of Pharmacology at UCSD as assistant professor in 2006 and was promoted to associate professor with tenure in 2012.

Dr. Yang’s major research achievements as an independent investigator brought forth recognition in resolving a lengthy controversy concerning EMT in cancer metastasis, as her lab used an inducible Twist1 mouse model to demonstrate a dynamic requirement for EMT in metastasis. She discovered that carcinoma cells undergo EMT to invade and disseminate from the primary tumor, but upon reaching distant sites, tumor cells need to revert to an epithelial state to form macrometastases (Tsai et al., Cancer Cell, 2012). Her lab further discovered a novel Twist1-G3BP2 mechanotransduction signaling pathway that senses physical forces exerted by extracellular matrix in the tumor microenvironment to generate biochemical and cellular responses that drive EMT and tumor metastasis (Wei et al.,

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Nature Cell Biology, 2015). Dr. Yang also identified a novel function of Twist1 in metastasis by promoting invadopodia-mediated matrix degradation (Eckert et al., Cancer Cell, 2011). This study provided the in vivo evidence for an essential role of invadopodia in tumor metastasis and identified novel therapeutic targets to inhibit tumor invasion and metastasis.

In addition to her superb research efforts, Dr. Yang directed the ASPET-sponsored SURF program at

UCSD for several years, has been deeply involved in teaching cancer pharmacology to graduate and medical students, and has been a terrific mentor for graduate students and fellows.

Dr. Yang will deliver the John J. Abel Lecture titled, “Epithelial-Mesenchymal Plasticity in Carcinoma Metastasis” on Monday, April 4 from 8:30AM – 9:20AM in Room 16AB of the San Diego Convention Center.

Louis S. Goodman & Alfred Gilman Award in Receptor Pharmacology The Louis S. Goodman and Alfred Gilman Award in Receptor Pharmacology, presented biennially, was established in 1980 to recognize and stimulate outstanding research in the pharmacology of biological receptors. Such research is the foundation for a better understanding of the mechanisms of biological processes and potentially provides the basis for the discovery of drugs useful in the treatment of diseases.

Bryan L. Roth, MD, PhD University of North Carolina, Chapel Hill Dr. Bryan L. Roth is the recipient of the 2016 Louis S. Goodman & Alfred Gilman Award in Receptor Pharmacology. Dr. Roth was nominated by Henrik Dohlman and Gary Johnson from the University of North Carolina, Jeffrey Benovic from Thomas Jefferson University, and Marc Caron from Duke University. Dr. Roth is being recognized for his compelling contributions in the field of receptor pharmacology.

Dr. Roth received his MD and PhD from St. Louis University and additional training at the NIH, where he began his investigations of the molecular pharmacology of opioid receptors. After a residency and fellowship in psychiatry at Stanford University, he joined the faculty at Case Western Reserve University, and in 2006 relocated to the University of North Carolina, Chapel Hill, where he is currently the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics for the Department of Pharmacology. During this time he

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amassed an impressive CV, with nearly 40 patents, 400 publications–including 13 in Nature or Science– and 30,000 citations to date.

Dr. Roth is recognized for at least three distinct landmark contributions in receptor pharmacology.

First, in a 2000 paper and a follow up 2007 paper in New England Journal of Medicine, he reported the mechanism underlying the valvulopathic side effects of several clinicallyapproved drugs, including the blockbuster obesity drug fenfluoramine (a component of fen-phen, since withdrawn). Second, in a 2002 paper, he identified the kappa-opioid receptor as the molecular target for salvinorin A, a widely abused hallucinogen. In a 2012 Nature paper, with longtime collaborator Ray Stevens, he described the first crystal structure determination of the receptor. Third, over the last few years he and his colleagues developed a chemogenetic platform called DREADD (designer receptors exclusively activated by designer drugs).

This technology allows selective, dose-dependent, reversible pharmacological manipulation of any cell containing an engineered G protein coupled receptor.

This technology has proven particularly useful for experimental manipulation of CNS activity and has led to new insights relating neurotransmitters, neuronal signaling, and behavior. Thomas Insel, Director of

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NIMH, has stated that DREADDs were one of the most important breakthrough technologies for the NIH brain initiative.

Dr. Roth will deliver the Goodman & Gilman Lecture titled “Towards an Atomic-level Understanding of

Psychoactive Drug Actions” on Sunday, April 3 from 2:00PM – 2:50PM in Room 16AB in the San Diego Convention Center.

Pharmacia-ASPET Award for Experimental Therapeutics The Pharmacia-ASPET Award for Experimental Therapeutics, presented annually, recognizes and stimulates outstanding research in pharmacology and experimental therapeutics, basic laboratory, or clinical research that has had, or potentially will have, a major impact on the pharmacological treatment of disease.

Csaba Szabo, MD, PhD University of Texas Medical Branch Dr. Csaba Szabo has been named the recipient of the 2016 Pharmacia-ASPET Award for Experimental Therapeutics.

Nominated by Dr. Andreas Papapetropoulos at the University of Athens School of Health Sciences, Greece, Dr. Szabo is highly regarded as a world renowned expert in the fields of oxidative and nitrosative stress, cardiovascular and inflammatory mechanisms, cell death and dysfunction, and gaseous transmitters. Over the last decade, his work significantly advanced our understanding of the physiological and pathological roles and translational potential of hydrogen sulfide, a novel endogenous gasotransmitter signaling molecule.

Dr. Szabo is a professor of anesthesiology at the University of Texas Medical Branch. Publishing over 500 original research articles, he was listed by the European Journal of Clinical Investigation as being in the top 400 of highly influential biomedical scientists in the world. He has been continuously funded by the National Institutes of Health since 1995. In his current

position, Dr. Szabo leads a multidisciplinary team of investigators with expertise in molecular biology, cell biology, pharmacology, physiology, pathophysiology, medicinal chemistry, and translational science.

Dr. Szabo has received numerous awards, including the Novartis Award of the British Pharmacological Society, the Dennis Gabor Innovation Award, and the Texas Star Award. He has served and currently serves on the editorial board of numerous leading journals, including the British Journal of Pharmacology, the Journal of Pharmacology and Experimental Therapeutics, Shock, and Molecular Medicine.

Dr. Szabo is also an elected fellow of the British Pharmacological Society and an elected member of the American Society for Clinical Investigation.

At this year’s ASPET Annual Meeting at Experimental Biology, Dr. Szabo will be giving a talk on the modulation of H2S as an anti-cancer strategy during the symposium titled “The Biology and Translational Potential of Hydrogen Sulfide: One Person's Trash is Another Person's Treasure” on Wednesday, April 6, 2016 at 3:00PM in Room 16B of the San Diego Convention Center.

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Robert R. Ruffolo Career Achievement Award in Pharmacology The Robert R. Ruffolo Career Achievement Award in Pharmacology, presently annually, was established in 2011 in recognition of the contributions made to drug discovery and development

by Dr. Ruffolo. The award recognizes the scientific achievements of scientists who are at the height of their careers and who have made significant contributions to any area of pharmacology.

William A. Catterall, PhD University of Washington Dr. William A. Catterall has been named the 2016 recipient of the Robert R. Ruffolo Career Achievement Award in Pharmacology. Nominated by Dr. John Scott, an investigator of the Howard Hughes Medical Institute and professor of pharmacology at the University of Washington, Dr. Catterall is being recognized for his outstanding research and for his exceptional contributions as an academic leader in pharmacology throughout the world Dr. Catterall received his BA in chemistry from Brown University 1968, PhD in physiological chemistry from Johns Hopkins 1972, and postdoctoral training in neurobiology and molecular pharmacology as a Muscular Dystrophy Association fellow with Dr. Marshall Nirenberg at the National Institutes of Health from 1972 to 1974. Following three years as a staff scientist at NIH, he joined the University of Washington in 1977 as associate professor of pharmacology, became professor in 1981, and chair in 1984. He completes his 32-year tenure as chair of pharmacology in June 2016.

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Dr. Catterall is the leading investigator of the structure, function, and molecular pharmacology of voltage-gated sodium and calcium channels. He discovered the sodium and calcium channel proteins, and his work shifted the paradigm in ion channel research from a focus on measurement of ionic currents to analysis of the ion channel proteins and their genes.

As chair of pharmacology, Dr. Catterall has led an internationally recognized research and educational program, ranked 7th worldwide by US News & World Report in 2014. He served as editor of Molecular Pharmacology, a longstanding member of the ASPET Board of Publication Trustees, a founding member of the ASPET Division of Molecular Pharmacology, the founding editor of IUPHAR’s Ion Channel Compendium and Ion Channel Database, and is currently the co-head of faculty in pharmacology and drug discovery for F1000Prime.

Dr. Catterall is the most highly cited ion channel researcher from 2004 to 2014 as ranked by ionchannels.org. He is a member the National Academy of Sciences, the National Academy of Medicine, and the Royal Society of London, UK.

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Julius Axelrod Award in Pharmacology The Julius Axelrod Award in Pharmacology, presented annually, was established in 1991 to honor the memory of the eminent American pharmacologist who shaped the fields of neuroscience, drug metabolism, and biochemistry and who served as a mentor for numerous eminent pharmacologists around the world. This award is presented for significant contributions to understanding the biochemical mechanisms underlying the pharmacological actions of drugs and for contributions to mentoring other pharmacologists.

Paul A. Insel, MD University of California, San Diego Dr. Paul A. Insel has been named the 2016 recipient of the Julius Axelrod Award in Pharmacology. Nominated by Dr. Joan Heller Brown at the University of California-San Diego (UCSD), Dr. Insel is being recognized for his time honored and groundbreaking research contributions, combined with his superlative achievements as a mentor.

Dr. Insel received his MD from the University of Michigan and subsequent training in internal medicine at Harvard Medical Service, Boston City Hospital.

He began research training/efforts at the NIH at the NICHD Gerontology Research Center and NCI Laboratory of Theoretical Biology and at the University of California, San Francisco.

He is currently vice-chair/distinguished professor of pharmacology and distinguished professor of dedicine at UCSD. Since 1989, he has been director of the UCSD Medical Scientist Training Program and actively involved in the National Association of MD/ PhD Programs, serving as its inaugural president. He is a member of the Advisory Panel on Research of the American Association of Medical Colleges. He holds a Doc. Hon. Causa from the University of Paris and is a fellow, American Association for the Advancement of Science. Dr. Insel has served as editor or senior editor of numerous scientific journals, including Molecular Pharmacology, Journal of Clinical Investigation, British Journal of Pharmacology, and the American Journal of Physiology-Cell Physiology. He is currently

the co-head of faculty in pharmacology and drug discovery for F1000Prime and editor, Annual Review of Pharmacology and Toxicology.

Dr. Insel’s major research efforts have focused on studies of G-protein-coupled receptors (GPCRs), their expression, signaling mechanisms, regulation, functional effects, and roles in disease.

In the great scope of achievements, Dr. Insel is an extraordinarily accomplished researcher in receptor pharmacology and signaling who has made critical contributions to the field. As an outstanding educator and mentor, Dr. Insel has inspired numerous undergraduates, graduates, and postdoctoral students to pursue training and develop meaningful careers in pharmacology. His students are loyal and dedicated admirers of his achievements, and consistently recognize the value of the guidance he has provided.

ASPET will present Dr. Insel with the Axelrod Award on Saturday, April 2, 2016 at 6:00PM at the Business Meeting and Awards Presentation at the ASPET Annual Meeting during Experimental Biology 2016 at the San Diego Convention Center in Room 16AB. Dr. Insel will present the Axelrod Lecture at the 2017 ASPET Annual Meeting during Experimental Biology in Chicago, Illinois, April 22–26, 2017.

The 2016 Axelrod Lecture will be given by last year’s recipient, Dr. Jean Rossier from Neuroscience Paris Seine who will deliver a lecture titled “Therapies of Brain Diseases, Past, Present and Future” on Sunday, April 3, 2016 at 8:30AM in Room 16AB at the San Diego Convention Center.

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Bernard B. Brodie Award in Drug Metabolism The ASPET Division for Drug Metabolism sponsors the Bernard B. Brodie Award in Drug Metabolism. This award was established to honor the fundamental contributions of Bernard B. Brodie in the field of drug metabolism and disposition. The award is presented biennially to recognize outstanding original research contributions in drug metabolism and disposition, particularly those having a major impact on future research in the field.

Masahiko Negishi, PhD National Institute of Environmental Health Sciences, NIH Dr. Masahiko Negishi has been named the recipient of the 2016 Bernard B. Brodie Award in Drug Metabolism. He was selected for this honor in recognition of his landmark contributions to the elucidation of the molecular mechanism of induction of cytochromes P450 by phenobarbital. He has been described as a brilliant scientist with an outstanding record of sustained research excellence and noted as one of the most important investigators in the area of drug metabolism over the last fifty years.

Dr. Negishi received his doctorate in science in biochemistry from the Institute of Protein Research at Osaka University in 1972 and worked as an assistant professor at Kansai Medical School for four years in Japan. He carried out postdoctoral training in the Department of Cell Biology at New York University and the National Institute of Child Health and Human Development from 1976 to 1983.

Since 1983, he has been a principal investigator and head of the pharmacogenetics section in the Reproductive and Developmental Biology Laboratory at the National Institute of Environmental Health Sciences, NIH. His laboratory is responsible for two major discoveries in the structure-activity relationship of drug-metabolizing enzymes and the regulation mechanisms of drug-induced gene expression. His laboratory has trained nearly 100 postdocs and students, many of whom have become professors and institute directors.

He was selected to be a member of the Senior Biomedical Research Service at NIH in 2000 and received the 2002 North America Scientific Achievement Award from the International Society for the Study of Xenobiotics, an honorary doctor degree from the University of Kuopio, Finland, in 2005, and was made a fellow of the Japanese Society for the Study of Xenobiotics in 2012.

Dr. Negishi will deliver the Bernard B. Brodie Award in Drug Metabolism Lecture titled, “Phenobarbital Induction of Drug Metabolism and Beyond” on Monday, April 4 from 2:00PM – 2:50PM in Room 15A of the San Diego Convention Center.

For information on upcoming scientific meetings and congresses, visit www.aspet.org/meetings_calendar

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P.B. Dews Lifetime Achievement Award for Research in Behavioral Pharmacology The ASPET Division for Behavioral Pharmacology sponsors the P.B. Dews Lifetime Achievement Award for Research in Behavioral Pharmacology to recognize outstanding lifetime achievements in research, teaching, and professional service in the field of behavioral pharmacology and to honor Peter Dews for his seminal contributions to the development of behavioral pharmacology as a discipline.

Travis Thompson, PhD University of Minnesota Roy W. Pickens, PhD Virginia Commonwealth University (retired) ASPET is pleased to announce that the 2016 P.B. Dews Lifetime Achievement Award for Research in Behavioral Pharmacology is being awarded to Drs. Travis Thompson and Roy W. Pickens.

Nominated by Michael Nader from Wake Forest School of Medicine, Drs. Thompson and Pickens were selected because of their individual and paramount contributions to the field of behavioral pharmacology. In consideration of the groundwork the two scientists did jointly and how innovative and significant their contributions were to the field, Dr. Nader believed it would be most deserving for them to receive the Dews award together.

Dr. Thompson is a professor in the Department of Educational Psychology at the University of Minnesota. Dr. Pickens is retired but most recently held positions at Virginia Commonwealth University as the special assistant to the vice president for research and as a professor in the Department of Psychiatry.

Dr. Thompson received his PhD in experimental psychology from the University of Minnesota

under the mentorship of Gordon Heistad and his postdoctoral training at the University of Maryland under the mentorship of Joseph Brady.

At the University of Minnesota, he has mentored close to 50 PhD students. Dr. Thompson has written several books, including the first textbook on Behavioral Pharmacology (1968), and has edited multiple volumes related to behavior and pharmacology including a seven-volume series Advances in Behavioral Pharmacology. In 1987 he received the NIDA Award for Outstanding Contribution to the National Drug Abuse Program for Training in Behavioral Pharmacology.

Dr. Pickens received his PhD in psychology from the University of Mississippi under the mentorship of William F. Crowder and conducted his postdoctoral research at the University of Minnesota under the mentorship of Gordon Heistad and Fred Shideman. He joined the faculty at the University of Minnesota in 1966 and moved up the ranks to full professor in 1973.

Dr. Pickens has been director of the Division of Clinical Research at NIDA, associate director for AIDS, past-director of the NIDA-Intramural Research Program, and professor of psychiatry at the Medical College of Virginia. He has mentored many pre- and postdoctoral fellows over his career.

Drs. Thompson and Pickens are recognized pioneers in the study of intravenous drug selfadministration and for their later work in clinical settings.

Dr. Thompson will deliver the Dews Lecture titled “Behavioral Mechanisms of Drug Action: Peter Dew’s Legacy,” on Monday, April 4 from 2:00PM – 2:50PM in Room 15B at the San Diego Convention Center.

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Paul M. Vanhoutte Distinguished Lectureship in Vascular Pharmacology The ASPET Division for Cardiovascular Pharmacology sponsors the Paul M. Vanhoutte Distinguished Lectureship in Vascular Pharmacology. This award, presented biennially, was established in 2008 to honor Dr. Vanhoutte’s lifelong scientific contributions to our better understanding and appreciation of the importance of endothelial cells and vascular smooth muscle function in health and disease and for his mentoring of countless prominent endothelial and vascular biologists and pharmacologists.

Mark T. Nelson, PhD University of Vermont Dr. Mark T. Nelson has been named the recipient of the 2016 Paul M. Vanhoutte Lectureship in Vascular Pharmacology.

Dr. Nelson was nominated by both Joseph Brayden from the University of Vermont and Swapnil Sonkusare from the University of Virginia.

Dr. Nelson is being recognized for his pioneering research in vascular pharmacology and for his expansive and instrumental discoveries and teachings.

Dr. Nelson is a university distinguished professor and chair of the Department of Pharmacology in the College of Medicine at the University of Vermont. He received his BA, with honors, in mathematics and biology from Tufts University and his PhD in neural sciences from Washington University. His work has been supported primarily by the National Institutes of Health, the National Science Foundation, and the American Heart Association.

He is a current member of the Vermont Academy of Sciences & Engineering and an ad hoc member of the NIH Pharmacology Study Section. He has

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served as councilor of the Biophysical Society Council, was awarded an Alexander von Humboldt-Stiftung fellowship while at the Universität Konstanz (1981), an American Heart Association fellowship while at the University of Maryland (1980), and a National Science Foundation summer fellowship while at Swarthmore College (1974). He has been named a university scholar at the University of Vermont (1996), an established investigator of the American Heart Association (1985), and was an honorable mention awardee from the American Heart Association for the Louis N. Katz Research Prize for Young Investigators (1982). Dr. Nelson has lectured and published widely, served as a consultant to several corporations, and has a particular research interest in the properties and roles of ion channels in smooth muscle function.

Dr. Nelson will present the Paul M. Vanhoutte Distinguished Lecture in Vascular Pharmacology titled, “Capillaries as Decoders of the Neural Rhythm of the Brain: Translating Thought into Blood Flow” during the ASPET Annual Meeting at Experimental Biology 2016 in San Diego, California. The lecture will take place on Tuesday, April 5, 2016 from 4:30PM – 5:30PM in Room 16A at the San Diego Convention Center. The award will also be presented at that time.

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The Chip Shot Heard Around the World

Rebecca J. Anderson, PhD On Christmas Eve 1984, the Food and Drug Administration approved an antiparasitic drug to treat reindeer (1).

It was not the drug’s first approval, and regulators would subsequently authorize many other indications. But the FDA’s yuletide decision, though purely coincidental, somehow seems poetically fitting. The drug was ivermectin, and it was truly a gift to the world.

Satoshi Ōmura’s journey would eventually end in Stockholm, but in 1971, his sights were set only on his sabbatical in the United States. He had received degrees in pharmaceutical science and chemistry, and since 1965, he had been a researcher at the Kitasato Institute.

The Tokyo-based Institute had a proud tradition of applied bioresearch accomplishments. Founded in 1914 by Shibasaburo Kitasato, who isolated the tetanus bacilli and discovered tetanus antibodies, the Institute housed many outstanding researchers. Kiyoshi Shiga discovered the dysentery bacillus, Shigella dysenteriase.

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14 While the Kitasato Institute could isolate and characterize potentially useful natural products, it did not have the resources to develop and market them. Ōmura saw the value of working with an industrial partner (3). With Tishler’s assistance, he approached Merck and proposed a collaboration, which was formally established in 1973 (3, 4).

Reprinted with permission from Elsevier, Photo: Andy Crump

Rebooting Antiparasitic Research

Dr. Satoshi Ōmura collecting a soil sample at the site where the original Streptomyces avermectinius sample was collected over 30 years earlier.

Sahachiro Hata, along with Paul Ehrlich, discovered Salvarsan for syphilis. Shinkichi Umeno invented the rabies vaccination system. And, Taichi Kitajima pioneered immunotherapy for cholera (2).

Like all of his colleagues, Ōmura followed Dr. Kitasato’s philosophy that “research should be applied as quickly as possible for the protection of people from contagious diseases” (2). In his first six years at the Institute, Ōmura devised several innovative methods for isolating and culturing microorganisms from soil and other environmental samples. He also enhanced the sensitivity of bioactivity screens, which accurately detected minute concentrations of medically relevant substances produced by those microorganisms.

During his 18-month sabbatical at Wesleyan University in Connecticut, Ōmura worked alongside Max Tishler, a professor of chemistry. Tishler had retired from Merck, Sharp, and Dohme after a distinguished 32-year career, rising to senior vice president of research and development.

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The timing could not have been better for Merck.

Since 1955, scientists in Merck’s animal health research division had been working to develop a profitable veterinary antiparasitic drug. At the time, veterinarians had no drugs that selectively eradicated intestinal worms (5).

The best source for such compounds (as with many antibiotics and other antimicrobial drugs) was thought to be environmental microbes—particularly those found in soil. Pharmaceutical researchers encouraged their coworkers to bring back a bag of dirt whenever they traveled for business or pleasure. Microbes were extracted from the soil samples and grown via fermentation. The natural products generated by those microbes during fermentation were then evaluated for medical utility.

The Merck scientists set up several in vitro assays to detect antiparasitic activity. Unfortunately, most of the compounds registering activity in those assays were toxic—killing both the parasite and its host (6).

Reluctantly, they turned to an in vivo assay using mice.

Although animal-based drug screening was expensive and time-consuming, the scientists could more easily distinguish between active and nonselectively toxic compounds.

Mice infected with a nematode (roundworm) were fed a lab chow that had been mixed with the experimental fermentation product. Later, fecal pellets and the animal’s intestines were examined for the presence of parasitic eggs and worms, respectively (6).

About 1% of the experimental substances they tested showed activity. Cultures of those microbes were regrown and the fermentation products retested, but unfortunately, most of them were still extremely toxic and could not be pursued further (6).

By the early 1970s, Merck researchers had tested many thousands of compounds, were facing diminished returns from their testing, and were finding it harder to justify the laborious mouse assay. When Ōmura approached Merck, they were keen to explore this new source of compounds (3).

15

In the public domain

22,23-dihydroavermectin B1b

22,23-dihydroavermectin B1a

Ivermectin (22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) is a broad-spectrum antiparasitic drug in the avermectin family.

Under the collaboration, Ōmura and his team at the Kitasato Institute were responsible for isolating microorganisms, identifying active compounds, and carrying out in vitro evaluations. Scientists at Merck’s research laboratories in Rahway, NJ, handled the in vivo work and were responsible for developing any promising compounds (2, 6).

In the second year of the collaboration, the Kitasato Institute sent a batch of 54 samples to Merck for testing. One of them was a fermentation broth from soil sample OS-3153, which had been collected at the oceanfront Kawana Golf Course in Japan’s Shizuoka Province (3, 5).

On May 9, 1975, the researchers fed a sample of the OS-3153-derived broth to a single mouse (7). The broth completely eliminated larval eggs and intestinal worms in the mouse—a level of antiparasitic activity the Merck scientists had never seen before (6). Over

the next few weeks, they repeated and expanded their studies of the OS-3153 sample in more mice and under a variety of conditions, confirming the substance’s amazing potency and selectivity.

The microorganism in the OS-3153 sample entered Merck’s culture collection as MA-4680, and it was submitted for detailed characterization. It was a brownish-gray bacterium with spiral side branches bearing smooth, spherical spores (6, 8). MA-4680 belonged to the Streptomyces genus of bacteria, but it was unlike any previously described species. They named it Streptomyces avermitilis, meaning the species that was “capable of separating from worms” (6).

The antiparasitic substance produced by S. avermitilis turned out to be a mixture of eight closely related macrocyclic lactones, which the Merck scientists called avermectin (6, 8). The chemical structure of the avermectins was unlike any previously known class of molecules, and they proved to have wide utility.

Reprinted with permission from Elsevier, Photo: Kitasato Institute

A Broad-Spectrum Drug

Photomicrograph of Streptomyces avermectinius

Characterizing the biological activity of the avermectins fell to an interdisciplinary team headed by parasitologist William Campbell (3). Born in Ireland, Campbell conducted his doctoral research at the University of Wisconsin-Madison on a Fulbright Scholarship. In 1957, he joined the Merck Institute for Therapeutic Research and became a US citizen in 1962.

Campbell always had a “particular fondness” for parasitic worms (7). The subject of his doctoral thesis was the liver fluke, a flatworm that threatened sheep in his native Ireland. Among his early successes at Merck was development of thiabendazole, a fungicide and antiparasitic drug that Merck launched in 1962 as Thibenzole® (4).

March 2016 • The Pharmacologist

16 After confirming the activity of the avermectins in the mouse nematode model, Campbell proceeded to test their efficacy in domesticated animals. In sheep, cattle, and chickens, the avermectins were effective against both mature and immature parasitic roundworms but had no effect on flatworms, protozoa, bacteria, or fungi (9).

Campbell’s group found that the avermectins were also effective against insects (6). Collaborating with the Boyce Thompson Institute for Plant Research in Ithaca, New York, the Merck scientists screened 75 structurally related natural products and semisynthetic avermectin derivatives in the Institute’s mite and insect screening assays under greenhouse conditions. Avermectin B1, the major fermentation product from S. avermitilis, emerged as the most promising candidate for agricultural use (6).

Avermectin B1 was given the Merck development code number MK-936 and was evaluated worldwide for efficacy in protecting a number of agricultural crops, including citrus, cotton, apples, pears, vegetables, potatoes, tree nuts, and grapes (6). Under field conditions, avermectin B1 provided excellent control of many pests, including the red mite, spider mite, Colorado potato beetle, diamond back moth, pear psylla, and red fire ant (6).

Avermectin B1 was even effective against mites and insects that had become tolerant to commercially available organophosphate, carbamate, chlorinated hydrocarbon, and pyrethroid pesticides (6). In 1979, Campbell’s group publicly announced, “The avermectins would appear to have unprecedented potency and spectrum of biological activity” (9).

The two avermectin B1 compounds generated

by Streptomyces avermitilis (avermectin B1a and avermectin B1b) both had impressive activity and could be produced in high yield (6, 8). However, a double bond between C22 and C23 restricted the molecules’ flexibility, and test results suggested that the structural constraint might be affecting bioactivity. Chemists therefore eliminated the double bond to produce semisynthetic 22, 23-dihydroavermectin B1a and B1b.

To distinguish the dihydro- compounds from the naturally generated avermectins, the researchers suggested “hyvermectin” as the new generic name.

Someone pointed out that “hyver” in some language meant testicles (7). They settled on ivermectin instead.

Chemically, the substance that underwent further development and commercialization as “ivermectin” is actually a mixture of the two semisynthetic analogs.

The Pharmacologist • March 2016

The manufacturing process specifies that ivermectin contains at least 80% of 22, 23-dihydroavermectin B1a and not more than 20% of 22, 23-dihydroavermectin B1b (6).

Campbell’s colleague, Lyndia Blair, tested ivermectin in an assay she had developed for evaluating compounds against heartworms in dogs. Ivermectin did not affect adult heartworms but did kill premature larvae and proved to be an effective maintenance treatment to prevent canine heartworm infection (7, 10).

A Veterinary Blockbuster Ivermectin represented a major breakthrough in veterinary medicine. Like other pesticides, it attacked insects, spiders, and parasites that live outside their hosts (e.g., fleas and mites). But importantly, ivermectin was the first “endectocide;” that is, it was effective against parasites that live inside their host (3, 5).

Ivermectin was effective in unprecedented low doses and could be used orally, topically, and parenterally without producing observable toxic reactions in the animal hosts. And, it had a unique mechanism of action (5).

Ivermectin forces opening of glutamate-gated chloride channels, which are common in roundworms, insects, and ticks. The uncontrolled influx of chloride ions paralyzes the organisms’ pharyngeal and somatic muscles. Flukes, tapeworms, and other flatworms lack these receptors, which probably accounts for their resistance to ivermectin. In vertebrates, ivermectin stimulates GABA release. Fortunately, GABA neurons are mostly in the brain and protected by the blood– brain barrier, making the drug exceptionally safe for mammals (5).

In 1981, ivermectin was introduced commercially as a veterinary antiparasitic agent, and in 1985 it was launched as an agricultural pesticide. It was immediately hailed as the most effective, broadspectrum antiparasitic drug ever developed (1). Within two years, ivermectin became the market leader, a position it has maintained ever since (4).

By 1987, ivermectin was Merck’s second largest selling product and now has annual sales of about $1 billion. It is marketed as Ivomec® for cattle, pigs, and sheep; Equalin® for horses; and Heartgard® for dogs (4). Livestock around the world are regularly treated (using dips, injections, feeds, and other formulations), and virtually every horse and pet dog in the US receives it to prevent dermatitis and heartworm infections, respectively (2, 5).

17

The Human Connection

Reprinted with permission from the CDC

In April 1978, while conducting the screening assays to characterize ivermectin’s spectrum of activity, Lyndia Blair found that the drug was effective against the larvae of Onchocerca cervicalis, a skindwelling parasite in horses (7, 11). O. cervicalis is fairly benign to horses, and this finding was of little commercial significance. However, the horse parasite belongs to the same genus as Onchocerca volvulus, a human roundworm parasite. O. volvulus causes onchocerciasis, a disease that afflicts millions of people worldwide (12).

When William Campbell saw Blair’s results, he decided to explore whether ivermectin had potential as a drug for humans. It was not the first time Campbell

had made this leap. While developing thiabendazole for the veterinary market, he facilitated Merck’s clinical trials of the drug for trichinosis. The FDA approved thiabendazole (Mintezol®) for trichinosis in 1964, the first antiparasitic drug to spin off from veterinary to human medicine (4).

In July 1978, Campbell sent ivermectin, along with the horse assay results, to researchers at James Cook University in Australia (11). The World Health Organization’s Special Program for Research and Training in Tropical Diseases (TDR) had contracted the Australian lab to screen drugs in cattle infected with Onchocerca gibsoni and O. gutturosa. This animal model was considered to be the best predictor of drug efficacy in humans with onchocerciasis (12).

Life cycle of Onchocerca volvulus

March 2016 • The Pharmacologist

Onchocerca volvulus in tissue, stained with H&E.

The Australians reported that ivermectin was “highly effective in preventing patent infections” of the cattle parasites (11).

River Blindness Onchocerca volvulus is a roundworm parasite whose existence depends entirely on finding the right insect and human hosts at the right times in its lifecycle. When black flies bite an infected person, they ingest microscopic worm larvae along with their blood meal. The tiny larvae mature through three stages as they migrate from the black fly’s gut to its head and mouth parts. The L3 larvae then enter the skin of another human victim the next time the fly feeds. The L3 larvae in the new human host then differentiate through three more stages and mature into male and female worms within about a year (13).

Adult male worms grow to 1.5 inches in length and females to 27 inches, forming nodules under the skin.

The fertilized females produce 1,000 micro-larvae per day for up to 12 years. These microscopic larvae move easily through the skin and lymphatic vessels of connective tissues, making them accessible when black flies next feed on the human host (13).

If the micro-larvae are not eaten by black flies, they cannot mature through the next larval stages.

Those that remain in the infected human die after 9-18 months, and it is the dead larvae that cause the most

The Pharmacologist • March 2016

damage to their human host (3, 13). The larval residue causes skin rashes, enlarged lymph nodes, and impaired vision. In the skin, the dead larvae induce depigmentation and itching so intense that it reputedly can lead to suicide (14).

Infiltration of micro-larvae in the eye leads to blindness—the second highest cause of blindness from infectious disease (12). Failing eyesight develops slowly, but by the age of 50, victims’ eyes become scarred and lifeless. Along the dusty roads everywhere in endemic regions, blind men are led by boys, each holding one end of a walking stick (14).

Black flies breed in the highly oxygenated, fastflowing rivers that irrigate Africa’s fertile savannas— some of the continent’s most productive agricultural lands. The concentration of black flies and farmers in these regions allows O. volvulus to thrive and has given the disease its common name, river blindness.

Of those infected worldwide, 99% live in Sub-Saharan Africa (15). To a lesser extent, river blindness also afflicts people in tropical regions of six Latin American countries and in Yemen.

WHO Takes Action In 1974, Robert McNamara, then head of the World Bank, recognized river blindness as a major disease with widespread health and socioeconomic consequences, especially in the West African savanna regions (12).

The World Bank joined the World Health Organization in launching the Onchocerciasis Control Program in West Africa (OCP). It targeted 30 million people who were at risk of infection in 11 West African countries.

Only two drugs were available to treat river blindness: diethylcarbamazine and suramin.

Diethylcarbamazine is taken orally for 7-10 days. Because it causes frequent side effects and serious complications (lymph node pain, myalgias, conjunctivitis, hypotension, keratitis, chorioretinal damage, and optic neuritis), diethylcarbamazine must be administered under a physician’s supervision (1, 16).

Diethylcarbamazine effectively kills and rapidly eliminates In the public domain

Reprinted with permission from the CDC

18

19 micro-larvae from the eye and keeps the eye clear for a year or more. Unfortunately, the acute accumulation of dead parasitic tissue (particularly in the eye) elicits a violent and dangerous hypersensitivity response called the Mazzotti reaction (3, 12, 16). This exaggerated inflammatory response often causes eye damage (12). Despite its drawbacks, diethylcarbamazine was the drug of choice.

Suramin (developed 50 years earlier to treat sleeping sickness) was the only drug option for killing adult worms, but it also has several disadvantages (12). It must be given intravenously once a week for six weeks and is highly toxic, often causing severe and occasionally fatal adverse reactions (1, 3, 12).

By the mid-1970s, it was clear that both drugs could actually worsen eye damage, and so their use as river blindness treatments was stopped (3).

Instead, OCP sought to kill the parasite’s vector, black flies, in West Africa. Intensive aerial insecticide spraying of the fly’s breeding waters was aimed at reducing their numbers enough to break the cycle of parasite transmission (5, 14).

Unfortunately, aerial spraying was not feasible or cost effective in the other regions of Sub-Saharan Africa where river blindness was also an endemic

problem (17). Also, some insects became resistant to the insecticides, and black flies were more mobile than expected. Consequently, people in areas that had been cleared of the parasite could be re-infected by a new wave of black flies (4, 14). Aerial spraying was not a long-term solution.

A New Approach Those afflicted with river blindness are among the world’s poorest people. Their inability to pay for medication—even if there was a drug—provided little incentive for pharmaceutical companies to find treatments (4).

When the World Health Organization launched TDR in 1975, its mandate was to find effective ways to combat eight neglected “diseases of poverty,” including river blindness (11, 12). TDR sponsored aggressive research—most significantly, a three-tiered screening program to find antiparasitic drugs. Because of the severe side effects (i.e., the Mazzotti reaction) associated with drugs like diethylcarbamazine that killed micro-larvae, TDR sought a new, nontoxic drug that killed adult roundworms (11, 12).

The Australian laboratory where Campbell sent ivermectin in 1978 had been contracted by TDR to screen promising drugs in cattle, a tertiary animal model for river blindness.

Transitioning to Patients On December 20, 1978, Campbell presented the Australian results to Merck’s senior research management council as evidence that ivermectin might be effective in treating river blindness (11). Roy Vagelos, Merck’s senior vice president for research, was still new to the pharmaceutical industry. He had moved from his position as chairman of biological chemistry at Washington University Medical School just three years earlier and his expertise was not parasitology, but he approved Campbell’s request for clinical research funds (11, 18).

An adult black fly with the parasite Onchocerca volvulus coming out of the insect's antenna, magnified 100x.

March 2016 • The Pharmacologist

Reprinted with permission from Leedy Hoque

20 Over the next year, Merck researchers met repeatedly with TDR officials and shared their ivermectin data. TDR expressed little enthusiasm and only offered some technical advice. Merck’s drug selectively killed micro-larvae, and TDR’s priority was to find a drug that killed adult worms (11). On January 16, 1980, Merck’s senior management decided to proceed independently with Phase I clinical trials (11).

Campbell passed responsibility for clinical development of ivermectin to Mohammed Aziz (4).

A native of Bangladesh, Aziz was senior director for clinical research at Merck. Prior to joining Merck, he had worked for WHO in Sub-Saharan Africa and was an expert in tropical medicine (18).

Aziz and a small group of Merck investigators went to Senegal (on the West coast of Africa) and initiated the Phase I trial at the University of Dakar on February 24, 1981 (18, 19). Using a doseescalation protocol in 32 men with mild infections (but no eye damage), Aziz found that ivermectin Dr. Mohammed Aziz reduced the number of micro-larvae in a dosedependent manner. A single oral dose of 50 µg/kg completely eliminated the larvae in skin snip specimens for a month, and all of the men tolerated the drug well (20). Best of all, despite the apparent efficient killing of micro-larvae, none of the men experienced eye damage or other inflammatory responses associated with the Mazzotti reaction (20).

In Paris, a second dose-ranging trial with 20 immigrants from Senegal and Mali—some with eye infections—confirmed and expanded the results.

Single oral doses up to 200 µg/kg were well tolerated.

Seven patients who were followed for a year maintained low skin micro-larval density and had no ophthalmological side effects (12, 20).

In November 1982, Merck visited TDR and OCP in Geneva and presented results from the Phase I trials (11, 12). The impressive clinical data and the growing ineffectiveness of OCP’s insecticide spraying program bolstered the World Health Organization’s interest in ivermectin (11, 19). TDR agreed to join Merck in a collaborative research program. But each party, though hopeful, proceeded with some wariness about the other organization (11).

The Pharmacologist • March 2016

The two sides had different motives (12). The WHO agencies saw ivermectin as a new community-level tool for disrupting parasite transmission and helping to reduce the prevalence of river blindness in endemic communities. They favored community-based trials under field conditions, an essential step toward masstreatment programs (12).

On the other hand, Merck approached the ivermectin clinical trials like any other regulatorycompliant development program. The company wanted a commercial product that would generate a return on its investment (12).

In 1983, Aziz proceeded with fairly standard Phase II and III clinical trials in Ghana, Guatemala, Côte d’Ivoire, Liberia, Mali, Senegal, and Togo (11, 12, 19). TDR provided Merck with access to its existing network of onchocerciasis researchers and institutions (11). Among these collaborations, Merck adopted a scoring system developed by Kwable Awadzi at the Onchocerciasis Chemotherapy Research Center in Ghana, a core facility supported by TDR. The method quantified commonly observed clinical responses to antiparasitic drugs (11, 12).

In the trials, a single dose of 150 to 200 µg/kg effectively reduced the density of micro-larvae to near zero within a month, and the larvae remained at low levels for up to 12 months (16, 19, 21). Adverse reactions were mild and transient—without triggering a Mazzotti reaction. Even in patients with severe larval infiltration in the eye, vision generally improved after the larvae cleared (21).

Because most of the countries where river blindness was endemic were former French colonies or had expatriates living in France, Merck submitted its ivermectiin application to the French regulatory authorities (5, 11, 18). The submitted data came exclusively from Merck’s clinical trials, which had enrolled 1,200 onchocerciasis patients (12). Ivermectin under the brand name Mectizan® was approved for human use on October 21, 1987, facilitating registration in other French-speaking countries (11).

A New Paradigm In parallel with the clinical trials, Merck’s marketing department struggled to find ways to recover development costs and make a profit on the approved product. Based on the anticipated advantages of ivermectin, production costs, the pricing of similar antiparasitic drugs, and other factors, they arrived at a price of $3 per tablet (4, 11). Unfortunately, as Roy

Reprinted with permission from Merck

21

Bottle of Mectizan

Vagelos explained to a reporter, “We realized that the patients who need it don’t have the money to support purchase of a drug at any price” (14).

By June 1986, Merck’s executives had considered and rejected all of their conventional marketing options. They began exploring novel alternatives.

Vagelos (who had become CEO of Merck) and his executive team searched extensively for partners willing to cover the company’s expenses, so they could make ivermectin available at no cost to patients (11).

They met with WHO, the US Agency for International Development, the US Department of State, European and African governments, and private organizations— all without success (4, 11). Senators Ted Kennedy (D-MA), Bill Bradley (D-NJ), Frank Lautenberg (D-NJ), and Richard Lugar (R-IN) sponsored congressional funding for worldwide distribution of ivermectin, but Congress rejected their proposal (4). Everyone thought the humanitarian effort was worthwhile, but no one was willing to cover the drug’s costs.

Within Merck, employees began discussing the idea of donating ivermectin, citing a philosophy first expressed in 1950 by George W. Merck, the founder’s son. He had told an audience at the Medical College of Virginia that “medicine is for the people…The profits will follow, and if we have remembered that, they have never failed to appear” (4).

Merck had already established a reputation as a socially conscious pharmaceutical company. After World War II, Merck donated a large supply of streptomycin to the Japanese, who were suffering from high rates of tuberculosis. In 1958, the company

established the Merck Medical Outreach Program, donating antibiotics, antiparasitics, and vaccines to ongoing humanitarian programs in developing countries and disaster situations (4).

The same day that ivermectin was approved for river blindness in Paris, Merck announced the Mectizan Donation Program at a press conference in Washington, DC (4, 11, 18). Having obtained consent from the Kitasato Institute, which agreed to forego its royalties, Vagelos said that Merck would provide ivermectin free of charge for the treatment of river blindness for “as long as it is needed” (3, 4).

The impressive income generated by the various ivermectin veterinary products made Merck’s decision somewhat easier. Those products were bringing in more than $300 million annually, and sales were growing at 15% per year—more than enough to cover the cost of the donation program. Offsetting the loss of income, the donation program fostered corporate good will, enhanced employee morale, and permitted an attractive tax write-off (4).

For the donation program, bulk quantities of avermectin were produced at a fermentation plant in Pennsylvania and shipped to the UK or Puerto Rico for chemical conversion into ivermectin. The bulk ivermectin was then formulated into tablets in the Netherlands, and the tablets were packaged in France for distribution (11). Merck paid all of the costs for production, shipping, customs, and other handling charges (3, 11, 19).

Medicine is for the people…The profits will follow, and if we have remembered that, they have never failed to appear Despite its willingness to donate ivermectin, Merck still had to resolve several other corporate concerns.

The company did not want to be responsible for deciding who received the drug or how it was distributed. However, to limit its liability, the company wanted a system for monitoring side effects. Merck was also concerned about illegal rerouting of the drug to the black market or to the veterinary drug market (11).

In February 1988, Merck and WHO established the Mectizan Expert Committee, comprised of seven international experts in tropical medicine and public health. This independent body was headquartered at

March 2016 • The Pharmacologist

22 the Carter Center in Atlanta, Georgia, and processed applications from organizations and governments wanting to distribute ivermectin (4, 11).

Community-Based Programs TDR and OCP still advocated community-based trials under field conditions—a necessary step toward mass-treatment programs. As Merck’s Phase III clinical trials were concluding, TDR and OCP pushed forward with field trials, with substantial support from Merck (11, 12).

Between 1987 and 1989, thirteen Phase IV community-based trials were conducted, involving 120,000 doses of ivermentin (11, 12). TDR funded five

Reprinted with permission from Merck

The Pharmacologist • March 2016

trials in Liberia, Cameroon, Malawi, Guatemala, and Nigeria. OCP funded eight other trials in Ghana, Mali, Togo, Benin, Ivory Coast, Guinea, Burkina Faso, and Senegal.

These community trials established that mass treatment with ivermectin could significantly reduce parasitic transmission (17). Black flies continued to land and feed on people. But because of ivermectin treatment, there were few or no micro-larvae in the skin, thus interrupting the parasite’s lifecycle and preventing its spread to new victims (21).

Mass distribution of ivermectin began in 1988 (4).

Initially, mobile teams of health workers from OCP and government health ministries visited communities to administer the ivermectin tablets (2, 4, 13). But this procedure was costly and inefficient (17). The mobile teams were often frustrated because villagers did not appear when they arrived, and they needed to remain in each village for 2-3 days to check for possible side effects (2).

By 1989, the accumulated experience and data made it clear that ivermectin was safe and easy to administer. WHO announced that individual medical supervision was not necessary (2, 21). TDR further refined and developed the Community-Directed Treatment with Ivermectin (CDTI) program, which was formalized in 1997 (2, 17).

CDTI empowered communities to organize, direct, and manage their own treatment. Selected residents in each community receive 2-3 days of training to treat themselves and their neighbors, monitor side effects, complete records, and keep track of drug distribution.

Dosing is determined using a measuring stick.

Children who stand shorter than the stick get one pill.

Adults and adolescents get two pills (5, 18).

The control of river blindness is now almost exclusively based on annual or semiannual treatment with ivermectin through CDTI. The program is selfsustaining and has become a way of life in Africa (18, 19). Now, many local volunteers who were recruited "Sightless Among Miracles" by R. T. Wallen, American, 1995. The 8-foot bronze sculpture commemorates the global effort to eliminate onchocerciasis, commonly known as river blindness. The study depicts a young boy leading his father, blinded by the disease. The sculpture was commissioned by Merck & Co. and placed in their world headquarters in 1995.

23 for the CDTI program also distribute vitamin A (also to prevent blindness) and coordinate home-based malaria and HIV/AIDS care for their communities (2, 18).

Public-Private Partnerships Public-private collaborations existed before the Mectizan Donation Program, but they were initiated by public sector institutions that sought corporate sponsorship. In contrast, Merck’s program emerged from the company’s decision to develop a drug without a market, donate it, and assemble public organizations to aid in its distribution (4).

The Mectizan Donation Program (comprised of Merck, WHO, 32 national governments, and 12 international nongovernment organizations) remains the largest ongoing medical donation program in history Public-private partnerships modeled on the ivermectin program now produce and distribute many other items for which there may be no likelihood of commercial return (2). But the Mectizan Donation Program (comprised of Merck, WHO, 32 national governments, and 12 international nongovernment organizations) remains the largest ongoing medical donation program in history (11, 19).

In recognition of Merck’s corporate philosophy and stewardship, Fortune magazine named Merck as America’s most admired company for seven straight years, from 1986 to 1992 (4).

Ivermectin Continues to Impress Further investigations demonstrated that ivermectin’s therapeutic utility extended beyond river blindness. In the 1990s, Merck and TDR reported the drug’s efficacy against lymphatic filariasis, also known as elephantiasis. Infected mosquitoes transmit the parasite larvae responsible for elephantiasis to humans through bites. Larvae develop into adult worms in the individual’s lymphatic vessels, causing painful, disfiguring swelling of the legs (12).

Lymphatic filiariasis ranks third behind malaria and tuberculosis among the most prevalent tropical diseases—worse and more widespread than river blindness (3). When combined with diethylcarbamazine

or albendazole, ivermectin in a once-annual treatment decreases micro-larval density by 99% (12).

In 1998, ivermectin was registered for lymphatic filariasis in France. Merck expanded its donation program to include lymphatic filariasis, and GlaxoSmithKline, the maker of albendazole, agreed to donate its drug. In 2000, WHO launched the Global Program to Eliminate Lymphatic Filariasis and adopted the two-drug combination for its community-based mass treatment program (3, 12).

According to data from the World Health Organization, over 2 billion ivermectin treatments have been administered for river blindness and elephantiasis since the donation programs began in 1987 and 2000, respectively (7). Each year, 110 million people receive ivermectin pills to combat river blindness and 218 million people take a dose for elephantiasis (7).

Ivermectin also effectively kills other worm infestations such as ascariasis, whipworm, pinworm, and leishmaniosis, as well as schistosomiasis, chlamydia, and cutaneous parasites (3, 5, 7, 12, 18).

Orally administered ivermectin has become a drug of choice for the treatment of mites and head lice, superseding topical creams, which are inconvenient and impractical for full-body application (5).

Tropical diseases are not a concern in the United States, but in 1996, the FDA finally approved ivermectin for human use to treat strongyloidiasis (18, 19).

Strongyloidiasis, a hookworm disease, is prevalent in temperate regions including the southern US, as well as in tropical and subtropical areas.

According to data from the World Health Organization, over 2 billion ivermectin treatments have been administered for river blindness and elephantiasis since the donation programs began in 1987 and 2000, respectively New Insights In 2002, Ōmura’s research group at the Kitasato Institute published morphological, physiological, biochemical, and phylogenetic evidence arguing for reclassification of Streptomyces avermitilis and renamed it Streptomyces avermectinius (3). The following year, they reported that the S. avermectinius

March 2016 • The Pharmacologist

24 genome contains 9 million base pairs, the largest bacterial genome sequenced so far (3, 5).

S. avermectinius turned out to be a marvel of bacterial engineering. Seventeen genes encode the necessary enzymes to produce avermectin in an elaborate 53-step synthesis (3, 5). Despite decades of searching worldwide, no other naturally occurring organism has been discovered with the ability to manufacture avermectin, and the only place where S. avermectinius has been found is at the golf course in Japan.

Some parasites of ruminants, including cattle, have become resistant, but despite 35 years of constant worldwide use, ivermectin remains an important veterinary drug. And after more than 25 years of constant monotherapy in humans, no convincing evidence of Onchocerca volvulus resistance to ivermectin has emerged (12). But, it looms as a possibility.

Investigators have seen a few cases of poor responsiveness, and residual micro-larvae have sometimes been observed after ivermectin treatment (5). Also, because ivermectin kills only immature larvae, it must be administered repeatedly as long as the adult worms are producing new larvae. For these reasons, the search continues for alternative drugs, especially those that target adult worms.

Skin Snip Assay The skin snip assay is a common diagnostic test for onchocerciasis. It involves removing some skin from an inflamed area and placing the snipped skin in saline to encourage micro-larvae to leave the skin. Microscopic examination determines the larval load.

In the meantime, the parasite responsible for river blindness is disappearing, thanks to the communitybased programs. Recent studies have shown that in some areas, where ivermectin treatment has been ongoing for 15-17 years, the parasite has been eliminated. In these areas, researchers stopped treatment with ivermectin for up to 5 years and saw no re-emergence of micro-larvae in skin snip samples.

The investigators thus established proof of principle that eradication of river blindness with ivermectin is possible and feasible (17). This has prompted WHO to change its strategy from control of onchocerciasis to onchocerciasis elimination (15, 17).

Ivermectin is a splendid gift from the earth

Reprinted with permission from Nobel Media AB 2105, Photo: Alexander Mahmoud

In 2015, Satoshi Ōmura and William Campbell received the Nobel Prize in Physiology or Medicine for their discovery of the avermectins and development of ivermectin. In his Nobel lecture, Ōmura, noting the soil origins of avermectin, said , “Ivermectin is a splendid gift from the earth” (7).

References 1. Steyer R (July 13, 1986) What’s new in animal health care: a bovine drug that helps people see. New York Times; available from: http://www.nytimes.com/1986/07/13/business/what-snew-in-animal-health-care-a-bovine-drug-that-helps-peoplesee.html.

2. Crump A and Otoguro K (2005) Satoshi Ōmura: in pursuit of nature’s bounty. Trends in Parasitology 21(3):126-132.

3. Ōmura S and Crump A (2004) The life and times of ivermectin—a success story. Nature Rev Microbiol 2:984-989.

4. Collins K (2004) Profitable gifts: A history of the Merck Mectizan® donation program and its implications for international health. Perspect Biol Med 47(1):100-109.

Dr. William C. Campbell beside his wife, Mrs. Mary Campbell

The Pharmacologist • March 2016

25 5. Ōmura S (2008) Ivermectin: 25 years and still going strong. Int J Antimicrob Agents 31:91-98.

6. Campbell WC, Burg RW, Fisher MH, and Dybas RA (1984) The discovery of ivermectin and other avermectins, in Pesticide Synthesis through Rational Approaches (Magee PS, Kohn GK, and Menn JJ eds) pp 5-20, ACS Symposium Series, Washington DC.

Biosketch:

7. Campbell WC and Ōmura S (December 7, 2015) Nobel Prize lectures; available from: http:// www.nobelprize.org/nobel_prizes/medicine/laureates/2015.

8. Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, Kong Y-L, Monaghan RL, Olson G, Putter I, et al. (1979) Avermectins, new family of potent anthelmintic agents: Producing organism and fermentation. Antimicrob Agents Chemother 15(3):361-367.

9. Egerton JR, Ostlind DA, Blair LS, Eary CH, Suhayda D, Cifelli S, Riek RF, and Campbell WC (1979) Avermectins, new family of potent anthelmintic agents: Efficacy of the B1a component.

Antimicrob. Agents Chemother 15(3):372-378.

10. Blair LS (1984) Synergistic treatment of adult canine heartworm with thiacetarsamide and ivermectin. US Patent No. 4,430,329. 1984 Feb 7.

11. Fujisaki T and Reich MR (February 12, 1997) Assessment of TDR’s contributions to product development for tropical diseases: The case of ivermectin for onchocerciasis. 3rd External Review of the Programme Activities, UNDP/World Bank/WHO/TDR; available from: http://www.who.int/tdr/about/history/Fujisaki_Reich_TDR_contribution.pdf.

12. Crump A and Ōmura S (2011) Ivermectin, “wonder drug” from Japan: the human use perspective. Proc Jpn Acad Ser B 87(2):13-28.

13. Basáñez M-G, Pion SDS, Churcher TS, Breitling LP, Little MP, and Boussinesq M (September 26, 2006) River blindness: a success story under threat? PLOS Medicine 3(9):e371 DOI: 10.1371/journal.pmed.0030371.

14. Eckholm E (January 8, 1989) River blindness: Conquering an ancient scourge. New York Times; available from: http://www.nytimes.com/1989/01/08/magazine/river-blindnessconquering-an-ancient-scourge.html.

15. Kim YE, Remme JHF, Steinmann P, Stolk WA, Roungou J-B, and Tediosi F (April 10, 2015) Control, elimination, and eradication of river blindness: Scenarios, timelines, and ivermectin treatment needs in Africa. PLOS Negl Trop Dis 9(4): e0003664 DOI: 10.1371/journal. pntd.0003664.

16. Greene BM, Taylor HR, Cupp EW, Murphy RP, White AT, Aziz MA, Schulz-Key H, D’Anna SA, Newland HS, Goldschmidt LP, et al. (1985) Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis. New Engl J Med 313(3): 133-138.

17. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, Doumbia K, Goita SF, Konate L, Mountkoro K, Seck AF, et al. (September 13, 2012) Proof-of-principle of onchocerciasis elimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Senegal.

PLOS Neglect Trop Dis 6(9): e1825 DOI: 10.1371/journal.pntd.0001825.

18. Rea PA, Zhang V, and Baras YS (2010) Ivermectin and river blindness. Am Sci 98:294-303.

19. Stanford University (2005) Ivermectin History: speech by Roy Vagelos; available from: http://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/History.htm 20. Aziz MA, Diallo S, Diop IM, Lariviere M, and Porta M (1982) Efficacy and tolerance of ivermectin in human onchocerciasis. Lancet 320(8291):171-173.

Rebecca J. Anderson holds a bachelor’s in chemistry from Coe College and earned her doctorate in pharmacology from Georgetown University. She has 25 years of experience in pharmaceutical research and development and now works as a technical writer.

Her most recent book is Nevirapine and the Quest to End Pediatric AIDS. Email

rebeccanderson@msn.com.

In the next issue of The Pharmacologist…

Dr. Anderson will share the story of Taxol - the evolution of a natural product to treat cancer.

Don’t miss the June 2016 issue.

21. Campbell WC (1991) Ivermectin as an antiparasitic agent for use in humans. Ann Rev Microbiol 45:445-474.

March 2016 • The Pharmacologist

26

Business Meeting and Opening Events Saturday, April 2, 2016 Meeting/Event ASPET Business Meeting and Awards Presentation ASPET-PhRMA Foundation Opening and Awards Reception

Location

Time

Room 16AB

6:00 pm - 7:30 pm

Mezzanine Terrace 7:30 pm - 9:30 pm

ASPET Annual Meeting Program Schedule subject to change. Check the EB2016 program book and mobile app for final schedule. All events are at the San Diego Convention Center unless otherwise noted. For full session descriptions and speaker information, visit www.aspet.org/Annual_Meeting_EB_2016/Program

Friday, April 1, 2016 Session/Event Give a Day of Service to San Diego at EB 2016 Contact Dr. Charles France to participate (france@uthscsa.edu or 210-567-6969)

Location

Time

St. Vincent de Paul Village

7:00 am - 3:00 pm

Room

Time

Room 15A

9:30 am - 12:00 pm

Room 15B

12:00 pm - 2:30 pm

Marriott, San Diego Ballroom B

2:45 pm - 5:15 pm

UG GS PD

Room 16AB

6:00 pm - 7:30 pm

UG GS PD

Mezzanine Terrace

7:30 pm - 9:30 pm

UG GS PD

Saturday, April 2, 2016 Session/Event Securing NIH Intramural Fellowships to Enhance Your Pharmacology Training Chairs: J. Clark and A. Reid Teaching Institute: Developing Mentees Using IDPs Chairs: K. Karpa and J.P. Neiswinger Graduate Student – Postdoctoral Colloquium: Mentoring Your Mentor: Key Skills for Effective Mentoring Relationships with Shared Responsibility Speaker: Rick McGee ASPET Business Meeting and Awards Presentation ASPET-PhRMA Foundation Opening and Awards Reception

GS PD

GS PD

UG GS PD

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Sunday, April 3, 2016 Session/Event

Room

Time

Marriott, Rancho Santa Fe 2

7:30 am - 9:30 am

Julius Axelrod Award in Pharmacology Lecture: Therapies of Brain Diseases, Past, Present and Future Keynote: Jean Rossier

Room 16AB

8:30 am - 9:20 am

Julius Axelrod Symposium: New Vistas on Drug and Gene Therapies of Cognitive Deficits in Down Syndrome, Autism, Leucodystrophies and Alzheimer’s Disease Chair: J. Rossier

Room 16AB

9:30 am - 12:00 pm

Emerging Roles for the Ubiquitin-Proteasome System in Therapeutics Chairs: B. Sjogren and H.L. Paulson

Room 17B

9:30 am - 12:00 pm

Undergraduate Research: Cultivating the Next Generation of Researchers Through SURF and Beyond Chairs: C. Fry, C. Davis, and L. Aleksunes

Marriott, San Diego Ballroom B

9:30 am - 12:00 pm

Drugs of Abuse and Antiretrovirals: Interactions and Toxicities Chairs: S. Kumar and K. Jordan-Sciutto

Room 17A

9:30 am - 12:00 pm

Newly Recognized GPCRs in Health, Disease, and as Therapeutic Targets Chairs: R. Corriden and P.A. Insel

Room 15A

9:30 am - 12:00 pm

Advances in Toxicogenetics of Metals Chairs: J. Kim and T. Maher

Room 15B

9:30 am - 12:00 pm

Diversity Mentoring Breakfast (by invitation only) Facilitator: M.A. Nivet

UG GS PD

UG

Follow ASPET’s Official Meeting Bloggers Katie Collette: sicknessisfascinating.blogspot.com Elizabeth Sandquist: everydaybiochemistry.wordpress.com

Don’t forget to also follow ASPET’s tweets and Facebook posts.

Use #expbio and #ASPET

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs March 2016 • The Pharmacologist

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Sunday, April 3, 2016 (continued) ASPET Undergraduate Networking and Career Development Luncheon (pre-registration required) Chairs: C. Beck and C. Davis ASPET Poster Presentations

UG

Marriott, 12:15 pm - 2:00 pm Rancho Santa Fe 2 Exhibit Hall

12:30 pm - 2:30 pm

Room 16AB

2:00 pm - 2:50 pm

Cannabinoid Signaling in Pain and Addiction: Translating Preclinical Basic Research to the Clinic Chairs: D. Morgan and J. Guindon

Room 17B

3:00 pm - 5:30 pm

Dose Selection Using Physiologically Based Modeling Chair: J. Wahlstrom

Room 15A

3:00 pm - 5:30 pm

Room 16AB

3:00 pm - 5:30 pm

Sex Differences in Cardiovascular and Renal Pharmacology Chairs: S.H. Lindsey and E. Gohar

Room 15B

3:00 pm - 5:30 pm

From Ligands to Signaling: Recent Advances in Adhesion GPCR Pharmacology and Biology Chairs: X. Piao and R.A. Hall

Room 17A

3:00 pm - 5:30 pm

Marriott, San Diego Ballroom B

3:00 pm - 5:30 pm

UG GS PD

Goodman and Gilman Award in Receptor Pharmacology Lecture: Towards an Atomic-level Understanding of Psychoactive Drug Actions Keynote: Bryan Roth

ASPET Presidential Symposium: Precision Medicine in Anti-Cancer Pharmacology Chairs: K. Thummel and S.P.C. Cole

Division for Pharmacology Education Symposium: Meet the New POPS - They’ll Flip Your Teaching Chairs: M.A. Simmons and R. Theobald You are encouraged to bring your laptop to this session.

ASPET Student/Postdoc Poster Competition

UG GS PD

Room 20B/C

6:30 pm - 8:30 pm

ASPET Student & Postdoc Mixer

UG GS PD

Center Terrace

8:30 pm - 11:00 pm

Visit the new ASPET member lounge!

• Grab your morning coffee • Hold one-on-one meetings • Meet ASPET members and leaders • Relax or catch up on work using ASPET Wifi San Diego Convention Center Mezzanine Foyer Sunday-Wednesday, 8:00 am - 3:00 pm

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs The Pharmacologist • March 2016

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Monday, April 4, 2016 Session/Event

Room

Time

Room 16AB

8:30 am - 9:20 am

Beyond Traditional Assessments of Pain: Implications for Drug Discovery of Novel Pain Therapeutics Chairs: C.A. Paronis and H. Neelakantan

Room 15B

9:30 am - 12:00 pm

Pharmacometabolomics Enabling Tools for Systems Pharmacology and Precision Medicine Chairs: R. Kaddurah-Daouk and R. Weinshilboum

Room 17A

9:30 am - 12:00 pm

Room 14B

9:30 am - 12:00 pm

Wnt Signaling: From Disease Mechanisms to Therapeutic Interventions Chairs: R. Gosens and W.M. Blankesteijn

Room 17B

9:30 am - 12:00 pm

Substrate Modulation of Organic Anion and Cation Transporters Chairs: B. Hagenbuch and J. Lampe

Room 15A

9:30 am - 12:00 pm

Room 16AB

9:30 am - 12:00 pm

Exhibit Hall

12:30 pm - 2:30 pm

P.B. Dews Lifetime Achievement Award for Research in Behavioral Pharmacology Lecture: Behavioral Mechanisms of Drug Action: Peter Dews's Legacy Keynote: Travis Thompson

Room 15B

2:00 pm - 2:50 pm

Bernard B. Brodie Award in Drug Metabolism Lecture: Phenobarbital Induction of Drug Metabolism and Beyond Keynote: Masahiko Negishi

Room 15A

2:00 pm - 2:50 pm

Room 17B

2:00 pm - 2:50 pm

Room 17A

3:00 pm - 5:30 pm

Division for Behavioral Pharmacology Symposium: Quantitative Pharmacological Analysis of In Vivo Data and Its Implications in CNS Drug Discovery Chairs: J. Li and L. Gerak

Room 15B

3:00 pm - 5:30 pm

Division for Drug Metabolism James Gillette Award and Platform Session Chairs: E.E. Scott and T.J. Carlson

Room 15A

3:00 pm - 5:30 pm

UG GS PD

Division for Molecular Pharmacology Postdoctoral Scientist Award Finalists Keynote: A.V. Smrcka

Room 17B

3:00 pm - 5:30 pm

UG GS PD

Room 16AB

3:00 pm - 5:30 pm

John J. Abel Award in Pharmacology Lecture: Epithelial-Mesenchymal Plasticity in Carcinoma Metastasis Keynote: Ying Jang

A Pharmacokinetics Primer: From Equations to Application Chair: R. Mehvar Seating at hands-on tables is on a first-come basis.

Hear It from the Editors: Navigating the Course through Journal Submission and Publication GS Chairs: M. Vore and E. Morgan ASPET Poster Presentations

Diversity 3.0: From Fairness to Excellence Speaker: Marc A. Nivet Division for Translational and Clinical Pharmacology: Young Investigator Awards Platform Session Chair: B.T. Green

PD

UG GS PD

UG GS PD

UG GS PD

Novel Platelet Therapies: Attacking Them from the Inside and Out Chair: M.T. Nieman

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs March 2016 • The Pharmacologist

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Monday, April 4, 2016 (continued) Division for Translational and Clinical Pharmacology Early Career Faculty Showcase Chair: P.J. Hornby Division Annual Meetings for: • Drug Metabolism • Behavioral Pharmacology • Pharmacology Education • Molecular Pharmacology • Translational and Clinical Pharamcology

UG GS PD

Room 17A

• Room 15A • Room 15B • Room 16AB • Room 17B • Room 17A

5:30 pm - 6:00 pm

5:30 pm - 6:30 pm

Division Mixers for: Marriott, • Behavioral Pharmacology and Neuropharmacology • Presidio • D rug Discovery and Development, Pharmacology Education, and • Torrey Pines 1-2 6:30 pm - 8:30 pm Translational and Clinical Pharmacology UG GS PD • Rancho Santa Fe 1-2 • Molecular Pharmacology Young Experimental Scientists Y.E.S. Mixer (EB sponsored event for students and postdocs)

Marriott, Marina Ballroom, Salon G

9:00 pm - 11:30 pm

Room

Time

Marriott - Meet at Rancho Santa Fe 3

7:00 am - 8:30 am

Invited Lecture: RhoA in Focus: Pathways from GPCRs to Disease Keynote: Joan Heller Brown

Room 16A

8:30 am - 9:20 am

Invited Symposium: GPCR and RhoA as Mediators of Disease Chairs: R. Neubig and S. Miyamoto

Room 16A

9:30 am - 12:00 pm

Central Mechanisms Contributing to Novel Antidepressant Efficacy Chair: D. Lodge

Room 16B

9:30 am - 12:00 pm

Chronopharmacology in Cancer: Does Time Really Matter?

Chair: S. Gaddameedhi

Room 15A

9:30 am - 12:00 pm

Nicotinic Agonist/Antagonist Drug Development: Implications for Treatment of Neurodegenerative and Addictive Disorders Chairs: A. Fleckenstein and M. Quik

Room 17B

9:30 am - 12:00 pm

Current Trends in Antibody Drug Conjugates: From Discovery to the Clinic Chairs: T. Esbenshade and L.C. Wienkers

Room 17A

9:30 am - 12:00 pm

Patient-Specific Stem Cells as Models for Gene-Disease, Drug, and Environment Interactions Chair: J. Richardson

Room 15B

9:30 am - 12:00 pm

ASPET Poster Presentations

Exhibit Hall

12:30 pm - 2:30 pm

Marriott, Torrey Pines 2-3

12:30 pm - 2:30 pm

UG GS PD

Tuesday, April 5, 2016 Session/Event ASPET Networking Walk UG GS PD

UG GS PD

Meet-the-Experts in Translational and Clinical Pharmacology UG Luncheon (pre-registration required)

GS PD

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs The Pharmacologist • March 2016

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Tuesday, April 5, 2016 (continued) Division for Cardiovascular Pharmacology Trainee Showcase

Room 16A

2:30 pm - 4:30 pm

Division for Drug Discovery and Development Symposium: Chemical Biology as an Engine for Drug Discovery Chairs: J.S. Lazo and C. Beeson

Room 17A

3:00 pm - 5:30 pm

Division for Cancer Pharmacology Division Programming: Cell Signaling in Cancer Biology and Therapeutics Chairs: R.K. Guy and J.C. Yalowich

Room 15A

3:00 pm - 5:30 pm

Room 16B

3:00 pm - 5:30 pm

Room 15B

3:00 pm - 5:30 pm

Room 33ABC

3:00 pm - 5:00 pm

Room 16A

4:30 pm - 5:30 pm

Chairs: C. McCarthy and J. Schilling

UG GS PD

Division for Neuropharmacology Postdoctoral Scientist Award Finalists UG Keynote: L.C. Daws

GS PD

Division for Toxicology Symposium: Fortuitous Protein Modification in Disease Pathogenesis and Treatment Chair: S.S. Lau Tang Prize in Biopharmaceutical Science Award Lecture Keynote: Tasuku Honjo (EB-wide lecture for all societies)

Paul M. Vanhoutte Distinguished Lectureship in Vascular Pharmacology: Capillaries as Decoders of the Neural Rhythm of the Brain: Translating Thought into Blood Flow Keynote: Mark T. Nelson Division Annual Meetings for: • Cancer Pharmacology • Toxicology • Cardiovascular Pharmacology • Neuropharmacology • Drug Discovery and Development

UG GS PD

Division Mixers for: • Cardiovascular Pharmacology • Drug Metabolism, Toxicology, and Cancer Pharmacology UG GS PD

• Room 15A • Room 15B • Room 16A • Room 16B • Room 17A Marriott, • Torrey Pines 1-2 • Rancho Santa Fe 1-2

5:30 pm - 6:30 pm

6:30 pm - 8:30 pm

ASPET Booth #1802 Visit the ASPET booth in the Experimental Biology exhibit hall!

Items for sale at “Shop ASPET” include scarves, ties, t-shirts, plush donkeys, and much more.

Plus, pick up some free ASPET souvenirs!

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs March 2016 • The Pharmacologist

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Wednesday, April 6, 2016 Session/Event

Room

Time

Ray Fuller Lecture in the Neurosciences: Sex Biased Stress Signaling Keynote: Rita J. Valentino

Room 16A

8:30 am - 9:20 am

Ray Fuller Symposium: Sex Differences in Biology: Challenges and Opportunities for Drug Development Chair: R.J. Valentino

Room 16A

9:30 am - 12:00 pm

Keep Calm and Target Peptides: Modulation of Stress-Related Behaviors by Neuropeptide Systems Chairs: S. Clark and V. Sabino

Room 17A

9:30 am - 12:00 pm

Novel Targets for Treatment of Cardiometabolic Diseases Chairs: J. Ren and S. Nair

Room 15A

9:30 am - 12:00 pm

Cancer Stem Cells as Pharmacological Targets Chairs: J.S. Gutkind and T. Reya

Room 17B

9:30 am - 12:00 pm

Intracellular GPCR and Lipid Signaling Chairs: A. Marchese and A. Smrcka

Room 15B

9:30 am - 12:00 pm

Drug Transporter Protein Quantification by LC-MS/MS for In Vitro to In Vivo Extrapolation (IVIVE) and Prediction of Interindividual Variability of Transporter Mediated Drug Disposition Chairs: B. Prasad and Y. Lai

Room 16B

9:30 am - 12:00 pm

ASPET Poster Presentations

Exhibit Hall

12:30 pm - 2:30 pm

Marriott

2:00 pm - 8:00 pm

Translating MicroRNA Cancer Biology to Therapy Chairs: A. Yu and A.G. Bader

Room 17B

3:00 pm - 5:30 pm

Modulation of BSEP and MDR3 in Drug-Induced Liver Injury (DILI) Chairs: K. He and D. Rodrigues

Room 17A

3:00 pm - 5:30 pm

The Biology and Translational Potential of Hydrogen Sulfide: One Person’s Trash is Another Person’s Treasure Chairs: J.L. Wallace and A. Papapetropoulos

Room 16B

3:00 pm - 5:30 pm

New Twists on Neurotransmitter Transport: Unraveling Novel Therapeutic Targets for Addiction and Psychiatric Disorders Chairs: L.C. Daws and H.H. Sitte

Room 16A

3:00 pm - 5:30 pm

Marriott, Poolside Terrace

6:00 pm - 8:00 pm

UG GS PD

Drug Discovery Colloquium – Individual Partnering Meetings (separate registration fee required)

ASPET Closing Reception

UG GS PD

Thursday, April 7, 2016 Session/Event

Room

Time

Room 6A

8:00 am - 8:00 pm

Drug Discovery in Academia: Recent Successes and Emerging Opportunities A colloquium sponsored by ASPET and Academic Drug Discovery Consortium

Chairs: M. Wood and B. Slusher (separate registration fee required)

UG GS PD

■ = Lectures ■ = Networking Time Included UG = Session of Interest for Undergraduate Students GS = Session of Interest for Graduate Students PD = Session of Interest for Postdocs The Pharmacologist • March 2016

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Division Meetings and Activities

Sunday, April 3

12:15 pm - 1:45 pm

BEH Executive Committee Meeting (invitation only)

Marriott, Torrey Pines 2

Monday, April 4 2:00 pm - 2:50 pm P.B. Dews Lifetime Achievement Award for Research in Behavioral Pharmacology Lecture

Room 15B

Monday, April 4 3:00 pm - 5:30 pm Division Programming: “Quantitative Pharmacological Analysis of In Vivo Data and Its Implications in CNS Drug Discovery”

Room 15B

Monday, April 4 5:30 pm - 6:30 pm BEH Annual Division Meeting

Room 15B

Monday, April 4 6:30 pm - 8:30 pm Joint Mixer - BEH with Neuropharmacology

Monday, April 4 7:00 am - 8:15 am

Marriott, Presidio

DCP Executive Committee Meeting (invitation only)

Marriott, Torrey Pines 1

Tuesday, April 5 3:00 pm - 5:30 pm Division Programming: “Cell Signaling in Cancer Biology and Therapeutics”

Room 15A

Tuesday, April 5 5:30 pm - 6:30 pm DCP Annual Division Meeting

Room 15A

Tuesday, April 5 6:30 pm - 8:30 pm Joint Mixer - DCP with Drug Metabolism & Toxicology

Monday, April 4 12:15 pm - 1:45 pm

Marriott, Rancho Santa Fe 1-2

CVP Executive Committee Meeting (invitation only)

Marriott, Rancho Santa Fe 1

Tuesday, April 5 2:30 pm - 4:30 pm Division Programming: Trainee Showcase

Room 16A

Tuesday, April 5 4:30 pm - 5:30 pm Paul M. Vanhoutte Distinguished Lectureship in Vascular Pharmacology

Room 16A

Tuesday, April 5 5:30 pm - 6:30 pm CVP Annual Division Meeting

Room 16A

Tuesday, April 5 6:30 pm - 8:30 pm CVP Mixer

Marriott, Torrey Pines 1-2

BEH = Behavioral Pharmacology, CVP = Cardiovascular Pharmacology, DCP = Cancer Pharmacology, DDD = Drug Discovery and Development, DM = Drug Metabolism, MP = Molecular Pharmacology, NEU = Neuropharmacology, DPE = Pharmacology Education, TCP = Translational and Clinical Pharmacology, TOX = Toxicology March 2016 • The Pharmacologist

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Monday, April 4 12:15 pm - 1:45 pm

DDD Executive Committee Meeting (invitation only)

Monday, April 4 6:30 pm - 8:30 pm Joint Mixer - DDD with Pharmacology Education & Translational and Clinical Pharmacology

Marriott, Torrey Pines 3 Marriott, Torrey Pines 1-2

Tuesday, April 5 3:00 pm - 5:30 pm Division Programming: “Chemical Biology as an Engine for Drug Discovery”

Room 17A

Tuesday, April 5 5:30 pm - 6:30 pm DDD Annual Division Meeting

Room 17A

Sunday, April 3

12:15 pm - 1:45 pm

DM Executive Committee Meeting (invitation only)

Marriott, Torrey Pines 1

Monday, April 4 2:00 pm - 2:50 pm Bernard B. Brodie Award in Drug Metabolism Lecture

Room 15A

Monday, April 4 3:00 pm - 5:30 pm Division Programming: James Gillette Award and Platform Session

Room 15A

Monday, April 4 5:30 pm - 6:30 pm DM Annual Division Meeting

Room 15A

Tuesday, April 5 6:30 pm - 8:30 pm Joint Mixer - DM with Cancer Pharmacology & Toxicology

Sunday, April 3

12:15 pm - 1:45 pm

MP Executive Committee Meeting (invitation only)

Marriott, Rancho Santa Fe 1-2

Marriott, Torrey Pines 3

Monday, April 4 3:00 pm - 5:30 pm Division Programming: Postdoctoral Scientist Award Finalists

Room 17B

Monday, April 4 5:30 pm - 6:30 pm MP Annual Division Meeting

Room 17B

Monday, April 4 6:30 pm - 8:30 pm MP Mixer

Monday, April 4 7:00 am - 8:15 am

NEU Executive Committee Meeting (invitation only)

Monday, April 4 6:30 pm - 8:30 pm Joint Mixer - NEU with Behavioral Pharmacology

Marriott, Rancho Santa Fe 1-2

Marriott, Torrey Pines 2 Marriott, Presidio

Tuesday, April 5 3:00 pm - 5:30 pm Division Programming: Postdoctoral Scientist Award Finalists

Room 16B

Tuesday, April 5 5:30 pm - 6:30 pm NEU Annual Division Meeting

Room 16B

BEH = Behavioral Pharmacology, CVP = Cardiovascular Pharmacology, DCP = Cancer Pharmacology, DDD = Drug Discovery and Development, DM = Drug Metabolism, MP = Molecular Pharmacology, NEU = Neuropharmacology, DPE = Pharmacology Education, TCP = Translational and Clinical Pharmacology, TOX = Toxicology The Pharmacologist • March 2016

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Sunday, April 3

3:00 pm - 5:30 pm Division Programming: “Meet the New POPS They’ll Flip Your Teaching”

Monday, April 4 7:00 am - 8:15 am

DPE Executive Committee Meeting (invitation only)

Marriott, Torrey Pines 3

Monday, April 4 5:30 pm - 6:30 pm DPE Annual Division Meeting

Room 16AB

Monday, April 4 6:30 pm - 8:30 pm Joint Mixer - DPE with Drug Discovery and Development & Translational and Clinical Pharmacology

Monday, April 4 12:15 pm - 1:45 pm

Marriott, San Diego Ballroom B

Marriott, Torrey Pines 1-2

TOX Executive Committee Meeting (invitation only)

Marriott, Torrey Pines 2

Tuesday, April 5 3:00 pm - 5:30 pm Division Programming: “Fortuitous Protein Modification in Disease Pathogenesis and Treatment”

Room 15B

Tuesday, April 5 5:30 pm - 6:30 pm TOX Annual Division Meeting

Room 15B

Tuesday, April 5 6:30 pm - 8:30 pm Joint Mixer - TOX with Drug Metabolism & Cancer Pharmacology

Monday, April 4 7:00 am - 8:15 am

TCP Executive Committee Meeting (invitation only)

Marriott, Rancho Santa Fe 1-2

Marriott, Rancho Santa Fe 1

Monday, April 4 3:00 pm - 5:30 pm Division Programming: Young Investigator Awards Platform Session

Room 17A

Monday, April 4 5:30 pm - 6:00 pm TCP Early Career Faculty Showcase

Room 17A

Monday, April 4 6:00 pm - 6:30 pm TCP Annual Division Meeting

Room 17A

Monday, April 4 6:30 pm - 8:30 pm Joint Mixer - TCP with Drug Discovery and Development & Pharmacology Education

Marriott, Torrey Pines 1-2

Tuesday, April 5 12:30 pm - 2:30 pm Meet-the-Experts in Translational and Clinical Pharmacology

Marriott, Torrey Pines 2-3

Don't miss your Division's Annual Meeting!

BEH = Behavioral Pharmacology, CVP = Cardiovascular Pharmacology, DCP = Cancer Pharmacology, DDD = Drug Discovery and Development, DM = Drug Metabolism, MP = Molecular Pharmacology, NEU = Neuropharmacology, DPE = Pharmacology Education, TCP = Translational and Clinical Pharmacology, TOX = Toxicology March 2016 • The Pharmacologist

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ASPET Meetings The following are invitation-only meetings. Schedule is subject to change.

Thursday, March 31 5:00 pm - 10:00 pm Finance Committee Meeting

Marriott, Rancho Santa Fe 1-2

Friday, April 1 8:00 am - 6:00 pm Council Meeting

Marriott, Rancho Santa Fe 1-2

11:00 am - 8:00 pm Mentoring Network: Coaching for Career Development

Marriott, Torrey Pines 2-3

1:00 pm - 5:00 pm

Marriott, Torrey Pines 1

Council of Division Chairs

Saturday, April 2 8:00 am - 2:00 pm Mentoring Network: Coaching for Career Development

Marriott, Torrey Pines 2-3

Sunday, April 3 7:00 am - 8:15 am

Division Communications Officers Meeting

Marriott, Torrey Pines 1

7:00 am - 9:00 am

JPET Associate Editors Meeting

Marriott, Torrey Pines 3

7:30 am - 9:30 am

Diversity Mentoring Breakfast

12:15 pm - 2:00 pm ASPET Undergraduate Networking and Career Development Luncheon

Marriott, Rancho Santa Fe 2 Marriott, Rancho Santa Fe 2

12:15 pm - 1:45 pm

Division for Molecular Pharmacology Executive Committee Meeting

Marriott, Torrey Pines 3

12:15 pm - 1:45 pm

Division for Behavioral Pharmacology Executive Committee Meeting

Marriott, Torrey Pines 2

12:15 pm - 1:45 pm

Division for Drug Metabolism Executive Committee Meeting

Marriott, Torrey Pines 1

12:30 pm - 2:30 pm ASPET Board of Publications Trustees Meeting 7:30 pm - 10:00 pm Board of Publications Trustees Joint Editorial Boards Dinner

Marriott, Rancho Santa Fe 1 Marriott, Marina Ballroom F

Monday, April 4 7:00 am - 8:15 am

Division for Translational and Clinical Pharmacology Executive Committee Meeting

7:00 am - 8:15 am

Division for Pharmacology Education Executive Committee Meeting

Marriott, Torrey Pines 3

7:00 am - 8:15 am

Division for Neuropharmacology Executive Committee Meeting

Marriott, Torrey Pines 2

7:00 am - 8:15 am

Division for Cancer Pharmacology Executive Committee Meeting

7:00 am - 9:00 am

Molecular Pharmacology Editorial Board Meeting

12:15 pm - 1:45 pm

Division for Drug Discovery and Development Executive Committee Meeting

Marriott, Torrey Pines 3

12:15 pm - 1:45 pm

Division for Toxicology Executive Committee Meeting

Marriott, Torrey Pines 2

The Pharmacologist • March 2016

Marriott, Rancho Santa Fe 1

Marriott, Torrey Pines 1 Marriott, Presidio

37 12:15 pm - 1:45 pm

Division for Cardiovascular Pharmacology Executive Committee Meeting

12:15 pm - 1:45 pm

Science Policy Committee Meeting

Marriott, Rancho Santa Fe 1 Marriott, Torrey Pines 1

12:30 pm - 2:30 pm Pharmacological Reviews Editorial Board Meeting

Marriott, Presidio

6:30 pm - 9:00 pm Past Presidents’ Dinner

Marriott, Carlsbad

Tuesday, April 5 7:00 am - 9:00 am

Drug Metabolism and Disposition Editorial Board Meeting

7:00 am - 8:15 am

Nominating Committee Meeting

12:15 pm - 2:15 pm

Mentoring and Career Development Committee Meeting

Marriott, Presidio Marriott, Torrey Pines 1 Marriott, Rancho Santa Fe 1

12:30 pm - 2:30 pm Pharmacology Research & Perspectives Editorial Board Meeting

Marriott, Rancho Santa Fe 2

3:00 pm - 5:00 pm

Marriott, Rancho Santa Fe 2

Pharmacology Research & Perspectives Management Committee Meeting

Wednesday, April 6 7:15 am - 8:15 am

Young Scientists Committee Meeting

Marriott, Rancho Santa Fe 1

12:00 pm - 3:00 pm Program Committee Meeting

Marriott, Rancho Santa Fe 1-2

8:00 pm - 10:00 pm President’s Reception

Check invitation for location

Ancillary Functions at EB2016 The following are affiliated events organized by groups other than ASPET but taking place during EB2016.

Please contact the organizers for times and locations.

AMSPC Reception

Sunday, April 3

Behavioral Pharmacology Society (BPS) - GUEST SOCIETY

Friday-Saturday April 1-2

Catecholamine Club Dinner

Tuesday, April 5

Global GI Club - GUEST SOCIETY

Sunday, April 3

Michigan State University Pharmacology and Toxicology Reception

Sunday, April 3

PhRMA Foundation Reception

Monday, April 4

University of Michigan Department of Pharmacology and Department of Biological Chemistry Social Hour

Saturday, April 2

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This colloquium sponsored by ASPET and the Academic Drug Discovery Consortium (ADDC) will include a full day of lectures, platform sessions, case studies, panel discussions, and scientific posters. It will explore drug discovery in academia, in particular, biological therapies, small-molecule success stories and emerging opportunities, and rare and neglected diseases.

Separate registration fee is required. Register at bit.ly/1MKOvVN.

Schedule at a Glance Wednesday, April 6, 2016

Marriott Marquis San Diego Marina 2:00 pm - 8:00 pm

Pharma-Academic Individual Partnering Meetings (Must be pre-registered to participate)

Thursday, April 7, 2016

San Diego Convention Center 7:00 am - 10:30 am 8:00 am - 12:00 pm 12:00 pm - 1:00 pm 1:00 pm - 3:00 pm 3:00 pm - 4:00 pm 4:00 pm - 5:00 pm 5:30 pm - 8:00 pm Hosted by The Pharmacologist • March 2016

Registration/Badge Pick-Up Small Molecule Success Stories and Emerging Opportunities Networking Lunch Rare and Neglected Diseases Government Funding Opportunities to Advance Drug Discovery Panel Session: Advancing and Partnering Drug Discovery Programs Scientific Poster Session and Dinner Reception

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Science Policy

Omnibus Bill Makes Science Research a Priority; FY2017 Budget Process Already Underway The December passage of the omnibus bill conveyed that legislators on both sides of the aisle recognized the importance of funding for scientific research. The spending bill allocates just over US$32.1 billion to the National Institutes of Health (NIH) agency: a 6.6% rise over its 2015 budget, as well as increases for the National Science Foundation (NSF), the Department of Energy Office of Science, Veterans Medical and Prosthetic Research, and

the Agriculture and Food Research Initiative at the US Department of Agriculture. This outcome was critical to the research community, with advocates delivering the message that funding has been mostly flat for the past decade.

FASEB President Parker Antin said in an op-ed published in The Hill, “Since 2003, the purchasing power of the NIH has declined by nearly 22% when corrected for inflation. As a result, the research community has had to cut

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back, delaying the development of treatments and cures that could help people worldwide. To restore the discovery engine in the United States, scientists and engineers need sufficient funding. The increased funding for science in the omnibus bill is a good start.”

The Food and Drug Administration did not fare quite as well; the bill granted the regulatory agency an additional $132 million from 2015, a 5% increase. Additionally, the bill prohibits the agency from spending money to review any applications for clinical trials that involve human embryos with heritable genetic modifications, effectively banning such research.

The NSF received a modest increase from 2015 with an allocation of $7.5 billion, a 1.6% increase over 2015 levels. Social-sciences spending remains flat.

Unlike the NIH, the NSF has not always received a consistent level of bipartisan support. Last June, the House of Representatives proposed requiring the foundation to spend 70% of its research funds on biology, computer science, engineering, mathematics and physical sciences, effectively cutting the funds available to social science and geoscience by about 15%.

The omnibus passage can only be viewed as a success, but is by no means an ideal outcome. The increases were made possible by the late-October agreement between Congress and the White House that set overall spending levels for both the 2016 and 2017 fiscal years. While it added $50 billion this year to the $1.017 trillion spent in 2015, there is only $30 billion for 2017, making appropriations allocations more important than ever.

FY2017 Budget and Appropriations Process Following passage of the omnibus, Congressional leadership established an ambitious goal of passing all 12 appropriations bills for fiscal year (FY) 2017.

If successful, it would be the first time since 1994.

But, legislators will have to overcome a calendar shortened by the presidential election and resolve major differences on policy issues in order to achieve this bold objective. As of this writing, the president is expected to release his final budget request to Congress in early February, with the appropriations process expected to ramp up quickly upon its release. With the top line discretionary allocations

The Pharmacologist • March 2016

already established for FY 2017 under the Bipartisan Budget Act, deeper spending cuts are needed in the budget resolutions if lawmakers want to balance the budget over 10 years.

This appropriations cycle will also be viewed as the first “test” for House Speaker Paul Ryan (R-WI), who largely distanced himself from the Bipartisan Budget Act of 2015, asserting that it was the design of predecessor John Boehner (R-OH). Some of the more fiscally conservative members of Congress said publically that they plan to hold their leadership accountable on fiscal matters. Representative Thomas Massie (R-KY) said conservatives told the speaker at a retreat that if there is another omnibus spending bill in December 2016, “he’ll get an F-minus grade.”

House Freedom Caucus member Dave Brat (R-VA) added, “The proof in the pudding for the speakership will be the budget and appropriations process.”

Ambivalence on Budget Resolution With the allocations already set by the Bipartisan Budget Act, there's little substantive reason for Congress to adopt a budget resolution this year (other than laying the groundwork for reconciliation).

Chairman Price and the House GOP are intent on writing a budget, but the prospects may be dimmer in the Senate. Still, there seems to be some appetite from Senate leadership to write a budget this year.

Senator John Thune (R-SD) went on record saying that they are considering doing the resolution, if for no other reason than to allow for reconciliation again this year. Given the tumultuous process in 2015, many legislators are keen to take a break from the budget process.

Even if Congress is unable to pass a budget resolution, there are several reasons to be optimistic about the outlook for FY 2017. Having the top line funding levels already established by the Bipartisan Budget Act of 2015 leaves time for more consideration in terms of specific appropriations allocations. The agreement increased spending for discretionary programs by $30 billion above the existing budget caps. Ryan and McConnell recently confirmed their commitment to passing bills at the higher spending levels and pledged to allow sufficient time for debate on the individual spending measures in the House and Senate. McConnell also has the support of Senate Minority Leader Harry Reid

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(D-NV) who announced that Democrats will not block votes on the appropriations legislation as they did in 2015.

As they have done in past years, the House Appropriations Committee will hold hearings on the agency funding requests. Reports indicate that the committee is already planning a session to discuss the budget for NIH. Once the hearings are complete, the subcommittees will mark up and debate the bills before a full committee debate on individual bills.

House Appropriations Committee votes could begin in early March. Senate Appropriations Chairman Thad Cochran (R-MS) has not announced plans for his committee yet but said he anticipates that markups will start in April. Both committees will try to get as much done as possible before Congress begins its summer break the week of July 15.

FY2017 Appropriations Process Ramps Up With the election, summer conventions, and a shortened number of legislative work days, appropriations will start sooner and proceed quicker this year. If the budget resolution process is resolved quickly, early movement will be possible.

Still, the accelerated schedule presents a highly challenging year for appropriators and their staffs.

Senior Congressional staff have shared off the record that, in the end, Congress may have to pass a 6-month Continuing Resolution in late September or early October and go home to campaign. On the record, however, that is not the current plan for this year. Instead, the Appropriations chairs and House and Senate leadership have all committed to a regular appropriations cycle, with bills emerging from committee, being voted upon on the floor, and eventually resolved in a House-Senate conference.

The bulk of that work will need to be done before the conventions, giving the process at least 2 fewer months to reach agreement and move the bulk of the 12 appropriations bills.

Hearings will need to be completed prior to Committee markups to start by early April, with the first (easiest) bills targeted for final passage by May. The remaining bills will need to be cleaned up in June and September. Many doubt that this “hurry-up appropriations agenda” is realistic, but the effort is going to be made nonetheless. Accordingly, ASPET will be speeding up our advocacy activities for the year.

ASPET Government Affairs and Science Policy 4th Quarter Summary ASPET advocacy efforts were in full swing during the final three months of 2015. The uncertainty of funding outcomes and the seemingly endless shortterm Continuing Resolutions led to an exhaustive effort by ASPET’s Science Policy Committee (Dr. Annette Fleckenstein, Chair), Council, and our coalition partners to ensure that Congress understood the importance of science research funding. The work, of course, goes on–we are already drafting testimony for 2017; but the year certainly ended on a high note for all of us in the biomedical research community. The summary below represents the highlights of our efforts. Jennifer Zeitzer, Government Affairs Director at FASEB, said it best: “Best Christmas present ever!”

Promoting Optimal Funding for Biological and Biomedical Research • ASPET President Ken Thummel and 21 other FASEB society presidents signed a letter to Congress expressing support for a passed budget with increased funding for all federally supported scientific agencies (October 1st).

• Collaborated with coalition partners to circulate a FY 2016 budget and omnibus e-action to Congress that generated over 9,400 and 17,000 messages in October and December, respectively.

• ASPET SPC member Mary-Ann Bjornsti worked with staff to publish a commentary on NIH funding

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Engaging with Science Community Policy Makers • Letters and statements regarding appropriations (see above) • ASPET responded to FDA Request for Comments on Ketamine Rescheduling (October 2nd) • ASPET President Ken Thummel submitted a letter with recommendations to House Energy and Commerce Chairman Fred Upton and Ranking Member Frank Pallone regarding H.R. 3537, the Synthetic Drug Control Act • ASPET was represented by FASEB in their response to the RFI on the NCATS Strategic Plan (December 2nd)

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Strengthening Strategic Partnerships • Collaborated with FASEB and other societies on e-messaging regarding appropriations (see above) • ASPET was represented in weekly meetings with the AdHoc Group for Medical Research, the Alliance for a Stronger FDA, and the Coalition for Health Funding • ASPET staff participated in weekly strategic planning meetings with FASEB’s Office of Public Affairs • ASPET leadership worked with FASEB to develop a report on rigor and reproducibility

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Education News Congratulations to the ASPET Mentoring Network Inaugural Class The ASPET Mentoring Network: Coaching for Career Development was established by the BIG IDEAS initiative in 2015 as a means to promote diversity in the scientific workforce through career coaching. This program follows a mentoring model that matches mid- to latecareer scientists with cohorts of young scientists to help guide them in their development and career advancement. The activities of the program are designed to complement, not replace, scientific mentors at participants’ home institutions. The yearlong program will include both one-on-one and group discussions that align with the interests and needs of the participants. The first year-long program will begin during EB2016 with in-person activities, followed by virtual interactions throughout the year. Activities at EB2016 will encourage relationship building across coaching groups, near-peer mentoring between graduate students and postdoctoral scientists, and networking. The program will lay the groundwork for how the ASPET Mentoring Network will work, with a special emphasis on deconstructing the skills needed to succeed scientifically, professionally, psychologically, and socially.

Led by Lynn Wecker, Susan Ingram, and members of the Mentoring and Career Development committee, the program will adapt a coaching model developed

by Rick McGee and his colleagues at Northwestern University. The leadership team identified coaches and solicited applications from graduate students and postdoctoral scientists in the fall of 2015. Coaches include Larry Carter (Jazz Pharmaceuticals), Susan Ingram (Oregon Health & Science University), Dave Jewett (University of Wisconsin, Eau Claire), and Stephanie Watts (Michigan State University). Lynn Wecker (University of South Florida) and Myron Toews

(University of Nebraska Medical Center) will also provide support to the coaching groups throughout the program. Rick McGee has contributed his expertise throughout the process, and will lead related sessions at EB2016. We congratulate the following young scientists who were chosen to participate in the ASPET Mentoring Network:

Postdoctoral Scientists Melissa Barker-Haliski, Univ of Utah Rebecca Benham Vautour, McLean Hospital/ Harvard Med Sch Lisa Brents, Univ of Arkansas for Med Sciences Eman Gohar, Univ of Alabama Birmingham Lauren Haar, Loyola Univ Chicago Naeem Patil, Vanderbilt Univ Med Center Ibolya Rutkai, Tulane Univ Sherrica Tai, Univ of Arkansas for Med Sciences

Graduate Students Seun Ajiboye, Johns Hopkins Univ Sara Humphreys, Washington State Univ Suleman Hussain, Univ of Texas at San Antonio Ram Kandasamy, Washington State Univ Sophia Kaska, Michigan State Univ Cameron Kieffer, Creighton Univ Cam McCarthy, Georgia Regents Univ Walatta Mesquitta, Univ of Wisconsin-Madison Amreen Mughal, North Dakota State Univ Anh Phan, Loyola Univ Chicago Angel Rubio, Boston Univ Tracey Suter, Brown Univ Zachary Tibbs, Univ of Alabama at Birmingham Alexandria Trujillo, SUNY at Buffalo Saurabh Vispute, St. John's Univ Chen-Shan Woodcock, Univ of Pittsburgh

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Journals News New Editorial Board Members The Board of Publications Trustees is pleased to announce the following new editorial board members since the last issue of The Pharmacologist.

Joining the Drug Metabolism and Disposition Editorial Advisory Board are: • Dr. J. Matthew Hutzler, Director of In Vitro Metabolism, Q2 Solutions • Dr. Ge Lin, Professor of Biomedical Sciences and Principal Investigator of the PK/PD Laboratory, Chinese University of Hong Kong; Chair, Joint Research Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; • Dr. Ikumi Tamai, Professor and Chair, Department of Membrane Transport and Biopharmaceutics, Kanazawa University • Dr. Shinji Yamazaki, Associate Research Fellow in Pharmacokinetics, Dynamics, and Metabolism, Pfizer • Dr. Grover P. Miller, Associate Professor of Biochemistry, University of Arkansas for the Medical Sciences • Dr. Maciej Zamec-Gliszczynski, Director of Mechanistic Safety and Disposition, GSK; Adjunct Professor of Pharmacy, University of North Carolina.

Pharmacological Reviews added six associate editors: • Dr. Robert Dantzer, Professor of Psychoneuroimmunology, University of Texas, MD Anderson Cancer Center • Dr. Charles P. France, Professor, Departments of Pharmacology and Psychiatry, University of Texas Health Science Center at San Antonio • Dr. Birgitte Holst, Professor in Molecular Metabolic Pharmacology, Institute of Neurobiology and Pharmacology • Dr. Graeme Milligan, Gardiner Professor of Biochemistry, University of Glasgow • Dr. Patrick M. Sexton, Professor of Pharmacology, Monash University; NHMRC principal Research Fellow and Theme Leader, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences • Dr. Alan V. Smrcka, Professor in the Aab Cardiovascular Research Institute; Louis C. Lasagna Professor of Experimental Therapeutics, Department of Pharmacology and Physiology, University of Rochester The Board of Publications Trustees welcomes these new editorial board members and is grateful for their service.

First Open Access Article Published ASPET’s open access option became available to authors of new manuscript submissions in December.

Often called “gold open access,” authors have the choice of publishing under a Creative Commons Attribution 4.0 International license (CC-BY) or an Attribution-Noncommercial 4.0 International license

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(CC-BY-NC). Both licenses allow authors to retain copyright and post, deposit, and share their article.

More information about the licenses is on the Creative Commons website at http://bit.ly/O9cHH0.

The new option was quickly taken up, and the first open access article was published in JPET on March 1:

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“Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling” by Gavin E. Jarvis, Roseli Barbosa, and Andrew J. Thompson is in the March issue [356(3):549-562]. The copyedited and

fully formatted version was made freely available immediately to all at http://bit.ly/1LhziIK. The manuscript version has been freely accessible since acceptance, which is the case for all manuscripts published in JPET as well as in DMD and Molecular Pharmacology.

PR&P at Pharmacology 2015 in London Dr. Darrell Abernethy, the new editor-in-chief of Pharmacology Research & Perspectives, spoke with attendees at Pharmacology 2015, the annual meeting of the British Pharmacological Society, in London this past December. Dr. Abernethy

presented his vision for the journal, its unique features and place in the pharmacology literature, and the benefits it provides to authors and readers. He and Dr. Andrew Lawrence, the new PR&P deputy editor, discuss the journal and its future in a video recorded by the British Pharmacological Society and available from ASPET’s website at http://bit.ly/1T8vXls.

Journals Symposium at ASPET Annual Meeting ”Hear It from the Editors: Navigating the Course through Journal Submission and Publication” will be this year’s journal symposium at ASPET’s Annual Meeting on Monday, April 4 from 9:30 AM to noon.

This symposium will serve as a practical guide for early-career scientists to enhance their writing and analytical skills, with a focus on publishing in ASPET’s journals. Presentations include how to choose a journal for your manuscript; how to write a competitive manuscript; communicating experimental design and analysis considerations; the peer-review process:

rejection, revision, and acceptance; and authorship, accountability, and ethics. The session will end with a panel discussion. Presenters include Dr. Mary Vore, Chair of the Board of Publications Trustees; Dr. Michael Jarvis, former JPET editor; Dr. Edward Morgan, DMD editor; Dr. Steven Traynelis, Molecular Pharmacology editor; and Rich Dodenhoff, ASPET journals director.

The panel discussion will be moderated by Dr. David R. Sibley, former editor of Pharmacological Reviews and ASPET president-elect.

Meet the Editors in San Diego The editors of Drug Metabolism and Disposition, JPET, Molecular Pharmacology, and PR&P will be available to meet with interested perspective authors and readers in the ASPET Member Lounge

at the San Diego Convention Center during ASPET’s Annual Meeting/Experimental Biology 2016. Check the annual meeting website www.aspet.org/eb2016 for exact dates and times.

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Membership News New Members REGULAR MEMBERS Michael A. Adams, Queen's Univ, Canada A O. Aderibigbe, Univ of Ibadan, Nigeria Saganuwan Alhaji Saganuwan, Univ of Agriculture, Nigeria Wayne B. Anderson, Albany Molecular Res, NY Ok-Nam Bae, Hanyang Univ, South Korea Annabelle Ballesta, Univ of Warwick Systems Biology Centre, UK Matthew J. Betzenhauser, Masonic Med Res Lab, NY Gouri Shankar Bhattacharyya, Fortis Hospital, India Jennifer Cash, Univ of Michigan Eric Chun Yong Chan, National Univ of Singapore Dominic J. Corkill, MedImmune Ltd, UK Upendra P. Dahal, Celgene Corporation, NJ Zeruesenay Desta, Indiana Univ Sch of Med Olivia Engmann, Friedman Brain Inst at Mount Sinai Sch of Med, NY Alessandra S. Eustaquio, Univ of Illinois at Chicago Dean Falb, Synlogic Therapeutics, MA Anindita Ganguly, Acorda Therapeutics, NY Chungang Gu, AstraZeneca, MA Charles M. Henley III, Independent Contractor & California Lutheran Univ Rachel A. Hunt, XOMA Corporation, CA William Joiner, Univ of California, San Diego

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Kevin S. Jones, Howard Univ, DC LaCreis R. Kidd, Univ of Louisville, KY Norikazu Kiguchi, Wake Forest Univ Sch of Med, NC Sandhya Kortagere, Drexel Univ - Col of Med, PA Nicole C. Kwiek, Ohio State Univ - Col of Pharmacy Jed N. Lampe, Univ of Kansas Med Center Peisong Ma, PhD, Univ of Pennsylvania Aanchal Mehrotra, Univ of Washington, WA Narasimha M. Midde, Univ of Tennessee HSC Michael Morgan, Washington State Univ Vancouver Rishi Pal, King George's Med Univ, India Bindu D. Paul, Johns Hopkins Univ Sch of Med, MD Alexey Pronin, Univ of Miami - Miller Sch of Med, FL Rana Rais, Johns Hopkins Drug Discovery, MD Luc R. Rougee, Eli Lilly & Company, IN Darizy F. Silva, Federal Univ of Bahia UFBA, GA Angela Slitt, Univ of Rhode Island Ramon Sotomayor Zarate, Univ de Valparaiso, Chile Brad L. Urquhart, Univ of Western Ontario, Canada Li Wang, Yale Univ Sch of Med, CT Long Wang, MD, California State Univ, Long Beach Shudong Wang, Univ of South Australia Yu Wang, The Univ of Hong Kong, China

Peter D. Ward, Janssen R&D, CA Lori A. Wetmore, William Jewell Col, MO Monte S. Willis, Univ of North Carolina Weibin Zha, Univ of Washington Miao Zhang, Chapman Univ, CA Rumin Zhang, Merck Res Labs, NJ Xin Zhou, Eli Lilly & Company, CA

POSTDOCTORAL MEMBERS Francie Barron, Nanomedical Diagnostics, CA Bandana Chakrvarti, Univ of Iowa Patrick L. Garcia, Univ of Alabama, Birmingham Audrey M. Hager, Univ of Texas HSC, San Antonio Wei Lei, Univ of Arizona, Tucson Hailiang Liu, Northeast Ohio Med Univ Saidu I. Ngulde, Univ of Maiduguri, Nigeria Newman Osafo, Kwame Nkrumah Univ of Science & Technology (KNUST), Ghana Amit Sharma, Med Col of Wisconsin Jennifer C. Shing, Mayo Clinic, MN Meijuan Tu, CA Inigo Valiente-Alandi, Cincinnati Children's Hospital Med Center, OH Philip A. Vieira, Univ of California Jaclyn Wisinski, Univ of Wisconsin, Madison Yan Zhao, Univ of California, San Francisco Zhichao Zhou, Karolinska Inst, Sweden

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AFFILIATE MEMEMBERS Abeer F. Alharbi, Saud bin Abdulaziz Univ for Hlth Sci, Saudi Arabia Stephen J. Black, Pacific Univ, OR

GRADUATE STUDENT MEMBERS Pramisha Adhikari, The Scripps Res Inst, FL Evelyn Ajelabi, Creighton Univ, TX Qasim Alhadidi, Univ of Toledo, OH Soumaya N. Allouch, Qatar Univ Zaid H. Almaayah, Univ of Alberta, Canada Doungkamol Alongkronrusmee, Purdue Univ, IN Hadir E. AlQot, Univ of Western Ontario, Canada Rachel Altshuler, Univ of Michigan Jennifer Amirhamzeh, Idaho State Univ Remya Ammassam Veettil, Texas Woman's Univ Swetha Arikatla, CA Kiran Aslam, Purdue Univ, IN Alicia J. Avelar, Univ of Texas HSC, San Antonio Carlo Barnaba, Washington State Univ Lili T. Belcastro, Univ of the Sciences in Philadelphia, PA Ricardo Belmares, Univ of North Texas HSC Elie Besserer-Offroy, Univ of Sherbrooke, Canada Ashenafi H. Betrie, Univ of Melbourne, Australia Janet K. Bobango, Idaho State Univ Mikael Boberg, Univ of Washington Amanda Bolles, Univ of Michigan Chandrashekhar D. Borkar, RTM Nagpur Univ, India Kelli H. Boxberger, Univ of Kansas Med Center Robert B. Cameron, Med Univ of South Carolina Brian D. Chapron, Univ of Washington Takondwa N. Chidumayo, Univ of Zambia

Amy M. Chinn, Univ of California, San Diego Jonathan P. Choiniere, Univ of Connecticut Marilyn Cisneros, Univ of New Mexico Kristan H. Cleveland, Western Univ of Health Sciences, CA Makini K. Cobourne-Duval, Florida A&M Univ Brilee Coleman, Emory Univ, GA Raian E. Contreras-Cardone, Hospital Germans Trias i Pujol, Spain Wenqi Cui, Univ of Kansas Marybeth E. Curtis, Tennessee State Univ Shuhang Dai, SUNY, Buffalo, NY Charlotte M. Detremmerie, Univ of Hong Kong Evan R. DeVallance, West Virginia Univ Pedro Espinosa, Univ de Valparaiso, Chile Letimicia S. Fears, Tennessee State Univ Leandra K. Figueroa-Hall, Oklahoma State Univ Alyssa C. Fournett, Louisiana State Univ HSC Mary A. Gannon, Univ of Alabama, Birmingham Kibrom G. Gebremedhin, Michigan State Univ Stacy G. Gibson, Univ of Calgary, Canada Michelle M. Giddens, Emory Univ, GA Grant Glatfelter, SUNY, Buffalo, NY Angela M. Gocher, SUNY, Buffalo, NY Patrick K. Gomez Menzies, Univ of California, San Diego Kirill Gorshkov, Johns Hopkins Univ Sch of Med, CA Shuchi Guo, Temple Univ - Lewis Katz Sch of Med, PA Sushmitha Gururaj, –SUNY, Buffalo Derick A. Haas, Drexel Univ, PA Alaa H. Habib, Nottingham Univ, UK Danielle N. Hagstrom, Univ of California, San Diego Xiao Han, Tufts Univ, MA Dhanush Haspula, FL Masoud Hassanpour Golakani, St Vincent - AUS Ctr for Applied Med Res, Australia Briana J. Hempel, American Univ, MD

Rachel D. Hendrix, Univ of Arkansas for Med Sci Nicole R. Hensch, Western Univ of Health Sciences, CA Christopher R. Himes, Loyola Univ Chicago, IL Jo-Hao Ho, The Scripps Res Inst, FL Pui Yan Ho, Univ of California, Davis Parham Jabbarzadeh Kaboli, Univ Putra Malaysia, Malaysia Ashish Jain, Univ de Montreal Pavillon Paul-G.-Desmarais, Canada Swati Jaiswal, CSIR-Central Drug Res Inst, India Joseph L. Jilek, Univ of California, Davis Jing Jing, Univ of Washington Joshua Jones, Univ of Illinois - Chicago Ram Kandasamy, Washington State Univ Rebecca Kent, Univ of Illinois - Chicago Mudasir A. Khanday, Jawaharlal Nehru Univ, India Jeong-Hyeon Kim, Hanyang Univ, South Korea Kyeong-A Kim, Hanynag Univ, South Korea Ayush Kishore, GA Na-Ra Lee, Univ of Kentucky Emma Leishman, Indiana Univ Cheri Z. Liu, Brown Univ, RI Christina M. Maher, Drexel Univ - Col of Med, PA Vanessa Marensi, Univ of Alberta, Canada Ashley J. McFalls, Pennsylvania State Col of Med Molly M. McGinnis, Wake Forest Univ Health Sciences, NC Nadia Milad, Univ of British Columbia, BC Catherine F. Moore, Boston Univ, MA Sean P. Moran, Vanderbilt Univ, TN Damian M. Mulenga, Univ of Zambia Soumyabrata Munshi, Rosalind Franklin Univ, IL Dabi Noh, Hanyang Univ, South Korea Blessing O. Ogunlade, Howard Univ, DC Folashade A. Ogunrinade, Univ of Huddersfield, UK Kendra H. Oliver, Vanderbilt Univ, TN Alfredo Oliveros, Mayo Clinic, MN

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Morgan C. Pait, Univ of North Carolina, Pembroke Stephanie Piekos, Univ of Connecticut David J. Polhemus, Louisiana State Univ HSC, New Orleans Evan P. Pratt, Purdue Univ, IN Hector D. Quinones, Rutgers Univ, NJ Sofiane Rahali, Univ of Montreal, Canada Kanumuri S. Raju, CSIR-Central Drug Res Inst, India Jeremiah Ramos, Univ of Texas, El Paso Krishnaraj S. Rathod, Queen Mary Univ London - William Harvey Res Inst, UK Daisy D. Reynaga, Univ of California, Irvine Zachary R. Robateau, Joan C. Edwards Sch of Med, WV Diara Santiago Gonzalez, SUNY, Buffalo, NY Allison Schafer, Cincinnati Children's Hospital Med Center, OH Robert W. Seaman Jr, SUNY Buffalo Sch of Med & Biomedical Sciences, NY Mariel P. Seiglie, Boston Univ - Sch of Med, MA Kelly Jean Sherman, Louisiana State Univ, New Orleans Young Jun Shin, Hanyang Univ, South Korea Mikaela Sifuentes, Univ of Texas HSC, San Antonio Newton Simfukwe, Univ of Zambia Daniel N. Sorensen, Washington State Univ - Col of Pharmacy Sarah Y. Sottile, Southern Illinois Univ Stephani L. Stancil, Children's Mercy Hospital, MO Faith Stevison, Univ of Washington Kim E. Sun, Hanyang Univ, South Korea Danielle Tomasello, SUNY, Buffalo, NY Christopher Tong, Pacific Univ - Sch of Pharmacy, OR Christopher W. Tschumi, Univ of Texas HSC, San Antonio

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Alastair J. Tulloch, Brown Univ, RI Ravikanth Velagapudi, Univ of Huddersfield, UK Rashmi Venkatesh, Georgetown Univ, DC Brittany M. Winner, Michigan State Univ Daniel J. Wolak, Univ of Wisconsin, Madison Sijia Wu, Univ of Massachusetts - Med Sch Kangmin Yang, Univ of Hong Kong Parry Yap, Univ of New England - Sch of Pharmacy, ME Fan Ying, Univ of Hong Kong Daniel Ysselstein, Purdue Univ, IN

UNDERGRADUATE STUDENT MEMBERS Austin T. Akers, Joan C. Edwards Sch of Med, WV Annalyn K. Brown, Univ of the Virgin Islands Dina M. Buitrago, Hunter Col, City Univ of New York Jonas J. Calsbeek, Washington State Univ Nicole Colon Carrion, Univ of Puerto Rico, Cayey Rafael L. Cruz de Jesus, Federal Univ of Bahia, Brazil Jamile M. de Albuquerque, Federal Univ of Bahia, Brazil Michael C. de Leon, Univ of Arizona Pascale L. Duvalsaint, City Univ of New York - Med Sch Lyndsie H. Elliott, Univ of North Carolina, Pembroke, NC Omar L. Eltair, MCPHS Univ, NJ Theresa A. Garcia, Univ of New Mexico James T. Hall, MCPHS Univ, MA Ashley K. Her, California State UnivFresno Edward J. Hilton, Duquesne Univ, PA Jennifer G. Hindieh, Long Island Univ C.W. Post, NY

Yanan Kang, Univ of California, Los Angeles Rody C. Kingston, Morehouse Col, GA Patrick Z. Liu, Northwestern Univ, OH Mary C. Logan, Mercer Univ - Sch of Med, GA Josephine C. McGowan, Barnard Col of Columbia Univ, NY Janette Mendoza, Univ of New Mexico Megan C. Myers, William Jewell Col, MO Alex Nanchanatt, Monmouth Univ, NJ Brittany K. Nixon, North Carolina Central Univ Nicholas A. Nolan, Joan C. Edwards Sch of Med, WV Ijeoma M. Nwabudike, Univ of Chicago, IL Amalia S. Parra, Univ of New Mexico Kimberly A. Rivera-Caraballo, Univ of Puerto Rico Nicole M. Robles, Univ of Puerto Rico Andrej J. Roczkowsky, Univ of Alberta, Canada Ivan G. Santiago, Univ of Puerto Rico Rohit Talluri, Bellevue Col, WA Katherine C. Tokarz, MCPHS Univ, CT Hannah G. Torres, NM Meilinn Tram, Univ of New Mexico Valencia L. Ueanimatang, NM Megan Warwick, Coe Col, IA Mark B. Wiley, Univ of Mount Union, OH

In Sympathy Leonard Cook Alfred G. Gilman Marion Sewer Odd S. Steinsland

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A Tribute to Dr. Alfred G. Gilman (1941-2015) Submitted by T. Kendall Harden, PhD

Biomedical science, and pharmacology in particular, lost an iconic leader with the passing of Alfred Goodman Gilman on December 23, 2015.

Al’s influence spanned from the field-pervading assay for cyclic AMP that bore his name, to his groundbreaking Nobel Prize-recognized research on basic mechanisms of cell signaling, to two decades as editor of the premier textbook of pharmacology, to the development and direction of one of the world’s best departments of pharmacology, to his deanship of a major medical school, and to his leadership of a major new effort supporting cancer research. He also provided enormously wide-ranging counsel for many university, government, and industrial agencies and endeavors over many decades.

Alfred Goodman Gilman was born on July 1, 1941 in New Haven, Connecticut. He often pointed out his good fortune of birth and the positive influence his parents had on his career. An oft-quoted joke about Al was that he was “named for a textbook (of pharmacology)”–and in effect he was since his second

name was in honor of Louis Goodman who coauthored the first editions of “The Pharmacological Basis of Therapeutics” with Al’s father, Alfred Z. Gilman. Al clearly was immersed in biomedical research from birth. His father was a professor in the Department of Pharmacology at Yale University and in 1956 became the first chair of pharmacology at Albert Einstein College of Medicine. Al colorfully described his early years in a number of publications including “Silver Spoons and Other Recollections” in the Annual Review of Pharmacology and Toxicology 52:1-19, 2011. One of those silver spoons much later served him an enormous amount of work after he assumed (for 25 years) the editorship of the now gargantuan textbook of pharmacology that his father and Lou Goodman had begun in 1941.

Dr. Gilman graduated with a major in biochemistry from Yale University in 1962 and was convinced by a future Nobel Awardee, Earl Sutherland, to join the new MD/PhD training program at Case Western Reserve in Cleveland, Ohio. Although Sutherland left for a position at Vanderbilt University, Al trained with Sutherland’s former postdoctoral fellow and co-discoverer of cyclic AMP, Ted Rall, carrying out early work on this “second messenger” in thyroid gland function. He moved to the NIH in 1969 as a postdoctoral fellow with Marshall Nirenberg, recipient of the 1968 Nobel Prize in Physiology or Medicine, to study neuronal development.

During this time Al developed the protein binding assay for cyclic AMP, which became known as the “Gilman assay,” and that afforded investigators worldwide a means to quantify cyclic AMP in small samples. This assay enormously expanded the number of laboratories engaged in

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cell signaling research, and the paper has been cited over 5000 times.

Dr. Gilman’s first academic appointment was as an assistant professor in the Department of Pharmacology at the University of Virginia (UVA) in 1971. Pharmacology at UVA, led at the time by Joseph Larner, was a hot-bed of early research on signal transduction, and much of Gilman’s groundbreaking work leading to the Nobel Prize was accomplished there. The overriding question was how do hormones like adrenaline pass signals across membranes to regulate activity inside cells?

Martin Rodbell (who in 1994 would share the Nobel Prize in Physiology or Medicine with Gilman) at NIH had shown the requirement of GTP for hormonestimulated production of cyclic AMP in well-washed plasma membrane preparations. Research of Rodbell and others including Gilman also strongly suggested that the adenylyl cyclase and the hormone receptor likely resided on separable proteins. Gilman’s work discovered that a third protein (a GTP-binding protein) existed in the middle, and he described what that protein really was. Much of the research identifying the adenylyl cyclase-activating G protein was driven

by Elliot Ross, a postdoctoral fellow in the Gilman lab.

In a series of simple but elegant experiments, Ross illustrated that the conversion of ATP to cyclic AMP and the capacity to bind GTP occurred independently on two separable proteins.

John Northup

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and Paul Sternweis, also postdocs in the Gilman lab, were the first to purify this GTPbinding protein Gs and then purified its co-conspirator in the regulation of adenylyl cyclase, Gi, which mediated receptorpromoted inhibition of the enzyme.

Dr. Gilman became chair of the Department of Pharmacology in 1981 at the University of Texas Southwestern (UTSW) Medical School in Dallas, TX. Although many of the key research advances that led to the Nobel Award had been accomplished by then, much of what is known about mechanism in the cyclic AMP generating pathway, and for certain, the breadth and depth of our current knowledge of heterotrimeric G protein signaling in general was to be learned in the decades that followed in Dallas.

The competition was no doubt fierce, and many outstanding scientists worldwide contributed to our collective knowledge of heterotrimeric G protein signaling. However, the Gilman lab continued to make front-of-the-field advances until after the turn of the millennium. The work had a remarkable signature.

Gilman papers almost always appeared with an enviable depth and breadth of information – and a quality that often seemed difficult to produce in one’s own work. One of us remembers devoting a week to read and try to understand the four papers published back-toback-to-back-to back that unveiled the reality of the Gi heterotrimer, its biochemical properties, its activation cycle, and a model of its mechanism of inhibition of adenylyl cyclase – a tour de force of depth rarely enjoyed in today’s rapidly changing/progressing scientific pursuits. The Gilman lab made many seminal advances in the 1980s and 1990s. In fruitful collaborations with the laboratory of Melvin Simon at Cal Tech,

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they introduced molecular cloning into the production of G protein subunits and adenylyl cyclase and produced a broad range of these signaling proteins in sufficient quantities to understand the complexities of their regulation in exquisite biochemical detail.

In a long-term collaboration with the structural biologist Stephen Sprang, they were the co-firsts (with the Sigler lab at Yale) to obtain structures of the heterotrimeric G proteins in their various activation states and provided the first structures of a G protein bound to its effector (adenylyl cyclase) and to a regulator of G protein signaling (RGS) protein. Thus, the processes of activation and deactivation of G proteins, and therefore of their downstream effectors, were described in intricate detail at the atomic level.

Al Gilman’s potent intellect was complemented by a sharp wit, a wonderful sense of humor, and an unsurpassable integrity. He selflessly mentored hundreds from all walks of biomedical science. His research goals, ambition, and technologies were at the front of the field for three decades, and his scientific influence continues to expand through the scores of scientists who trained in his laboratory over the years. Most who passed through his lab will argue that there could not have been a more stimulating and productive research environment than the one he directed. The weekly research meetings, Friday at 8:15 AM, of the Gilman lab were legendary – they often lasted all morning, had a laser focus on what is the important question and how can it truly be answered, and frankly, were not for the faint of heart. Gilman-lead excellence in training also was routinely proffered in the bimonthly “B and B”s (definition of acronym not to be revealed) where an individual faculty member from the UTSW Department of Pharmacology presented a “chalk talk” (no slides please!) on her/ his current and future research directions.

These provided wonderful research The Gilman Family

training opportunity for students and postdocs, as well as faculty both young and old. Then there was the Christmas party. Al negotiated with the dean on his recruitment to be allowed to have a departmental party at the Faculty Club. Live music, a wonderful buffet, an open bar, and of course the “Ignobel Award Ceremony” were on the agenda. The Ignobel was awarded to the departmental honorees who committed the most ignoble act(s) of the year. And why the party? It was the annual Pharmacology Family Christmas Party, and it was a fun time for Al’s science family.

The Department of Pharmacology at UT Southwestern became one of the premier departments worldwide during Gilman’s 25-year tenure as chair.

Remarkably, he became dean of UT Southwestern Medical School in 2004, and served as executive vice president for academic affairs and provost in 2006 until his academic retirement in 2009. He then became the initial Chief Scientific Officer of the Cancer Prevention and Research Institute of Texas serving until 2012.

In addition to the 1994 Nobel Prize in Physiology or Medicine, Al Gilman received many honors and awards. He was a member of the National Academy of Science (1985) and received the Albert Lasker Basic Medical Research Award in 1989. He also was recipient of ASPET’s John Jacob Abel Award (1975), the Goodman and Gilman Award (1990), and the Torald Sollman Award (1997). He was a founding scientist of Regeneron Pharmaceuticals, and for over two decades was a member of the Board of Directors of Regeneron and of Eli Lilly and Company.

Al Gilman is survived by his wife, Kathryn, two daughters, a son, and five grandchildren. As a proud scientific father, he also is survived by all his scientific family and progeny and their progenies.

Dr. Gilman was a member of ASPET since 1973.

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A Tribute to Dr. Leonard Cook (1924-2016) Submitted by Judith Siuciak, PhD Leonard Cook, one of the world’s leading psychopharmacologists, passed away on January 30th, 2016 at the age of 91. Dr. Cook was born in Newark, NJ in 1924. He earned a degree in pharmacology from Yale Medical School in 1951 and Dr. Leonard Cook subsequently joined Smith Kline & French Laboratories where he played a dominant role in the discovery of “Compazine” and “Stelazine,” the first drugs for schizophrenia, as well as in the early development of their Department of Pharmacology.

Dr. Cook joined Hoffmann-LaRoche in 1969 where he was appointed director of pharmacology and led research in the identification of drugs for treating anxiety. In 1983, he joined DuPont de Nemours as director of their CNS research and expanded their

CNS research program to focus on Alzheimer’s disease therapy.

Dr. Cook held academic posts as adjunct professor of pharmacology at Temple Medical School and in psychiatry at the University of Pennsylvania. He was also visiting professor of pharmacology at Beijing and Shanghai Medical Schools. Dr. Cook served for many years as a consultant to the National Institute of Drug Abuse, particularly in their pursuit for pharmacological agents useful in treating drug abuse. He also served as a special consultant to the Pentagon.

Dr. Cook was the recipient of the ASPET P.B. Dews Lifetime Achievement Award in Behavioral Pharmacology in 2006. His lecture was titled “Reflections on my career in psychopharmacology” and was published in The Pharmacologist.

Dr. Cook was a member of ASPET since 1955.

A Tribute to Dr. Marion Sewer (1972-2016) Submitted by Namandjé N. Bumpus, PhD, Edward T. Morgan, PhD, and Michael R. Waterman, PhD Dr. Marion Sewer, a national and international leader in the field of steroid hormone biosynthesis, passed away on January 28th, 2016 at the age of 43. Dr. Sewer grew up in Saint John, U.S. Virgin Islands. She graduated from Spelman College Dr. Marion Sewer with a BS in biochemistry in 1993 and then went on to earn a PhD in pharmacology at Emory University under the mentorship of Dr. Edward Morgan.

Dr. Sewer trained as a postdoctoral fellow at Vanderbilt University in the laboratory of Dr. Michael Waterman.

Dr. Sewer began her career as a faculty member at Georgia Institute of Technology and moved to the University of California, San Diego in 2009 where she rose to the rank of full professor.

Dr. Sewer’s work was at the leading edge of her field. Notably, she made the seminal finding that nuclear receptors are targets for sphingolipids. Her lab identified distinct sphingolipid and phospholipid

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species as endogenous ligands for the nuclear receptor steroidogenic factor 1, thereby revealing a novel role for nuclear phospholipids and sphingolipids in the control of gene transcription.

Dr. Sewer had a tremendous commitment to service within the scientific community. Among her many important roles, she served on several NIH and NSF study sections, including membership on the Molecular and Cellular Endocrinology IRG. In addition, Dr. Sewer chaired symposia at prestigious national and international meetings, served on the editorial boards of Endocrinology and Steroids and was secretary/treasurer of the Drug Metabolism Division of ASPET. Improving diversity in science was a passion of Dr. Sewer’s and she worked tirelessly toward this mission as a member of the Mentoring Committee of Women in Endocrinology and a member of the Minority Affairs Committees of both the Endocrine Society and ASBMB. Dr. Sewer was a member of ASPET since 2010.

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Recruit a New ASPET Member Contribute to the growth and sustainability of ASPET by telling your students, friends, and colleagues about ASPET membership!

A growing ASPET means greater recognition for the field of pharmacology, more resources and support for our members, and a louder voice with policy makers. Get started recruiting today!

Benefits include:  Reduced page charges to publish in ASPET journals  Free full-text access to ASPET journals  Reduced registration fees for ASPET meetings  Awards opportunities  Networking opportunities

For a full listing of all our benefits, visit www.aspet.org or contact the membership department at membership@aspet.org.

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Members in the News Achievements, Awards, Promotions, and Scientific Breakthroughs Lynn Wecker, PhD

Dr. Lynn Wecker University of South Florida, Morsani College of Medicine

Dr. Lakshmi Devi Mount Sinai School of Medicine

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Dr. Lynn Wecker, distinguished university professor of psychiatry and behavioral neurosciences in the USF Morsani College of Medicine, has just been elected chair-elect of the Section on Pharmaceutical Sciences of the AAAS. Her term of office for chair-elect is from February 16, 2016 to February 20, 2017, at which time she will become chair and serve from February 21, 2017 to February 19, 2018. Dr. Wecker was chair of the Department of Pharmacology and Molecular Therapeutics at USF from 1991-2006, and associate dean for research from 2006-2007. She has served as treasurer, program chair, and president of ASPET, and treasurer of FASEB. She has over 100 peer-reviewed publications and book chapters and is the editor of Brody's Human Pharmacology. Her research has focused on the regulation of nicotinic receptors in the brain and their involvement in addiction, depression, schizophrenia, and most recently, ataxia.

Dr. Wecker has been a member of ASPET since 1980. She is a member of the Division for

Neuropharmacology, Division for Behavioral Pharmacology, Division for Pharmacology Education, and Division for Molecular Pharmacology.

Lakshmi Devi, PhD Lakshmi A. Devi, PhD, has been selected for the 2016 INRC Founders' Lectureship. The lecture will be delivered at the annual meeting of the International Narcotics Research Conference in Bath, UK (July 10-14, 2016).

The INRC Founders' Lectureship is to honor individuals who have made a sustained and substantial contribution to the science upon which the conference is based.

This award is intended to honor the scientific integrity and vision of the INRC’s founders by choosing an individual who represents those ideals and has helped create the intellectual foundation of our current thinking in the field.

Dr. Devi has been a member of ASPET since 1999. She is a member of the Division for Neuropharmacology and the Division for Molecular Pharmacology.

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Pancras Wong, PhD Dr. Pancras Wong along with five of his colleagues at Bristol-Myers Squibb received the prestigious American Chemical Society (ACS) 2015 Heroes of Chemistry Award for the discovery of Eliquis (apixiban).

The award honors outstanding individuals who have excelled in innovation at prominent international corporations, and have developed numerous commercial products that demonstrate strong financial performance. The initial press release is featured at: http://www. acs.org/content/acs/en/pressroom/ newsreleases/2015/june/heroesof-chemistry-developed-productsthat-improve-health-homes-andautomobiles.html.

Dr. Wong is a senior research fellow in cardiovascular drug

discovery at Bristol-Myers Squibb and conducts research in thrombosis and heart failure. He received his BA in chemistry from the University of Oregon, Eugene, and PhD in pharmacology from the University of Minnesota, Twin Cities. This is the second time Dr. Wong received an award from the ACS. In 1997, Pancras was a corecipient of the ACS Team Innovation Award for the discovery of Cozaar (losartan). He also received the Robert R. Ruffolo Career Achievement Award in Pharmacology from ASPET in 2013.

Dr. Wong has been a member of ASPET since 1990. He is a member of the Division for Cardiovascular Pharmacology.

Dr. Pancras Wong Bristol-Myers Squibb Co.

The Bristol-Myer Squibb American Chemical Society’s 2015 Heroes of Chemistry are (left to right) Diane Grob Schmidt (ACS President), Michael Orwat, Donald Pinto, Pancras Wong (center), Robert Knabb, Mimi Quan and Patrick Lam. Photo: Peter Cutts, ACS

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Kelly Karpa, PhD

Dr. Kelly Karpa Penn State University College of Medicine

Kelly Karpa, PhD, associate professor of pharmacology at Penn State University College of Medicine, was recently promoted to the director of the Office of Interprofessional Collaborative Education and Teamwork. In addition, Dr. Karpa received a scholarship in education award from Penn State for the creation of videos that are used as teaching tools to compare and contrast teambased care in primary care. This work was subsequently published as MedEd Portal (Karpa et al., 2015; www. mededportal.org/publication/10116).

Dr. Karpa has been a member of ASPET since 2010. She is a member of the Division for Pharmacology Education.

V. Craig Jordan, PhD

Dr. V. Craig Jordan University of Texas MD Anderson Cancer Center

Dr. Rebecca Anderson

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V. Craig Jordan, PhD, a professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, has been named a recipient of the Sir James Black Award from the British Pharmacological Society (BPS). Dr. Jordan was presented the award in December at Pharmacology 2015, the annual meeting of the BPS. The award recognizes scientists for discoveries of important principles for drug treatment. Dr. Jordan is credited with reinventing a failed contraceptive (known as ICI 46,474) as a breast cancer treatment. The drug, in existence since the 1960s, was originally created to block estrogen in the hopes of preventing pregnancy.

Jordan developed the strategy of long-term adjuvant tamoxifen therapy, as well as describing and deciphering the properties of a new group of medicines called selective estrogen receptor modulators (SERMs). He was

the first to discover the preventive abilities of both tamoxifen and the drug raloxifene. The medicines were approved by the Food and Drug Administration for reducing breast cancer incidence in high-risk women.

At MD Anderson, Jordan focuses on the new biology of estrogeninduced cell death with the goal of developing translational approaches for treating and preventing cancer.

His long and distinguished career has included leadership positions at some of the world’s most prestigious biomedical institutions. Prior to joining MD Anderson, he served as scientific director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington D.C., and the Vincent T. Lombardi Chair of Translational Cancer Research.

Dr. Jordan has been a member of ASPET since 1981. He is a member of the Division for Molecular Pharmacology, Division for Drug Discovery and Development, Division for Drug Metabolism, Division for Pharmacology Education, Division for Translational and Clinical Pharmacology, and Division for Toxicology.

Rebecca J. Anderson, PhD Rebecca J. Anderson, PhD’s book, Nevirapine and the Quest to End Pediatric AIDS, which was published

by McFarland Publishing was named as a finalist for a Lambda Literary Award, and also as a finalist for a Next Generation Indie Book Award. Both finalist awards were in the nonfiction category for 2015.

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Dr. Anderson holds a BA in chemistry from Coe College and earned her doctorate in pharmacology from Georgetown University. She has 25 years of experience in pharmaceutical research and development and now works as a technical writer. Her articles have been featured in The

Pharmacologist since 2013 and before that, she regularly wrote articles for Molecular Interventions.

Dr. Anderson has been a member of ASPET since 1980. She is a member of the Division for Neuropharmacology.

ASPET History answer key Crossword puzzle on page 64

K I N I T A C D E M A M E T S H O S L O L A Y U L S M A Y E A G E N A N I N E N E X A W L T I B E M L A M B A L U E L O N S P E O B I T E N A D E E

D O N E E P E R P E T U A L L Y T E N T

E M S E N I C L D O G L S T R E S C A N J O H N J N D E H A H E A N E R A N R O C E E N H U S E B U N T E R A L P A C A C P H A R M L A S T E R P A N A T S K I T E L R E S E

D U C A T I N E A R E E R E M A P E T A C O B A S P A I R P O S T A I I R S R I E N D R E D E A A M T C E R E C I N O R I D L Y A C O L O S K R E P E N A I L O I S E R V E S

O R C R A B

T A K E M T O K R O I A B I D E G I L M A N

N E M O F I N B E

T O A D B U R N E O R O N N N U M E N A G L P L A M A Y S A G P A Y E R T O T H R E W D E I G H F I O A L R A N E C R E T H E C E R D O R B R I G S E L A I N S O L V E O N E E

D E W E Y O A T T E L E G R A M E S E

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Division News 2016 Division Elections The 2016 elections received an enthusiastic response from ASPET members for the following Divisions.

• Division for Cancer Pharmacology • Division for Drug Discovery and Development • Division for Drug Metabolism • Division for Molecular Pharmacology • Division for Neuropharmacology

• Division for Toxicology • Division for Translational and Clinical Pharmacology Please join us in welcoming all newly elected chairs and secretary-treasurers to their respective Division’s executive committee. The new officers will take office on July 1, 2016.

Division for Cancer Pharmacology Secretary/Treasurer-Elect

Chair-Elect

Jack C. Yalowich, PhD Professor and Chair, Division of Pharmacology, The Ohio State University College of Pharmacy

Mary-Ann Bjornsti, PhD Professor and Chair, Department of Pharmacology and Toxicology, University of Alabama at Birmingham; Newman H. Waters Chair of Clinical Pharmacology; Associate Director for Translational Research, UAB Comprehensive Cancer Center

Division for Drug Discovery and Development Chair-Elect

Secretary/Treasurer-Elect Timothy A. Esbenshade, PhD Project Director/Sr. Principal Research Scientist, Global Research and Development, AbbVie

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Tom J. Parry, PhD Senior Director, Pharmacology and Safety, Research and Development, Acorda Therapeutics, Inc.

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Division for Drug Metabolism Chair-Elect

Secretary/Treasurer-Elect Nina Isoherranen, PhD Associate Professor, Pharmaceutics, School of Pharmacy, University of Washington

NamandjĂŠ N. Bumpus, PhD Associate Professor, Medicine and Pharmacology, Johns Hopkins University School of Medicine; Associate Dean for Institutional and Student Equity

Division for Molecular Pharmacology Chair-Elect

Secretary/Treasurer-Elect Henrik G. Dohlman, PhD Professor, Department of Biochemistry and Biophysics, University of North Carolina

Lisa Hazelwood, PhD Senior Scientist III, Liver Fibrosis, AbbVie

Division for Neuropharmacology Secretary/Treasurer-Elect

Chair-Elect John Traynor, PhD Professor of Pharmacology and Associate Chair for Research, Department of Pharmacology, University of Michigan Medical School

Styliani-Anna (Stella) E. Tsirka, PhD Professor, Department of Pharmacological Sciences, Stony Brook University

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Division for Toxicology Secretary/Treasurer-Elect

Chair-Elect

Qin M. Chen, PhD Professor, Department of Pharmacology, University of Arizona College of Medicine

Monica A. Valentovic, PhD Professor, Department of Pharmacology, Physiology, and Toxicology, Marshall University School of Medicine; Toxicology Research Cluster Coordinator

Division for Translational and Clinical Pharmacology Chair-Elect

Secretary/Treasurer-Elect Michael Holinstat, PhD Associate Professor, Pharmacology and Internal Medicine, University of Michigan Medical School

Felix Kim, PhD Assistant Professor, Department of Pharmacology and Physiology, Drexel University College of Medicine; Director of the Graduate Program in Pharmacology

Division for Drug Metabolism James R. Gillette Drug Metabolism Best Paper of 2015 Dr. Lilly East (previously Li Liu), researcher in the laboratory of Dr. Unadkat at the University of Washington, was recently announced as the 2015 recipient of the James R. Gillette Drug Metabolism Best Paper in the category of drug transport and pharmacokinetics. Gillette Paper Awards are presented each year by the ASPET Drug Metabolism Division for the top paper published in Drug Metabolism and Disposition in the area of drug

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metabolism or drug transport and pharmacokinetics.

The winner for the drug metabolism category will be announced in the next issue of The Pharmacologist.

The winning drug transport and pharmacokinetics paper is titled “Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study” with the complete author list including L Liu, AC Collier, JM Link, KB Domino, DA Mankoff, JF Eary, CF

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Spiekerman, P Hsiao, AK Deo, and JD Unadkat. This group of researchers developed positron emission tomography (PET) imaging approaches to investigate P-gp modulation at the human blood-brain barrier in healthy volunteers by the approved P-gp inhibitor quinidine, or by the P-gp inducer rifampin.

Findings from this study demonstrated that at clinically relevant plasma concentrations quinidine did not completely inhibit P-gp at the human bloodbrain barrier. However, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. The magnitude of P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Rifampin treatment reduced the brain extraction ratio of 11C-radioactivity by only 6%. Thus at the usual clinical dose given in Alzheimer’s disease, it cannot be used to induce P-gp at the human bloodbrain barrier to a clinically meaningful extent and is unlikely to cause inadvertent blood-brain barrierinductive drug interactions.

Dr. East was a graduate student in the lab of Dr. Jashvant Unadkat (2006-2012) and dedicated her thesis research in clinical PET-imaging studies of human blood-brain barrier P-gp, as well as in delineating the complex drug-drug interactions associated with HIV protease inhibitors. She currently works at Merck Inc. in quantitative pharmacology and pharmacometrics, within the Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism.

Dr. Jashvant “Jash” Unadkat is a professor in the Department of Pharmaceutics and joined the department in 1985. He studies the transport and

metabolism of HIV and other antiviral drugs. His research into drug transport could potentially lead to better ways to treat diseases such as hepatitis C, AIDS and Alzheimer’s. Dr. Unadkat is the 2012 recipient of the American Association of Pharmaceutical Scientists (AAPS) Research Achievement Award in Pharmacokinetics, Pharmacodynamics, and Drug Metabolism. He has published more than 170 peerreviewed research papers and is a fellow of American Association for the Advancement of Science and the Japanese Society for the Study of Xenobiotics. He is the founding cochair and a member of the AAPS Drug Transport and Uptake Focus Group. Dr. Unadkat created and leads the University of Washington Research Affiliates Program on Transporters, a cooperative effort between the UW School of Pharmacy and pharmaceutical companies. He also leads a NIDA-funded program project grant on drug disposition during pregnancy.

As first author, Dr. East will be presented with the award and give an invited lecture during the James Gillette Award and Platform Session at the EB2016 meeting. The platform session will be held Monday, April 4, 3-5:30PM in Room 15A of the San Diego Convention Center.

The Gillette Award honors the late NIH Pharmacologist James R. Gillette, Ph.D. (http://dmd. aspetjournals.org/cgi/reprint/31/12/1474.pdf), a scholar, major contributor to the field of drug metabolism and pharmacokinetics, philosopher, scientist, and supervisor of pharmacologists worldwide. During his scientific career, Gillette published more than 300 papers and chapters, and coedited seven books. He was considered a visionary and significant contributor to the field of drug metabolism and pharmacokinetics.

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Division for Toxicology Member Spotlight: Interview with Dr. Xiaochao Ma Submitted by Allison Harrill, PhD and Lauren Aleksunes, PharmD, PhD, DABT Dr. Xiaochao Ma of the Division for Toxicology is a tenured associate professor in the Center for Pharmacogenetics, which is in the School of Pharmacy at the University of Pittsburgh.

Dr. Ma received an award from the Division for Toxicology as a postdoctoral fellow in 2007. We Dr. Xiaochao Ma recently caught up with Dr. Ma to learn more about how ASPET membership played a role in his career development and what advice he might have for graduate student and postdoctoral members of ASPET today.

What sparked your interest in toxicology?

In 1998, I graduated from Henan Medical University [in Zhengzhou, China] where I learned that drugs can save a patient, but can also kill a patient because of side effects. I spent a lot of time thinking—How do drug toxicities happen? With this question in mind, I went to graduate school in the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, with toxicology as my major. I completed my PhD study in 2003, and then I joined Dr. Frank Gonzalez’ laboratory at the National Cancer Institute within the National Institutes of Health for postdoctoral training in the same year.

You received an award for your research from the Division for Toxicology in 2007. What path has your career taken since then?

It was a great honor for me to receive the Postdoctoral Scientist Award in Toxicology in 2007,

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sponsored by ASPET [Dr. Ma received the first place award]. This award strongly encouraged me and brought me a lot of confidence in research. In 2008, I started my own laboratory and continued to pursue the mechanisms of drug toxicity.

What is your current role and research area?

I am currently an associate professor in the School of Pharmacy at the University of Pittsburgh. My research focuses on mechanisms of drug toxicity associated with anti-tuberculosis (TB) and antiHIV therapy. This research project is related to my postdoctoral project for which I received the ASPET award. We use genetically engineered mouse models and metabolomic approaches in our research.

The goal of our research is to develop mechanismbased strategies to predict and then prevent the toxicity of anti-TB and anti-HIV drugs. We have found that human pregnenolone X receptor plays a key role in the hepatotoxicity associated with rifampicin and isoniazid cotherapy.

How has membership in ASPET benefited you and your career?

It has been a great help to my career. By coming to the ASPET-sponsored meetings, I learn a lot from other members. I have also found good friends and collaborators in the ASPET family.

What advice would you offer to aspiring toxicologists?

Believe in yourself and keep working; you will make the world safer.

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Chapter News New York Pharmacology Society 5th Annual Scientific Meeting – Receptors in Sensory Systems The New York Pharmacology Society (NYPS) Chapter of ASPET will hold its 5th Annual Scientific Meeting on Tuesday, May 17, 2016 at the University of Rochester Medical Center in Rochester, NY. The theme of the scientific meeting is receptors in sensory systems.

Dr. Kirill A. Martemyanov is the keynote speaker of the meeting and will address the dynamics of G protein pathways in the retina including molecular events at the first visual synapse and the role of regulators of G protein signaling in these events. Dr. Martemyanov is Dr. Kirill A. associate professor of neuroscience Martemyanov, Keynote Speaker at the Scripps Research Institute in Jupiter, Florida. He earned his PhD

from the Institute of Protein Research at the Russian Academy of Sciences. Dr. Martemyanov’s current laboratory research is directed at the discovery and characterization of novel G protein regulators, delineation of protein-protein interactions, and the logistics of signaling pathway organization. He has characterized some of the molecular mechanisms responsible for the selective connectivity of rod and cone photoreceptors with downstream bipolar cells.

Other thematic speakers will expand on the theme of receptors in sensory systems.

Information about the 5th annual NYPS meeting including program, registration, abstract submission, and map links for the University of Rochester Medical Center can be found at the chapter’s annual meeting website: www.aspet.org/NYPS.

Great Lakes Chapter 29th Annual Meeting, July 7th, 2016 The Great Lakes Chapter (GLC) of ASPET will hold its 29th Annual Scientific Meeting on Thursday, July 7, 2016 at the Feinberg School of Medicine, Northwestern University, Hughes Auditorium, Lurie Building, 303 E Superior Street, Chicago, IL. Check the GLC website www.aspet.org/GLC for more information about the 29th annual GLC meeting.

Abstracts are due by June 27th, 2016.

The meeting schedule includes: • Poster Session (8:30 – 10:30 AM) • Vendor Exhibit (8:30 AM – 12:00 PM) • Young Investigator Symposium (10:45 – 11:45 AM) • Lunch & Learn Career Workshop (12:00 – 1:30 PM)

•S ymposium: Basic and Translational Advances in Neurological Disease: From Signaling to Therapeutics (1:30 – 4:45 PM) Keynote: Dr. Alfred George (Northwestern University): “Therapeutic Targeting of Ion Channels in Genetic Epilepsy” Speakers: Dr. Eric Karran (AbbVie), Dr. Robert Vassar (Northwestern Univ.), Dr. Natalie Tronson (Univ. of Michigan), Dr. Anthony West (Rosalind Franklin Univ.)

• Poster Awards & Business Meeting (4:45 PM – 5:30 PM)

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Crossword ASPET History

By Rich Dodenhoff

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2

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18

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106 German pen 34 brand 40 108 Bitterly 111 (C2H5)2O 49 114 Bangladesh river 115 Drug adjective 118 Wagnerian Earth 60 goddess 67 119 North Carolina liberal arts 70 university 78 120 Endure 121 Peel 122 Either 86 123 Fly boy?

126 Resist 128 Navy jails 98 131 Japanese sash 133 Cannibalizes?

135 20th Ogham 114 alphabet letter 136 ____ Sanders119 Bush, president, 2006 138 Renter 131 140 Plaza girl 138 142 Frees from guilt 144 N,N-Diethyl3-methylbenzamide 145 Holds 146 Ne 147 Extra wide

Down 1 Josh 2 Article 3 Nominate 4 Receiver 5 Stops 6 Do, ray, ___ 7 Stamp out 8 ____ ____ Hirst, Chicago Tribune health care reporter 9 Per ____ 10 Int’l org.

11 Third letter 12 Retirement group 13 ____ ____ Resort, Kanchanaburi, Thailand 14 Rotate 15 Either 16 Exception 17 Rec room

8

19

9

10

11

24

35

26

54 63

45

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33 38

47

N

39

48 52

55

56

64

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58

65

68

77

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72 79

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84

92 99 106

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89 94

101

102

107

103

96

109

116

110 117

125

133

126 134

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140 145

19 Brothel 21 ___ Airport, Whitley Garden, CA 22 President, 1988 25 Large 27 Grouch 28 President, 1992 33 Recall?

34 President, 1913-15 36 Lad 39 Pant 41 Samarium 42 Adjectival ending 44 Acetylsalicylic acid 45 Navy coat 46 Desert respite 47 Drill piece 50 Incessantly 52 ____ ____ ____ be with you 54 Great blue or common European 64 German university city 66 Movie director Nicolas

112

113

129

130

118 122

127

128

135 141

97

111

121

124

132

144

95

105

120 123

91

104

108 115

85

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93 100

59

66

69

78

87

17 22

37 44

53

16

29

51

62

15

28

32

43 50

76

14

27

36

42

61

13 21

25

31

41

12

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23 30

Across 1 Family 4 Not Reps 8 Instructor 14 An amphibian 18 Pertaining to acid 20 Straight 21 Far overdone 23 Require 24 Leer 26 One who puts up 29 Single 30 Allots 31 Apetalous plants genus 32 A year 35 Him 36 View 37 Grab 38 Aromatic stock 40 European capital 43 Founder 48 Frolic 49 Hoops shot 51 Hopelessness 52 Fifth months 53 Opp. of NW 55 Roman forsaker of faith 57 Silver 58 Milan river 60 President, 1977 63 Hebrew girl’s name 65 President, 1957 67 Ripen 68 Paleozoic ____ 69 French king 70 Sodium 71 Mythic giant raptor 72 Tossed 78 Founding year 83 Connection 84 Honest ____ 85 That is, abbrev.

87 Man ____ 90 Tiny ____ 91 Every 92 Tipper 94 Nigerian city of the middle ages 96 Indian princess 98 Exist 100 Caesar’s 1050 101 Scarface actor 105 Chromium

7

136 142 146

69 See again 72 ___ Ameritrade 73 The ocean state, abbrev.

74 At the same time 76 Salamander 77 Former partner 78 Plural suffix 79 Portuguese patch 80 Endure 81 Verne’s captain 82 Former Western Union offering 86 Vestment 87 Sand castle?

88 Web address 89 Ghana capital 91 One 93 Protected 95 Turns baked goods?

97 Through traffic adj.

99 Israeli carrier 102 Has a share 103 Computing soc.

104 1984 Apple model

137

143 147

107 Calcium channel blocker 109 Rube 110 Fiver 112 Personnel 113 Phys. ____ 114 Drunk 115 Double fold 116 Vipers 117 President, 1960 122 Synthetic fiber 124 Pup or circus 125 Middle East waterway 127 Leisure 128 Madrid kiss 129 Donate 130 Koko’s weapon 132 Foundation 134 And not 137 Kansas City to N. Orleans dir.

139 Scottish village and river 141 >III and <V 143 Live Answers on page 57

The Pharmacologist • March 2016

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