The Pharmacologist September 2016

the

A Publication by The American Society for Pharmacology and Experimental Therapeutics

Pharmacologist Vol. 58 • Number 3 • September 2016

Inside: Message from President David R. Sibley EB2017 Meeting Highlights

Chlorpromazine and the Dawn of Antipsychotics

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

Contents 133 Message from the President 135 ASPET Annual Meeting at EB2017 142 Feature Story: Chlorpromazine and the Dawn of Antipsychotics

155 Meeting News 157 Science Policy News 160 Education News 165 Journals News 167 Membership News 172 Members in the News 173 Division News 175 Chapter News

THE PHARMACOLOGIST PRODUCTION TEAM Rich Dodenhoff Catherine L. Fry, PhD Dana Kauffman Judith A. Siuciak, PhD Suzie Thompson COUNCIL President David R. Sibley, PhD President-Elect John D. Schuetz, PhD Past President Kenneth E. Thummel, PhD Secretary/Treasurer Charles P. France, PhD Secretary/Treasurer-Elect John J. Tesmer, PhD Past Secretary/Treasurer Dennis C. Marshall, PhD Councilors Wayne L. Backes, PhD Carol L. Beck, PharmD, PhD Margaret E. Gnegy, PhD Chair, Board of Publications Trustees Mary E. Vore, PhD Chair, Program Committee Scott A. 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.

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Message from

The President Dear ASPET Members,

It is truly a great honor to serve as the 85th President of the American Society for Pharmacology and Experimental Therapeutics and a privilege to work with the dedicated ASPET staff and member volunteers that make this Society so special.

At the outset, I want to thank our past Presidents Drs. Ken Thummel and Annette Fleckenstein, our Executive Officer, Dr. Judy Siuciak, her staff, and all Council and committee members for their devotion and tireless work on behalf of ASPET over the last year. Through their collective efforts we have increased opportunities for our members to meet and exchange ideas formally and informally. An example of the latter was the successful inauguration of a members’ lounge that provided WiFi and, importantly, coffee at the last EB meeting.

To further support our trainees, the Young Scientists Committee was established to provide additional opportunities for leadership and service. In addition, Pharmacology Industry Internships for PhD Students (PIIPS), a new program originating from the “BIG IDEAS” initiative, was launched earlier this year. The goal of the PIIPS program is to provide students with experience in industrial settings, such as the pharmaceutical/ biotechnology or government regulatory sectors, during their graduate training.

A highlight of the year included the EB2016 meeting, which featured two of our recent “BIG IDEAS” initiatives: From Senior Mentor to Highly Skilled Career Coach: A Novel Approach to Breaking the Diversity Roadblock, led by Drs. Lynn Wecker and Susan Ingram; and Enhancing Undergraduate Engagement in ASPET at EB Meetings, an initiative led by Drs. Carol Beck and Catherine Davis. Council also recently approved another “BIG IDEAS” initiative led by Drs. Kan He, Tom Woolf and Paul Hollenberg – Surmounting the Insurmountable: Obstacles in Drug Discovery and Development – Real World Case Studies, which will debut at EB2017. Our EB2017 program committee, led by Dr. Scott Waldman, has been working hard to put together an exciting program that you won’t want to miss. Please plan on joining us in Chicago next spring!

Our recent legislative outreach has also had a positive impact. ASPET was given an opportunity to provide testimony to both Senate and House congressional budget appropriation committees to encourage their continued support of biomedical research.

This coming year promises to be an exciting and important one for ASPET. It has been over 15 years since ASPET has formulated a strategic plan to help guide the activities of the Society. Thus, at the EB2016 meeting, Council decided to engage in an intensive, year-long strategic planning effort that will help to shape our goals of where we want to be in 3-5 years and how to get there. ASPET has engaged the services of an external consultant to help survey the Society leadership as well as its membership. Thank you if you responded to our recent online membership survey! Our overall goal will be to provide the membership with an actionable strategic plan during the EB2017 meeting.

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134 Given the strong international representation at our recent annual meeting (over 35 countries), it is fitting that ASPET continues to demonstrate its commitment to increasing our international outreach. This includes leading a delegation to “Pharmacology 2016,” the annual meeting of the British Pharmacological Society (BPS) this December, as well as an invited research presentation by Dr. Ken Thummel at the 14th National Conference of the Chinese Pharmacological Society in Beijing, China, October 22-25, 2016, where possible future interactions between our societies will be discussed. Also, please read about Dr. Jeff Conn’s lecture at the 89th annual meeting of the Japanese Pharmacological Society (JPS) held March 9-11, 2016 in Yokohama, Japan in the June issue of the The Pharmacologist. Looking forward, as part of our ongoing lecturer exchange program with the JPS, Dr. Masamitsu Iino (Nihon University Medical School, Tokyo, Japan) will be presenting on “Imaging Ca2+ signals in the brain in health and disease” at EB2017. The following year, the BPS will join us in San Diego, CA as a guest society during the ASPET Annual Meeting at EB2018.

Through the oversight of Dr. Mary Vore, Chair of the Board of Publications Trustees, and Journals Director, Rich Dodenhoff, our journals continue to thrive and, importantly, they represent a major source of revenue for the Society. I would like to welcome our newest editors, Drs. Kenneth Tew of the Journal of Pharmacology and Experimental Therapeutics and Eric Barker of Pharmacological Reviews, who join existing editors Drs. Eddie Morgan of Drug Metabolism and Disposition, and Darrell Abernethy of Pharmacology Research and Perspectives. Also, an early welcome to Dr. Kay Meier who will replace Dr. Steve Traynelis as Editor of Molecular Pharmacology at the end of this year. Thank you, Steve, for your service! Also, later this month we will see an exciting transition of our journals to an updated web interface that will provide an enhanced look and feel to our journal content.

Under the leadership of our Executive Officer, Dr. Judy Siuciak, the ASPET office has recently recruited a number of new staff members, including: Dave Chalker, Webmaster; Dana Kauffman, Marketing Communications Coordinator; and Chris Keene, Content Licensing and Sales Manager. Welcome to all and thanks to the ASPET staff for their hard work.

I look forward to an exciting and productive year working with ASPET members, staff, and the Society leadership to chart our next strategic course and serve as the leading face of our great community of members. Please do not hesitate to contact me with any thoughts, concerns, or suggestions that you might have related to ASPET.

Warm regards,

David R. Sibley, Ph.D. President, ASPET

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Meeting Highlights Join us in Chicago next spring for the ASPET Annual Meeting at Experimental Biology 2017.

The meeting will be held at the McCormick Place Convention Center from April 22-26, 2017.

The ASPET program includes a wide variety of scientific symposia with invited and abstract-based speakers, award-winning lecturers, poster sessions, division-focused sessions, education and career development sessions, a student and postdoc

poster competition, and numerous mixers and networking events.

At the Annual Meeting you will learn about the latest developments in your field to push your research forward. Not only will your participation help you gain scientific information, but it will also bring you in contact with others from your scientific community who can advise you on any research issues and career concerns.

Submit your Abstract at www.aspet.org/Annual_Meeting_EB_ 2017/Abstracts/

Register Now at www.aspet.org/Annual_Meeting_EB_ 2017/Registration/

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5 Reasons to be in Chicago for EB2017 1) Hear the latest cutting-edge science in more than 50 ASPET symposia and lectures which will add a new dimension to the work in your lab or office.

2) P resent your own research and receive feedback from experts across the globe.

3) Interact face-to-face with current and potential collaborators and mentors in the ASPET member lounge or at ASPET division mixers.

4) P ut yourself in the path of pharmacology experts, NIH directors, journal editors, and potential employers.

5) G row the non-research skills that are critical for professional scientists at all levels with career-focused training workshops in the EB Career Center as well as specific pharmacology career development opportunities.

Exciting Meeting Events • Presentation of the ASPET Scientific Achievement Awards • Keynote lectures by award winners • International lecture exchange with the Japanese Pharmacological Society • Student-Postdoc Poster Competition • Student-Postdoc mixer

The ASPET 2017 Annual Meeting Website Visit the annual meeting website at www.aspet. org/EB2017 to access full information on the meeting program, abstracts, speakers, special events, and sponsorship opportunities. Be sure to bookmark the website and visit often as the content is being updated frequently.

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• Nightly division mixers • The return of the popular ASPET members lounge • The Shop ASPET store open in ASPET booth #601 • Closing reception

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2017 Lecture Highlights At the University of California, San Diego, Dr. Insel is the vice-chair of the Department of Pharmacology and a Distinguished Professor of Pharmacology and Medicine. Since 1989, he has been director of the UCSD Medical Scientist (MD/PhD) Training Program.

Dr. Insel will present the Paul A. Insel, MD Julius Axelrod Award in Pharmacology Lecture: Lessons from Endogenously Expressed GPCRs: Nature Knows Best!

Masamitsu Iino, MD, PhD

Important Dates

ASPET is pleased to welcome Dr. Iino as part of a lecturer exchange collaboration with the Japanese Pharmacological Society. Dr. Iino comes to us from the Division of Cellular and Molecular Pharmacology at the Nihon University Medical School in Tokyo, Japan. He will present a lecture titled Imaging Ca2+ Signals in the Brain in Health and Disease.

Dr. Choi was the inaugural recipient of the ASPET David Lehr Research Award in 2015. As the award term closes, he will present a lecture on his research titled Adenosine-Regulated Glutamate Signaling in Neuron-Glia Interaction and Alcoholism. At the Mayo Clinic, Dr. Choi is a Doo-Sup Choi, PhD professor of pharmacology in the College of Medicine and serves as the director of Mayo’s Samuel C. Johnson Genomics of Addiction Program.

Jack Bergman, PhD

Dr. Bergman is an associate professor of psychobiology in the Department of Psychiatry at Harvard Medical School and director of the Preclinical Pharmacology Laboratory at McLean Hospital/Harvard Medical School. He will deliver the Norman Weiner Lecture.

Thursday, November 17, 2016 Abstract Submission Deadline Thursday, February 23, 2017 Discounted Registration Deadline Friday, March 31, 2017 Discounted Housing Deadline Saturday, April 22, 2017 ASPET Business Meeting and Awards Presentation April 22-26, 2017 ASPET Annual Meeting at EB2017

*Please be advised that the abstract submission deadline is fixed and will not be extended. Abstracts not received by November 17, 2016 are considered late breaking.

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ASPET Best Presentation Awards Application Deadline: Monday, November 21, 2016 Best Presentation Awards are awarded for outstanding poster and oral presentations by postdoctoral fellows, graduate students, and undergraduates attending the ASPET Annual Meeting at EB2017.

ASPET members in good standing must submit an abstract to an ASPET topic category to be considered for this competition. The deadline for EB2017 abstract submission is November 17th, 2016.

Selected finalists may be asked to present their research at the Student/Postdoc Poster Competition on Sunday evening, April 23, 2017 or at a division oral session. or more information and to apply for a Best Presentation Award, F please visit: https://www.aspet.org/awards/best-presentation/.

ASPET Travel Awards to Experimental Biology Application Deadline: Thursday, December 1, 2016 Undergraduate students, graduate students, and postdoctoral fellows are invited to apply for a Travel Award to help defray the costs of registration, travel, and housing to attend the ASPET Annual Meeting at EB2017. Travel awards are only open to ASPET members and you must also submit an abstract to EB2017 in an ASPET topic category by the EB deadline of November 17, 2016.

For more information and to apply for a travel award, please visit: https://www.aspet.org/ ASPET_Travel_Awards/.

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Preliminary Program For additional program details, visit: www.aspet.org/eb2017.

LECTURES John J. Abel Award in Pharmacology Lecture Keynote to be announced in January

Science and Government: How to Make a Difference through Advocacy Chairs: Allyson Marshall and Naeem Patil

Julius Axelrod Award in Pharmacology Lecture Lessons from Endogenously Expressed GPCRs: Nature Knows Best!

Keynote: Paul A. Insel

Surmounting the Insurmountable: Obstacles in Drug Discovery and Development – Real World Case Studies Chairs: Kan He and Paul F. Hollenberg

David Lehr Research Award Lecture Adenosine-Regulated Glutamate Signaling in Neuron-Glia Interaction and Alcoholism Keynote: Doo-Sup Choi

DIVISION FOR BEHAVIORAL PHARMACOLOGY Mushrooming Potential of Psychedelics as Therapeutics Chairs: William Fantegrossi and Roland Griffiths

Joint Lecture with the Japanese Pharmacological Society

Behavioral Models of Age-related Cognitive Decline Chairs: Kevin Murnane and Jennifer Bizon

Imaging Ca2+ Signals in the Brain in Health and Disease Keynote: Masamitsu Iino Reynold Spector Award in Clinical Pharmacology Lecture Keynote to be announced in January Otto Krayer Award in Pharmacology Lecture Keynote to be announced in January

Nonpharmacological Factors Influencing Drug Action Chair: Michael Nader Division Programming Symposium Chair: TBD DIVISION FOR CANCER PHARMACOLOGY 3-D Biology in Cancer Pharmacology - Is Flat Biology Dead?

Chair: Mary-Ann Bjornsti

Norman Weiner Lecture Keynote: Jack Bergman

Challenges and Opportunities for Childhood Cancer Drug Development Chair: Peter Houghton

SYMPOSIA

Stem Cells in Cancer Chairs: Kip Guy and Shannon McKinney-Freeman

ASPET Presidential Symposium: Leveraging New Paradigms for GPCR Drug Discovery Chair: David Sibley Julius Axelrod Symposium: Evolving Insights Regarding GPCRs: Compartmentation, Signaling and Clinical Utility Chair: Paul A. Insel ASPET Journals Symposium: Hear It from the Editors Chairs: Mary Vore and Rich Dodenhoff

Division Programming Session Featuring presentations selected from EB abstracts submitted to ASPET topic categories DIVISION FOR CARDIOVASCULAR PHARMACOLOGY Cardiovascular Pathobiology of Inflammasomes Chairs: Yang Zhang and Krishna Boini Perinatal Therapeutics and the Programming of Adult Cardiometabolic Disease Chairs: Stephane Bourque and Stella Goulopoulou

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140 Cardiovascular Pharmacology Division Trainee Showcase and Lucchesi Award Lucchesi Award nominations accepted until December 1 through the ASPET Awards Portal.

Showcase applications accepted until November 21.

You must submit your abstract through both EB2017 and the ASPET Awards Portal.

DIVISION FOR MOLECULAR PHARMACOLOGY The CRISPR-Cas9 Revolution in Pharmacology Chairs: Karen Tonsfeldt and Lakshmi Devi

DIVISION FOR DRUG DISCOVERY AND DEVELOPMENT Tools and Targets: Overcoming Challenges in Modern Drug Discovery Chairs: Don Mattison and Craig Beeson

Chemical Biology and Drug Discovery in Epigenetics Chairs: Dong Wang and Chuan He

Emerging Technologies for Selectively Modulating the Tumor Immune Contexture Chair: Shiladitya Sengupta and Ashish Kulkarni Surmounting the Insurmountable: Obstacles in Drug Discovery and Development – Real World Case Studies Chairs: Kan He and Paul F. Hollenberg Targeting of GRKs and Beta-arrestins for Cardiovascular Therapy: Picking on Certain Siblings over Others in Some (Protein) Families Chairs: Anastasios Lymperopoulos and Guido Iaccarino DIVISION FOR DRUG METABOLISM Transporter Roles in Intracellular Drug Concentrations Chairs: Yurong Lai and Ikumi Tamai Physiological Regulation of Drug Metabolism and Transport Chair: Edward Morgan

The Pharmacological and Therapeutic Legacy of Dr. Alfred G. Gilman Chairs: Myron Toews and Paul Sternweis

Division for Molecular Pharmacology Postdoctoral Scientist Award Finalists Featuring presentations selected from EB abstracts submitted to ASPET topic categories DIVISION FOR NEUROPHARMACOLOGY Therapeutic Prospectives for Cannabinoids: Beyond Marijuana and Pain Chairs: Harshini Neelakantan and Sara Ward Developing Novel Therapeutic Strategies to Modulate K+/Cl- Co-transporter 2 (KCC2) Function Chairs: Paul Davies and Tarek Deeb Mechanistic Studies in Cholinergic Neurobiology: Focus on Nicotinic Acetylcholine Receptors Chair: Ryan Drenan Division for Neuropharmacology Postdoctoral Scientist Award Finalists Applications accepted until November 21. You must submit your abstract through both EB2017 and the ASPET Awards Portal.

Cytochrome P450 Structure in Human Health Chairs: Ross Wilderman and James Halpert

DIVISION FOR PHARMACOLOGY EDUCATION Game-Based Learning and Clinical Simulation for Pharmacology Chairs: Mark Hernandez and Kelly Quesnelle

Emerging Technologies for Characterizing Preclinical Biotherapeutics Chairs: Larry Wienkers and Dan Rock

Teaching Institute: Supporting Experiment Design and Rigor in Graduate Training Chairs: Joey Barnett and Richard Okita

Early Career Achievement Award, James Gillette Awards, and Platform Session Featuring talks from the Early Career Achievement Award winner, the Gillette winners and presentations selected from EB abstracts submitted to ASPET topic categories

IPE: Educating a New Generation of Healthcare Professionals Chair: Ashley McFalls

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Delivering Innovative Solutions in Pharmacology Education: Leveraging Web-Based Technologies Chairs: John Szarek and Simon Maxwell

141 DIVISION FOR TOXICOLOGY Intestine-liver Crosstalk, New Frontier for Drug Metabolism, Liver Injury and Repair Chairs: Grace Guo and Lauren Aleksunes

Quantitative Systems Pharmacology: Application to Cancer Drug Development and Personalized/precision Medicine Chairs: Jessie Au and Jerry Lee

Mitochondria: Guardians of the Cell Chairs: John Schuetz and Rick Schnellmann

Release and Processing of Extracellular ATP: New Insights and Therapeutic Targets Chairs: Ross Corriden and Amanda MacLeod

Epigenetic Regulation of Toxicity and Implications for Risk Assessment Chairs: Brian Cummings and Dana Dolinoy Division Programming Symposium Chair: Monica Valentovic DIVISION FOR TRANSLATIONAL AND CLINICAL PHARMACOLOGY Novel Regulators of Platelet Function and Thrombogenesis: Multiple Trails Towards a Broadway Chairs: Fadi Khasawneh and Michael Holinstat

Young Investigator Awards Platform Session and Early Career Faculty Showcase Featuring presentations selected from EB abstracts submitted to ASPET topic categories MENTORING AND CAREER DEVELOPMENT COMMITTEE Graduate Student - Postdoctoral Colloquium Saturday, April 22, 2017 Sponsored by the Mentoring and Career Development Committee

Give a Day of Service at EB2017 Since 2009, EB attendees have given a day of volunteer service in the local communities where we convene.

Volunteer activities have included home construction, painting, cleaning, stocking, food preparation, and other needed services. ASPET will again sponsor a volunteer opportunity at EB2017 in Chicago.

If you plan to join us, please contact Dr. Charles P. France at france@uthscsa.edu or 210-567-6969. Further details will follow to those who express an interest in volunteering.

ASPET volunteers donate their time at Cradles to Crayons during EB2015 in Boston.

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Chlorpromazine and the Dawn of Antipsychotics Rebecca J. Anderson, PhD

Reprinted from https://en.wikipedia.org/wiki/Henri_Laborit under the Creative Commons Attribution-ShareAlike License.

A cab driver suffering from hay fever took an antihistamine and thought nothing more about it—until he was stopped by a policeman and fined for running a red light.

In hindsight, the most revealing thing about this little incident was that he told the officer he had seen the traffic light but just didn’t care enough to stop.

Physicians were well aware that, in addition to alleviating allergy symptoms, antihistamines had “sedative side effects.” The drowsiness, they cautioned, might impair work performance and perhaps pose a safety hazard. But this was not sedation in the usual sense. The cab driver was fully conscious. His memory was intact.

Dr. Henri Laborit But his ability to process thoughts on an emotional level had been dulled.

The anti-allergy effect of antihistamines was well understood, but the sedative side effects were not. It would take an astute surgeon, who was trying to improve surgical outcomes, to turn this special type of “sedation” into a major medical breakthrough.

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Preventing Shock Henri Laborit was born in Hanoi (then French Indochina) and received his medical training at Ecole de Santé Navale in Bordeaux, France. He became a Navy surgeon, serving in Tunisia during World War II, and returned to France after the liberation (1-3).

In Tunisia and later at the French Navy’s medical center in Toulon, Laborit was concerned about anesthetic and surgical shock (1-3). Patients who feared or were anxious about surgery required deeper levels of general anesthesia, which in turn increased the chances of cardiovascular collapse (i.e., surgical shock), postoperative complications, and mortality.

From 1947-1950, Laborit experimented with various drug combinations that permitted surgery under lighter general anesthesia. When he prescribed promethazine to some of his patients for its antihistaminic action, he immediately recognized that it also seemed to be beneficial against surgical shock (1, 3).

Promethazine calmed and relaxed patients prior to surgery. Like the cab driver, Laborit’s patients were conscious and responsive, but were disinterested in the things going on around them. They also appeared to suffer less after major operations (1-3).

Laborit recognized that the “sedative side effect” of promethazine was quite different from other central depressant drugs and called it “ataraxy”—a tranquilizing effect (1).

Potentiation and Artificial Hibernation Laborit published his findings in the Parisian journal La Presse Médicale, which had the highest circulation of all French medical journals (1, 2). Among those who were impressed was Pierre Huguenard, an anesthetist in Paris, who was writing his doctoral thesis in medicine. He was reading all the literature on surgery and anesthesia and wrote Laborit for more information (3).

In early 1951, Laborit was transferred to Val-deGrâce, France’s famed military hospital in Paris, and given a laboratory for his research. Each week, he chaired a group discussion of civilian and military researchers. Still only in his mid-30s, Laborit expressed himself with clarity and logic, smiled easily, and was persuasive. In short, he was a charmer (3).

Huguenard soon joined Laborit’s weekly meetings, and the two developed a close collaboration (3).

Together, they worked out Laborit’s technique of “potentiated” anesthesia—using synergistic drugs

to reduce the amount of general anesthetic during surgery (2-4).

When the operation involved lowering body temperature (e.g., icepacks for leg amputation), patients were even more resistant to surgical shock (3). Laborit and Huguenard therefore proposed a method of “artificial hibernation.” They first administered their cocktail of hypnotics, analgesics, curare, and an antihistamine and then cooled the patient with icepacks or air conditioning during surgery (1, 3, 5). Promethazine was satisfactory, but Laborit wanted a “super-stabilizer” with a stronger, more selective effect (1, 3).

Rhône-Poulenc Research Chemically, promethazine is a phenothiazine.

Since 1944, Rhône-Poulenc chemist Paul Charpentier had prepared a series of phenothiazine analogs, which his colleague, Simone Courvoisier, assessed pharmacologically. They wanted compounds with maximal antihistamine properties and minimal “sedative side effects.” Weak antihistaminic compounds were quickly shelved without evaluating them for sedation (2).

On October 3, 1950, the assistant scientific director at Rhône-Poulenc proposed a sharp departure from this strategy. Phenothiazines’ side effect, he said, could be useful for new therapeutic indications. In a 7-page research proposal, he outlined the rationale for developing a phenothiazine that had effects predominantly on the brain (2).

Citing the work of Laborit, who had kept the Parisian medical community well informed via his La Presse Médicale reports, the proposal suggested that such drugs might be useful as pre-anesthetics, as well as analgesics, antispasmodics, and antiparkinson drugs. The proposal ended with the prophetic statement, “we think that such substances would have an application in psychiatry” (2).

Available evidence suggested that the antihistaminic and central actions of the phenothiazines were inversely related. Pyrilamine, for example, was a strong antihistamine with weak central effects. Dimenhydrinate (Dramamine®) and diphenhydramine (Benadryl®) were weak antihistamines but had a strong central action, and in fact, were marketed as an antiemetic and sleep aid, respectively (2).

Complying with the new directive, Courvoisier began pulling the failed phenothiazines off the shelf

September 2016 • The Pharmacologist

In the Public Domain

144 and evaluated them specifically for their central activity. For this, she used a rope climbing test adapted

by Charles Winter, a Merck pharmacologist (6).

Trained rats could easily climb the rope. After treatment with a muscle relaxant, they attempted to climb the rope but appeared weak and became easily fatigued. On the other hand, promethazine made the rats confused and “unable to decide whether to climb or not” but without loss of muscle strength (6). Courvoisier used promethazine as the reference standard in her search for more selective compounds (2).

One compound, promazine, looked promising.

It had originally been made by Charpentier in 1947 but had been promptly rejected because of its poor antihistamine activity (1). To further enhance promazine’s central actions, Charpentier synthesized a new compound, 4560 RP, by adding a chlorine substituent. On December 11, 1950, he sent 4560 RP to Courvoisier for pharmacologic testing (1, 2, 7).

Rats treated with 4560 RP made no attempt to climb the rope, although their muscle strength and motor activity seemed unimpaired. With further testing, Courvoisier found that 4560 RP was also an Chemical structure of chlorpromazine antispasmodic, hypnotic, analgesic, and weak analeptic. It potentiated general anesthesia but had no antihistaminic activity (2).

Rhône-Poulenc moved forward with Phase I clinical trials in April 1951. Over the next 5 months, samples of 4560 RP were sent to 35 investigators, mostly in Paris, for clinical pharmacology assessment (2). Among them was Dr. J. Schneider at Broussais Hospital. On April 13, 1951, Schneider reported to Rhône-Poulenc that the drug potentiated the effects of barbiturates in a woman with acute mania (2).

Laborit’s Influence During 1950-1951, Laborit made frequent visits to Rhône-Poulenc’s research laboratories in Paris and discussed his success with potentiators of

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anesthesia (2). Despite these visits, though, he knew nothing about 4560 RP, until he asked for a more selective analog of promethazine. Rhône-Poulenc had just the drug. It was 4560 RP, which Charpentier had named chlorpromazine.

On June 26, 1951, Laborit became the twelfth investigator to receive chlorpromazine (2). Huguenard found that chlorpromazine eliminated patients’ anxiety before surgery, and he could drastically reduce the amount of morphine and general anesthetic during surgery (3, 7). It also counteracted post-operative nausea.

On October 13, 1951, Laborit and Huguenard published their progress with the artificial hibernation technique, which had been hampered by the weak and inconsistent efficacy of their drug cocktails (2, 7). They enthusiastically announced, “Now we have a drug… extremely effective for its low toxicity and it greatly facilitates therapeutic techniques…It is 4560 RP” (1).

From September 9, 1951 to March 10, 1952, RhônePoulenc shipped samples of chlorpromazine to 118 clinical investigators in Europe for the phase II trials.

Rhône-Poulenc did not design or plan specific clinical trials. Rather, the company asked the investigators to explore a range of therapeutic uses, assess the patients’ tolerance to the drug, and send in their findings (2).

In Paris, investigators reported chlorpromazine’s wide range of pharmacologic properties and prescribed it for a variety of ailments (1). On December 1, 1951, Rhône-Poulenc noted use of chlorpromazine in surgery (potentiation of general anesthesia) and medicine/obstetrics (hypnotic, sedative, antispasmodic, antipyretic, and anticonvulsive). Based on the clinical observations of Schneider, Laborit, and others, as well as Courvoisier’s preclinical assay results, the company added “interrupt maniacal crises” to its list of possible uses (2).

Mental Illness Before Chlorpromazine Up to the mid-twentieth century, mentally ill patients were shunted to the fringes of society. Psychotic patients experienced frightening delusions and hallucinations. Manic patients could be assaultive and destructive. In psychiatric wards, they lay strapped in their beds: arms bound in straitjackets, feet tied to the bedposts, and heads restrained with a halter (3). Some were put in seclusion. They screamed, shouted, hurled abuse and insults, sang, and cried. The constant noise often disturbed people living nearby (3).

145 Drugs had always been a large part of psychiatrists’ therapy. But since nothing was known about the pathophysiology of mental disorders, all medicinal treatments were trial-and-error. These included injection of cocaine, manganese, castor oil, oil of turpentine, and even animal blood (5).

Sedatives such as chloral hydrate and the barbiturates came in and out of vogue depending on the prevailing knowledge of pharmacology (9).

Barbiturates calmed belligerent and unruly patients, but it was merely a substitute for mechanical restraints and palliative rather than therapeutic (9). In addition, patients became more violent and aggressive afterward, having found new strength during their forced rest (3).

Sleep therapy proved more successful and was especially popular in Europe. Hypnotic and sedative drugs such as the barbiturates, opium alkaloids, and scopolamine were used to induce and maintain sleep for 8-12 days in a darkened room (1).

Although effective in some patients, especially those in manic states, sleep therapy involved major risks and required hospitalization with continuous

In the Public Domain

Nurses grew accustomed to the habitual noise, cleaned up feces, and spoon-fed recalcitrant patients who often, laughingly, spit mouthfuls of well-chewed food back into their faces (3).

Psychotic patients often stayed in asylums and psychiatric hospitals for months or years, and the institutionalized population was growing by 7% per year (3, 8). By the 1950s, things had reached a crisis.

Psychiatric wards were bursting at the seams (2).

Many therapeutic options were tried with very limited success. In the late 1930s, surgeons performed frontal lobotomies. Some patients were calmer after surgery but others remained unchanged. Of course, lobotomy caused irreversible brain damage, whether the results were good, bad, or indifferent. And one surgeon said candidly, “The good results in some cases did not make up for the bad ones” (3).

In the 1940s, malaria fever therapy proved effective against some psychoses. Patients were infected with malaria to produce a high malarial fever. After 10-13 bouts of fever, about 30% of the patients showed improvement (3). Their malaria infection was then treated with quinine or other antimalarials.

The scene at Bedlam depicted by William Hogarth in A Rake’s Progress

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146 In 1938, electroshock treatment was introduced.

It provided excellent and immediate control of symptoms but could cause confusion, restlessness, amnesia, and aggression (3, 5). Injuries to bones and muscles were also a problem. Concurrent use of muscle relaxants avoided that problem but caused other complications (paralysis, hypoxia, etc.). As they gained experience, investigators found that the real value of electroshock was for depression, rather than psychotic states such as schizophrenia (3, 5).

...since nothing was known about the pathophysiology of mental disorders, all medicinal treatments were trial-and-error.

All of these interventions sought to improve the patient’s psychological state through major, often life-threatening, alterations in physiological functions: sleep, coma, or convulsions (5). No treatment targeted specific neural pathways or processes because no one knew what alterations in the brain were responsible for mental illness. In fact, many psychiatrists denied that the etiology was biochemical, hormonal, or pathophysiological. Freudian psychoanalysis dominated American psychiatric practice (2).

In the Public Domain

nursing care and medical supervision (1, 5). The drugs had a narrow safety margin and were addictive. Some patients developed pneumonia, an often fatal complication at a time when antibiotics were not available (5).

Hypoglycemic shock therapy was introduced in 1927. Insulin was injected to induce a deep coma for 1-2 hours and then reversed by giving the patient a glucose syrup. Repeated, reversible insulin-induced comas gave more reliable therapeutic results, frequently leading to full remissions (5). But, again, close monitoring was required, and according to one investigator, “Justifying these insulin comas took courage” (3).

One Hungarian psychiatrist theorized that epilepsy and schizophrenia were opposite states of brain function and that inducing seizures might improve schizophrenia. At first, he induced convulsions chemically with intramuscular injections of camphor (3). But the seizures were unpredictable.

The patient might be walking in hazardous places such as stairways when the seizure struck (5).

In 1929, intravenous metrazol was introduced as the chemical convulsant and produced faster, more favorable results. But metrazol caused patients to experience a brief period of extreme anxiety, and they remembered it. So, cooperation for follow up treatments was a major problem (3, 5).

Popular Mode of Curing Insanity! Lizzie Bonnere punishing Miss Hodson, on suspicion of taking her key

The Pharmacologist • September 2016

Laborit Urges Psychiatrists Based on his observations in surgical patients, Laborit thought that chlorpromazine would work in psychiatry, in which, as in surgery, patients are stressed.

“For months after I began using chlorpromazine, I urged the psychiatrists I saw daily at Val-de-Grâce, often during lunch at the cafeteria, to try it with their patients” (2).

However, French psychiatrists were not easily persuaded. They had already tried innumerable sedative drugs without much success (1, 2). In an effort to sway professional opinion, Laborit invited a prominent

147 Unfortunately, the chlorpromazine infusion caused irritation at the injection site, and on several occasions, Hamon’s team substituted barbiturates and electroshock for chlorpromazine. Even so, after 20 days and a total of 855 mg of chlorpromazine, Jacques was discharged, “ready to resume normal life” (1, 7).

Colonel Paraire reported the Val-de-Grâce team’s clinical findings on February 25, 1952, at a meeting of the Société Médico-Psychologique in Paris. In March 1952, their paper appeared in the Society’s official journal—the first published account of chlorpromazine in psychiatry (7). Although Jacques received multiple treatments (chlorpromazine, an opiate, a barbiturate, and electroshock), this marked a turning point in psychiatry (4).

Rhone-Poulenc’s Psychiatric Trials

Reprinted with permission from Smithsonian Institution Archives, Photo: Smithsonian Institution Archives. Image# SIA2008-0983.)

Also in March 1952, Rhône-Poulenc reconsidered chlorpromazine’s potential therapeutic indications.

In addition to potentiating the effects of anesthetic, analgesic, and hypnotic agents, the company included psychiatric uses (manic states, schizophrenia, detoxification cure, and sleep cure) as well as neurosis, anxiety, and epilepsy (2). But clinical trials were still passive. Investigators had to take the initiative to request samples.

Some learned about chlorpromazine through Rhône-Poulenc’s formal communications. Others were familiar with Laborit’s work. Pierre Deniker heard about chlorpromazine from his brother-in-law, who was a surgeon (1-3).

A native Parisian, Pierre Deniker received his MD from the Faculty of Medicine in Paris and was serving on its faculty, as well as on the staff at Hôpital SteAnne, a renowned psychiatric hospital in Paris. At St. Anne’s, he was in charge of the men’s department in Jean Delay’s clinic (3).

Reprinted with permission from http://www.histrecmed.fr.

Parisian psychiatrist to attend a demonstration of chlorpromazine’s effects. C. Quarti, a psychiatrist and friend, volunteered as Laborit’s experimental subject (1).

On November 9, 1951, Quarti was injected with chlorpromazine and later documented her experiences, which were similar to the reactions of Laborit’s surgical patients (2). Unfortunately, the demonstration backfired. Quarti fainted, due to brief but severe orthostatic hypotension—an inconvenient problem for psychiatric patients. The prominent psychiatrist was not impressed, and in fact, this fainting episode worked to further dissuade psychiatrists (1).

Undeterred, Laborit continued to press his case.

On February 13, 1952, he and Huguenard published a 2-page article entirely devoted to chlorpromazine.

The article described chlorpromazine as a “stabilizer” with unique calming effects. In conclusion, they said, “These facts let us foresee certain indications for this drug in psychiatry…” (1, 2, 4).

Colonel Joseph Hamon, director of the Neuropsychiatric Service at Val-de-Grâce Hospital, finally consented to try chlorpromazine, but “without much conviction” (1, 2). He was assisted by Colonel Jean Paraire and Lieutenant Colonel Jean Velluz.

Their subject was Jacques Lh, a 24-year-old severely agitated psychotic patient (7). Jacques experienced his first manic attack in 1949. From September 9 to October 10, he received 15 electroshock treatments and 4 pentothal treatments at Val-de-Grâce. His mania subsided (2).

On February 6, 1951, he was admitted again after suffering a similar manic attack. During his 2-month hospitalization, he received 9 electroshock treatments, followed by 15 insulin-induced comas (1, 2).

On January 17, 1952, Jacques was again admitted to Val-de-Grâce, again exhibiting severe agitation. At 10:00 am on January 19, Hamon’s staff administered an intramuscular injection of meperidine (an opiate) and a 50 mg intravenous dose of chlorpromazine. Jacques immediately became calm, remained responsive when awake, and at times slept (2, 7).

After about seven hours, Jacques’s agitation and violent behavior returned with the same intensity, until another chlorpromazine injection halted it. The behavioral pattern was the same before and after each injection. After 12 days, Jacques’s periods of calmness became progressively longer, and the intervals of excitement became shorter and less violent (2, 7).

Dr. Jean Delay

Dr. Pierre Deniker

September 2016 • The Pharmacologist

Jean Delay was an inspiring renaissance man. At 40, he was the youngest-ever chairman of the mental disease clinic at St. Anne’s. His wide-ranging interests included philosophy, literature, and psychology, but he was first and foremost a physician. Deniker wanted to pursue experimental drug therapies, and the broad-minded Delay encouraged his efforts (3).

Deniker requested chlorpromazine from RhônePoulenc and began treating patients at St. Anne’s on March 24, 1952. In short order, he found that a daily dose of 75 mg was sufficient to control behavior and, unlike the exploratory uses at Val-deGrâce, without the need for other drugs, treatment procedures, or icepacks (7).

When Deniker informed his boss, Delay was immediately interested in chlorpromazine but insisted on a larger number of cases before they reported their findings to the scientific community. Delay recommended that all patients arriving at St. Anne’s in a state of agitation, excitation, and mental confusion be assigned to Deniker’s department (3).

On May 25, 1952, Delay and Deniker presented their initial findings at a meeting of the Société Médico-Psychologique (7). By July 1952, they had published 6 reports describing 40 psychiatric patients in whom chlorpromazine had induced a “syndrome of psychomotor indifference” (4).

These were the first published reports showing that a single drug could effectively treat major psychoses (4, 7). Delay and Deniker’s observations were promptly confirmed and reported by other investigators in France, Italy, and Austria (5, 7).

In addition to these psychiatric effects and confirming the pharmacologic properties Courvoisier had documented preclinically (analgesic, ganglionic blockade, antiemetic, antipyretic, antishock, anticonvulsant, antispasmodic), clinical investigators also reported chlorpromazine-induced orthostatic hypotension, heart palpitation, and hypothermia (2).

Chlorpromazine even cured hiccups (9).

In November 1952, just two years after Paul Charpentier had first synthesized it, Rhône-Poulenc launched chlorpromazine as a prescription medication in France (7). Because of the drug’s wide range of pharmacologic properties, the company branded it Largactil®, a drug “large in action” (4, 7).

1953 – A Pivotal Year In 1953, psychiatry was completely transformed by three events. The first was the persistence of

The Pharmacologist • September 2016

Reprinted with permission from The Canadian Medical Hall of Fame.

148 chlorpromazine’s champions, Delay and Deniker in Paris and Heinz Lehmann in Montreal.

Deniker traveled to many European university centers, describing his therapeutic successes, and European psychiatrists came to St. Anne’s to meet with him (3). Delay and Deniker also organized the first psychiatric conference entirely devoted to chlorpromazine, held in Basel, Switzerland, in November 1953 (1). By the end of 1953, chlorpromazine dominated treatment in mental institutions across Europe (1).

Meanwhile, Heinz Lehmann was introducing chlorpromazine to American psychiatrists. Lehmann fled from Germany to Canada in 1937 (7, 10). Working at the Verdun Protestant Hospital in Montreal and fluent in French as well as German and English, Lehmann read the publications of Delay and Deniker. In 1953, he received a “generous amount” of chlorpromazine from Rhône-Poulenc and treated 71 psychiatric patients (11).

Lehmann confirmed Delay and Deniker’s observations, saying, “The drug is of unique value in the symptomatic control of almost any kind of severe excitement” (11).

His paper, published in English in February 1954, introduced chlorpromazine to North American psychiatrists (7).

Lehmann continued Dr. Heinz Lehmann to lead efforts, along with a few others, in raising the prominence of pharmacological therapy in American psychiatry. He also helped devise a comprehensive battery of preclinical and clinical assessments for evaluating new psychotropic agents (10).

SKF Partnership The second major event of 1953 was RhônePoulenc’s success in penetrating the US market. In the 1950s, European drug companies faced big hurdles to marketing their drugs because US regulations were more restrictive than in Europe and American physicians were skeptical of European scientific and clinical data (2).

149 Rhône-Poulenc’s first attempts to interest an American partner failed. One drug company said chlorpromazine had “no large market potential” (2).

The reception at Smith, Kline & French (SKF) Laboratories in Philadelphia was more favorable.

Unlike most American firms at the time, SKF was actively fostering close collaborations (2). SKF had a good portfolio of drugs to offer European companies, and Francis Boyer, SKF’s president, had already made several trips to Europe to establish relationships.

When Rhône-Poulenc’s inquiry arrived in April 1952, Boyer, who was fluent in French, quickly built a rapport with his Rhône-Poulenc counterpart (2).

Coincidently, SKF scientists were exploring the interesting properties of SKF 525. SKF 525 potentiated barbiturate anesthesia and also potentiated centrally acting stimulants such as amphetamine (2). Chlorpromazine, an anesthetic potentiator, fit nicely into their research plans.

Other SKF scientists were looking for a drug that was more specific for treating nausea and vomiting than Dramamine. They were interested in chlorpromazine’s antiemetic properties (2).

In May 1952, the two companies exchanged 200 mg samples of SKF 525 and chlorpromazine (2).

The swap turned out to be a better deal regarding chlorpromazine than SKF 525. The effects of SKF 525 seen in the laboratory could not be duplicated in humans. Rather than acting as a potentiator like chlorpromazine, SKF 525 inhibits CYP450. Clinical trials were shelved, but later, SKF 525 became a valuable research tool for studying microsomal metabolism.

SKF quickly confirmed Courvoisier’s preclinical results and initiated clinical trials on October 28, 1952 (2). Unlike Rhône-Poulenc, which allowed investigators free rein, SKF played a direct role and planned specific clinical trials. Among the clinical investigators who conducted these early trials was Louis Goodman at the University of Utah (2).

By December 1952, the American clinical results showed that chlorpromazine effectively controls nausea and vomiting, markedly sedates acute manic patients, lowers refractory fevers due to head trauma or uncontrolled infections, and relieves the itching associated with Hodgkin’s disease (2).

With a view toward rapid market entry, SKF gave priority to the clinical trials for an antiemetic indication because it was the easiest to demonstrate (2). In a study of 70 patients at Peter Bent Brigham Hospital in Boston, chlorpromazine had “a powerful

selective effect against nausea and vomiting…without producing any degree of sedation” in patients suffering due to cancer chemotherapy, pregnancy, and many other emetic conditions (12). This clinical report, which appeared four months before Lehmann’s paper, was the first American publication of chlorpromazine results.

In contrast, the clinical data from psychiatrists trickled in, but by February 1953, SKF was impressed.

Chlorpromazine induced a “strikingly unusual type of sedation…giving complete relaxation without actively inducing sleep” (2). As the year progressed and the evidence grew stronger, SKF added psychiatric indications as a top priority in its development plan.

More psychiatry investigators were added, including N. William Winkelman at Sidney Hillman Medical Center in Philadelphia and Winfred Overholser at St. Elizabeths Hospital in Washington, DC (2, 9, 13).

Then, SKF’s plans for registering and marketing chlorpromazine were nearly derailed (2). In SKF’s manufacturing plant, almost everyone who handled the drug experienced contact dermatitis. Workers developed skin rashes, and their eyes became irritated and bloodshot. It was a drug-induced photosensitivity reaction that was also seen in some patients. Rhône-Poulenc advised manufacturing precautions (i.e., protective clothing, goggles, and special ventilation devices), which prevented further problems at SKF (2).

Another side effect problem, jaundice, was much more challenging. SKF spent considerable time and effort and added clinical trials to elucidate the safety risk (2). Unfortunately, no pattern emerged to establish that jaundice was drug-related. Some investigators suspected it was coincidental and due to concurrent hepatitis infections. In any case, SKF agreed to include a warning about jaundice in its prescribing instructions, which remains on the current label.

To persuade American physicians—especially psychiatrists—to use chlorpromazine, SKF sponsored a promotional tour for Laborit and Deniker (2). These two pioneers of chlorpromazine met for the first time in November 1953 when they boarded the airplane that brought them to the US (3).

Laborit’s demonstrations of his artificial hibernation technique on dogs were less than impressive. Most of the dogs died. This only added to the skepticism of American anesthesiologists about artificial hibernation, and SKF subsequently dropped the indication (2).

September 2016 • The Pharmacologist

150 Deniker’s hectic tour encompassed all of the major mental institutions in North America, and he was warmly received. His articulate presentations describing chlorpromazine-treated schizophrenic patients inspired and convinced many influential psychiatrists (2).

By the end of 1953, SKF had supplied over 600 physicians with chlorpromazine, by far the largest group of investigators ever to test an investigational drug from SKF. But the dataset included only 104 psychiatric patients, whereas more than 1,000 patients had clearly established chlorpromazine’s efficacy as an antiemetic drug (2).

On March 4, 1954, SKF submitted chlorpromazine to the Food and Drug Administration (FDA) for approval. The application contained 22 major clinical studies, of which 9 were antiemetic trials.

The psychiatric data came from 6 investigators, including Lehmann in Montreal and Winkelman in Philadelphia (11, 13).

On March 26, 1954, the FDA approved Thorazine® (SKF’s brand of chlorpromazine) for nausea and vomiting and in neuropsychiatry (2).

In 1931, Indian researchers isolated five alkaloids from the Rauwolfia root (1, 3). In 1952, chemists at the Swiss drug company Ciba successfully synthesized reserpine (Serpasil®), the alkaloid that accounts for about half of the pharmacologic activity of the Rauwolfia root, for use in hypertension (2, 3, 5).

The Indian reports of hypertension and psychoses efficacy were published in English and available in the US. But American psychiatrists remained unaware of reserpine until Kline’s chance reading in The New York Times (1).

After testing tablets of the whole Rauwolfia root and reserpine on himself, Kline treated over 700 psychiatric patients at Rockland State Hospital

The third pivotal event of 1953 was triggered by an article in the Sunday edition of The New York Times. On March 15, 1953, Nathan Kline, an American psychiatrist, was reading The New York Times when a report from India caught his eye. R. A. Hakim had been awarded a gold medal at a medical conference in Bombay for his presentation of a paper on the cure of schizophrenia (14). There was no drug in Western medicine that cured schizophrenia, so Kline was intrigued.

Hakim’s potion consisted of a half-dozen herbs, but the main ingredient was Rauwolfia serpentina, a shrub with red blossoms that grows wild in many parts of India (1, 3, 14, 15). For hundreds of years, Rauwolfia had been a common household remedy for insect and snake bites, insomnia, intestinal diseases, and to facilitate childbirth (1, 14, 16). It had also been used for fevers, to induce sleep in children, and as a cure for insanity (15, 16).

In the 1930s and 1940s, several Indian investigators reported that Rauwolfia serpentina was an effective treatment for hypertension (1, 3). Tablets made from the dried Rauwolfia root were in “such unprecedented popularity” that nearly every patient with high blood pressure in India had used it (16).

The Pharmacologist • September 2016

In the Public Domain

Reserpine

An advertisement from the early 1960s for Thorazine®, Smith, Kline & French (SKF) Laboratories’ brand of chlorpromazine

151 Lasker Clinical Medical Research Award for their contributions in launching chlorpromazine and reserpine use in psychiatry (3, 7).

Psychiatry Transformed

Rauwolfia serpentina plant

Reprinted from https://en.wikipedia.org/wiki/Reserpine under the Creative Commons Attribution-ShareAlike License.

in New York (14). His measures of efficacy were observational but quantitative: fewer physical assaults, a decreased need to restrain the patients, and fewer patients put in seclusion. The wards were also less “noisy” (14). Kline’s report to the New York Academy of Sciences announced the first Western psychiatric use of reserpine (2).

During Deniker’s US tour, Harvard University pharmacologists told him that reserpine-treated hypertensive patients exhibited a syndrome of “indifference” similar to his descriptions of chlorpromazine-treated patients. When Deniker returned to St. Anne’s, he promptly confirmed Kline’s observations, but the dose of reserpine required for psychiatric efficacy was 10-fold higher than that used for hypertension (4).

In 1957, Henri Laborit, Pierre Deniker, Heinz Lehmann, and Nathan Kline shared the Albert

Initially, many psychiatrists favored reserpine and used it before chlorpromazine, largely because it seemed to have fewer side effects (2, 3, 9). But, chlorpromazine has a faster onset of action, and use of reserpine soon declined (2-5, 9).

Chlorpromazine’s impact was most apparent in mental institutions (7, 9). Fewer patients were subjected to shock treatments, sleep therapy, or seclusion. Straitjackets were stored away (2, 3, 9). The most obvious change was the silence. In the wards, chlorpromazine’s efficacy could be measured in decibels (3).

Henry Brill, a New York psychiatrist, noted, “I remember walking into the dayroom and seeing this small group of patients dressed, quiet, cooperative, and in surprisingly good contact – with their psychiatric symptoms wiped away. That was perhaps the most spectacular demonstration anyone could ask for” (2).

At St. Elizabeths Hospital in Washington, D.C., America’s foremost mental institution, many patients who had been ill for years and were serious ward problems responded to chlorpromazine (9). There was a veritable exodus of patients from mental institutions. The average length of hospital stay dropped from years to weeks, and less than 10% of schizophrenic patients remained hospitalized long term (3, 8).

In 1956, the population of American institutionalized patients declined for the first time in 175 years, and the trend continued for more than 15 years (1-3). Patients could expect to spend most of

Chemical structure of reserpine

September 2016 • The Pharmacologist

152 their life in the community and be self-supporting (8).

“Asylum” virtually disappeared from the layman’s vocabulary.

Chlorpromazine’s phenomenal commercial success prompted drug makers to search for better analogs (1, 3, 7). Phenothiazines that had been shelved and newly synthesized analogs were screened for chlorpromazine-like activity.

Within 10 years, 20 phenothiazines were in development for psychosis, as well as new drug classes, most notably the butyrophenones (5). None of these compounds was superior in overall therapeutic efficacy to chlorpromazine. They differed from each other only in their potency and side effects (5).

Drug Classification From the very beginning, psychiatrists realized that chlorpromazine and reserpine were different from all of the drugs they had previously administered.

“Sedative” did not properly describe them. A new pharmacologic classification was needed.

There was a veritable exodus of patients from mental institutions In January 1955, Delay and Deniker proposed “neuroleptic” from the Greek, “that takes hold of the nerves” (4). Most Europeans adopted neuroleptic, but Americans preferred “tranquilizer” (1, 4).

The introduction of meprobamate, another drug with tranquilizing properties but of a different sort, forced a rethinking. “Major tranquilizer” was coined to distinguish drugs like chlorpromazine, which reduces mania and psychosis, from “minor tranquilizers” like meprobamate and the benzodiazepines, which do not (2, 4).

In 1956-1957, yet another group, the antidepressants, was introduced (2). Subsequently, “minor tranquilizer” was replaced with “anxiolytic” to highlight the drugs’ primary effect. “Major tranquilizer” was replaced with “antipsychotic,” even though the antidepressants and lithium are active in manic-depressive psychosis and might also rightly be called antipsychotics (4).

Chlorpromazine also spawned a new line of research, which was directed at elucidating its unique therapeutic effects and determining its mechanism of action. This new scientific discipline,

The Pharmacologist • September 2016

psychopharmacology, fostered a close collaboration between clinical psychiatrists, who used the drugs in patients, and laboratory researchers, who used the drugs as tools to explore the etiology of psychosis (2, 3).

Extrapyramidal Syndrome Dosing strategies for chlorpromazine varied considerably. Most French psychiatrists followed the lead of Delay and Deniker and dosed conservatively (1). In the US, many psychiatrists followed the flawed philosophy that “if some is good, more is better.”

When moderate doses were ineffective, they escalated to as much as 3,000 mg per day (1, 5).

Unfortunately, some patients were simply refractory to drug treatment, at any dose.

In 1954, a psychiatrist in Switzerland, where patients were also treated aggressively, first reported seeing an “extrapyramidal syndrome” (4, 5). The cluster of movement disorders included parkinsonian disturbances (tremor, rigidity, and slowed movement) along with muscle spasms and motor restlessness.

(Since the 1940s, Indian physicians had also observed Rauwolfia-induced parkinsonism (1).)

In 1959, another aspect of the extrapyramidal syndrome was first reported. Long-term antipsychotic treatment induced abnormal, involuntary mouth movements (lip smacking, puckering, and tongue movements). These rapid movements (the opposite of parkinsonism) also occurred sometimes in the limbs. This dyskinesia seemed to appear only after years of treatment, and it persisted for a long time after the drug was terminated. Because of its tardy onset and persistence after drug withdrawal, some authors began calling it “tardive” dyskinesia (1).

Chlorpromazine had a broad range of pharmacologic properties—some useful, some not. Of them all, though, the decidedly unpleasant extrapyramidal syndrome, especially tardive dyskinesia, threatened to end treatment of schizophrenia (5). Only after years of experience, systematic trials, and the introduction of clozapine (the first atypical antipsychotic) did researchers show that therapeutic efficacy could be separated from the extrapyramidal syndrome (1, 5).

A New Age The discovery of chlorpromazine was a major medical milestone. For the first time, a single drug

153

Reprinted from University of Gothenburg, Photo: Johan Wingborg

treat various psychiatric conditions. But none of them has surpassed the effectiveness of chlorpromazine.

In 2007, Thomas Ban, a noted psychopharmacologist, wrote, “If an agitated and aggressive psychotic patient in the emergency room fails to respond to some of the excellent new medications that may offer distinct advantages in terms of one or another side effect, one should not hesitate in prescribing good old chlorpromazine that has remained even after 50 years one of the most reliable antipsychotic drugs” (7).

And chlorpromazine is still the only drug approved by the FDA for intractable Nobel Prize Laureate Arvid Carlsson hiccups.

no. 6, Radiology, vol. 63,

Advertisements from the mid-1950s for Thorazine®, which is used to treat stubborn hiccups

of Surgery, vol.

1954 and Annals

141, no. 6, 1955.

effectively controlled psychiatric disorders without relying on sleep, hyperthermia, or electric or insulin shock. Chlorpromazine achieved the long-desired objective of all psychiatrists: to quickly reduce all signs of mental illness, restore patients’ mental state, and allow them to return to their families and society (3).

Chlorpromazine moved psychiatry back into the mainstream of medicine (7). Psychiatrists, especially in North America, began to accept that schizophrenia resulted from underlying neurochemical abnormalities, not just environmental and social influences (5). Drugs became their primary treatment, but rather than eliminating psychoanalysis, chlorpromazine made patients more amenable to both individual and group therapy sessions (7).

Because of chlorpromazine, psychopharmacology emerged as a research discipline. Arvid Carlsson’s revelation that chlorpromazine was a dopamine antagonist provided the rationale for the “dopamine hypothesis.” Chlorpromazine and other antipsychotic drugs were then used as research tools to identify neural pathways and other neurotransmitters implicated in psychiatric disorders (7, 17).

Considerable progress has been made in understanding brain mechanisms, and more selective drugs with fewer side effects have been developed to

September 2016 • The Pharmacologist

154

References

Biosketch:

1. Caldwell A E (1970) Origins of Psychopharmacology from CPZ to LSD. Charles C. Thomas, Springfield, IL. 2. Swazey J P (1974) Chlorpromazine in Psychiatry: A Study of Therapeutic Innovation. MIT Press, Cambridge, MA. 3. Thuillier J (1999) Ten Years that Changed the Face of Mental Illness (English edition, Healy D, ed) Martin Dunitz Ltd., London.

4. Deniker P (1983) Discovery of the clinical use of neuroleptics, in Discoveries in Pharmacology: Psycho- and Neuro-pharmacology (Parnham MJ and Bruinvels J eds) pp 163180, Elsevier, New York.

5. Lehmann H E and Ban T A (1997) The history of the psychopharmacology of schizophrenia.

Can J Psychiatry 42(2):152-162.

6. Winter C A and Flataker L (1951) The effect of antihistaminic drugs upon the performance of trained rats. J Pharmacol Exp Ther 101(2):156-162.

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.

7. Ban T A (2007) Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat 3(4): 495-500.

8. Editorial (1965) Changes in schizophrenia. BMJ 1:141-142.

9. Overholser W (1956) Has chlorpromazine inaugurated a new era in mental hospitals? J Clin Exp Psychopathol 17(3):197-201.

10. Healy D (1998) Pioneers in psychopharmacology. Intl J Neuropsychopharm 1:191-194.

11. Lehmann H E and Hanrahan G E (1954) Chlorpromazine: new inhibiting agent for psychomotor excitement and manic states. AMA Arch NeurPsych 71(2):227-237.

12. Friend D G and Cummins J F (1953) New antiemetic drug: preliminary report. JAMA 153: 480-481.

13. Winkelman N W (1954) Chlorpromazine in the treatment of neuropsychiatric disorders. JAMA 155(1):18-21.

14. Kline N S (1954) Use of Rauwolfia serpentina Benth. in neuropsychiatric conditions. Ann NY Acad Sci 59(1):107-132.

15. Gupta J C, Ghosh S, Dutta A T, and Kahali B S (1947) A note on the hypnotic principle of Rauwolfia serpentina. J Amer Pharm Ass (Sci) 36:416.

In the next issue of The Pharmacologist…

Dr. Anderson will share the story of the quest for cortisone.

16. Vakil R J (1949) A clinical trial of Rauwolfia serpentina in essential hypertension. Br Heart J 11(4): 350-355.

17. Carlsson A (1983) Antipsychotic agents: elucidation of their mode of action, in Discoveries in Pharmacology: Psycho- and Neuro-pharmacology (Parnham MJ and Bruinvels J eds) pp 197206, Elsevier, New York.

Don’t miss the December 2016 issue.

The Pharmacologist • September 2016

155

Meeting News Annual British Pharmacological Society Meeting: Pharmacology 2016 Guest Societies: ASPET, ASCPT, CNPHARS December 13-15, 2016 Queen Elizabeth II Centre, London, UK 16 Angel Gate, The Schild Plot, on EC1V 2PT City Road, Lond United Kingdom 0177 T: +44(0)20 7239 0114 F: +44(0)20 7417 info@bps.ac.uk www.bps.ac.uk

bers, Dear ASPET mem

ster for you can now regi to announce that ology 2016 ety is delighted London. Pharmac macological Soci ed attendees ember 2016 in The British Phar already register e on 13–15 Dec are plac e g ther takin ety and and 6, d– 201 ET is a guest soci across the worl Pharmacology This year, ASP 0 scientists from and Australasia.

Asia attracts over 1,00 pe, Euro rica, Africa, London. to you of y from North Ame to welcoming man we look forward Ben, the Abbey and Big cology rical Westminster ons and poster About Pharma oral communicati opposite the histo me already. plenary lectures, heart of London, the full program cal symposia, Located in the topi view of can ction You a sele pharmacology. of meeting includes trum spec the whole ities to build your rtun oppo sessions covering ng orki ts offering netw tion. If you have ber of social even e during registra e will be a num e for these onlin to say about the book your plac In addition, ther macologists have ections. You can what other phar international conn years, find out nt rece in . or year not been before video from last hing our short meeting by watc 6 out for in 201 me science What to look slating microbio of the bowel: Tran rding GPCR expression The long reach rega t symposium, nal and - new findings  The ASPET gues for systemic human diseases of newly recognized non-traditio role ets. into therapeutics tissues and the l therapeutic targ cell types and and as potentia of oral tion ber func in a variety of num n est orga larg in regulating abstracts, the orphan GPCRs tions of submitted y yet. platform presenta uate at Pharmacolog  At least 100 for student, grad to be included llite conference s communications y, a special sate Young Scientist olog ET’s mac ASP phar of from future n Tonsfeldt, your Society Kare ugh ists.  Shaping the thro re olog futu l pharmac ping the and post-doctora get involved: Sha discuss How to Committee, will membership. . s. Register now registration rate Registration reduced affiliate el available. are eligible for odation and trav ASPET members about accomm ion mat infor There is also . an abstract now tract ntime, if you tember. Submit Submit an abs ission is 9 Sep page. In the mea abstract subm to contact the ology 2016 web The deadline for on the Pharmac se don’t hesitate er information presenting, plea You can find furth questions about attending or al 7239 0176).

0 tion (0)2 addi +44 any or have ac.uk (meetings@bps.

Meetings Team er.

London in Decemb to seeing you in We look forward

ASPET is pleased to be a guest society at the British Pharmacological Society’s annual meeting Pharmacology 2016 in London.

Pharmacology 2016 will be held in the heart of London, opposite historic Westminster Abbey and Big Ben. The meeting will include a selection of topical symposia, plenary lectures, oral communications, and poster sessions covering the whole spectrum of pharmacology. In addition, there will be a number of social events offering networking opportunities so attendees can build international connections.

Best wishes, ara McDermott ical Society Professor Barb sh Pharmacolog – Meetings, Briti Vice President & r ical Society Talja Dempste sh Pharmacolog s & Events, Briti Head of Meeting

September 2016 • The Pharmacologist

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ASPET Guest Symposium The Long Reach of the Bowel: Translating Microbiome Science into Therapeutics for System Human Diseases Chairs: Pamela J. Hornby, Janssen (USA) and Ross Corriden, University of California, San Diego (USA) Speakers: Mohamed Donia, Princeton University (USA); Helen Cox, King’s College London (UK); Niall Hyland, University College Cork (Ireland); Jennifer Pluznick, Johns Hopkins Medical School (USA), Dean Falb, Synlogic (USA) The overall objective of this symposium is to present new findings regarding GPCR expression in a variety of cell types and tissues and the role of newly recognized non-traditional and orphan GPCRs in regulating organ function and as potential therapeutic targets.

At the end of the program the audience will have translational insights and a balanced view of the promise and challenges of microbiome hypothesis generation and testing, especially with respect to its metabolic role. They will also learn about the latest pharmacological tools and potential therapeutic approaches for drug discovery using bacteria.

ASPET Young Scientists Committee Chair Speaks at Pharmacology 2016 Karen Tonsfeldt, ASPET’s Young Scientists Committee Chair, will be discussing How to Get Involved: Shaping the Future Through your Society Membership at the special satellite conference, Shaping the Future of Pharmacology, for students and postdoctoral fellows.

View the full program at www.bps. ac.uk/pharmacology2016.

Booth Stop by ASPET’s booth to learn more about ASPET initiatives, programs, and member benefits.

Travel Awards ASPET is pleased to provide young scientists with travel awards to Pharmacology 2016. Award winners will be notified by October 15, 2016.

Registration ASPET members are eligible for reduced affiliate registration rates. Register now at http://bit.ly/2bTNT4r.

Save the Date for WCP2018 Kyoto 18th World Congress of Basic and Clinical Pharmacology: Pharmacology for the Future – Science, Drug Development, and Therapeutics July 1-6, 2018 Kyoto International Conference Center, Kyoto, Japan Stay tuned for further information about the program, registration, abstract submission, and ASPET travel awards to WCP2018.

http://www.wcp2018.org/index.html

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Science Policy News

Bipartisan Support for Research in Appropriations Process; Outcome Remains Uncertain Congress returns from summer recess with little hope of passing budget legislation before the fiscal year (FY) ends, shifting the primary focus to keeping the government from another shutdown. To that end, it is likely that Congress will have to pass another short-term continuing resolution (CR) to keep the government running while they negotiate either a sequestration relief deal or the terms of a yearlong CR.

The House and Senate passed all 12 appropriations bills through their respective committees, yet few will make it to the floor. Congressional leadership began the year determined to return the appropriations process to “regular order� by completing action on the FY2017 spending bills before September 30, but they left for a nearly two-month summer break, falling far short of what they hoped to achieve. There was little time

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dedicated to completing the appropriations process with legislators eager to return to their districts for the final days of the campaign cycle.

Although no decisions had been made as this issue went to press, the duration of the CR is already prompting a dispute among members of Congress.

House Republican leaders are said to be considering a temporary measure through March of 2017 in order to gain support from conservatives who indicated they will oppose any attempt to finalize the spending bills after Election Day. However, appropriators would prefer to adopt a shorter CR through early December and then return to Capitol Hill before Christmas to negotiate an omnibus bill combining all of the appropriations measures into a single package.

Representative Mike Simpson (R-ID), a member of the Appropriations Committee, noted, “Relying on a

continuing resolution for half of a fiscal year is hard for agencies to live with because such stopgaps merely extend current funding levels without allowing for any new spending projects or programs.”

Historically, Congress has been more inclined to adopt longer-term CR’s in election years. The retirement of Senate Appropriations Committee Ranking Member Barbara Mikulski (D-MD), as well as Republican Caucus rules that will require Senator Thad Cochran (R-MS) and Representative Hal Rogers (R-KY) to give up their chairmanships in 2017, are additional factors that may influence the outcome of the FY2017 appropriations process. All three lawmakers have indicated a strong interest in developing an omnibus spending bill while they still hold leadership roles on the appropriations committees.

House and Senate Appropriators Approve FY2017 Labor Health and Human Services (LHHS) Bills The Senate Appropriations Committee approved S. 3040 by a vote of 29–1. The spending measure provides an additional $2 billion for biomedical research, raising the National Institutes of Health (NIH) budget to $34.1 billion (a 6.2 percent increase). Within the $2 billion increase, the measure specified support for several NIH initiatives: • Precision Medicine – $100 million increase • Alzheimer’s Disease – $400 million increase • Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative – $100 million increase • Combating Antimicrobial Resistance – $50 million increase • Institutional Development Award Program – $12.5 million increase Following the lead in the Senate, the House LHHS – Education Appropriations Subcommittee approved its FY2017 spending bill, albeit with Democrats objecting to several provisions in the bill.

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The Committee approved the final bill by a vote of 31-19. The measure provides $33.3 billion for the NIH, an increase of $1.25 billion (4 percent) compared to the FY2016 level and $2.25 billion above President Obama’s request.

Noting that the Senate Appropriations Committee provided a $2 billion increase for the NIH, House LHHS Subcommittee Chairman Tom Cole (R-OK) said that the smaller increase in the House bill was “a floor, not a ceiling.” Others also highlighted the additional funding for NIH, including LHHS Subcommittee Ranking Member Rosa DeLauro (D-CT), House Appropriations Committee Chairman Hal Rogers (RKY), and Appropriations Committee Ranking Member Nita Lowey (D-NY).

Within the total for the NIH, the bill specified funding for the following initiatives: • $511.5 million for Clinical and Translational Sciences Awards • $333.3 million for the Institutional Development Award Program

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• $350 million increase for Alzheimer’s research • $195 million for Brain Research through Advancing Innovative Neurotechnologies Initiative • $300 million for the Precision Medicine Initiative • $12.6 million for pediatric cancer research

Partisan fighting over amendments stalled the completion of the process despite the passing of the individual spending bills. The House passed only five of the 12 measures; the Senate approved three, including the bill that funds the Department of Energy Office of Science.

Senate Pushes Back Work on “Cures” Legislation In April, a successful bipartisan committee process approved the last of 19 bipartisan pieces of legislation that complete the Senate companion to the House 21st Century Cures Act. The Senate had optimistically maintained that a Cures bill reaching the floor was eminent; but as has been the case so often with this Congress, lawmakers all but abandoned the effort before departing for summer recess.

The House’s 21st Century Cures Act was generated from the passage of H.R. 6 on July 10, 2015 on a vote of 344 to 77. H.R. 6 is the result of a series of hearings and roundtable meetings hosted by the House Energy and Commerce Committee dating back to spring 2014. While consisting of many different provisions, H.R. 6 is primarily focused on efforts to increase strategic investments in medical research at the NIH and change some aspects of how the Food and Drug Administration (FDA) executes its regulatory oversight mission with regard to the review and approval of new drugs, biologics, and medical devices. Similarly, the Senate bills support medical innovation, primarily through reforms within the Department of Health and Human Services (HHS) including the NIH and changes to the drug, biologic, and device approval pathways at the FDA. Despite the limited window of time, not all hope is lost and some are not declaring the effort dead.

Senate Health Committee Chairman Lamar Alexander (R-TN) said in July that he hopes the Senate can

reach an agreement and pass the legislation in the fall. “This could be the most important legislation Congress passes this year, and there’s no excuse for not finishing our work in September,” the chairman said in a statement, noting that the package would include funding for President Obama’s Precision Medicine Initiative and Vice President Joe Biden’s cancer research program.

However, Senators are less optimistic that much progress can be made in the height of the election season. If the legislation fails to come to the floor before the election, it would remain possible to finish the work in a “lame duck” session of Congress, when lawmakers often try to pass stalled bills at the last minute.

Despite bipartisan support for the effort, legislation has been stalled for weeks as Republicans have struggled with Democrats over funding levels and what programs should be cut to pay for it. Since the bills made it out of committee, a fierce battle over how much money the NIH should receive has been brewing on both sides of the aisle. Some Republicans are trying to make cuts to other HHS programs to pay for the new funding, while Democrats have been pushing for mandatory NIH funding.

This legislation is critical to the biomedical research community and the progress made in both chambers is a testament to growing understanding of the importance of medical research.

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Education News Revised Pharmacology Patient-Oriented Problem-Solving Exercises Now Available Submitted by Mark A. Simmons, PhD Over the last year and a half, members of the ASPET Division for Pharmacology Education have been working on revisions to the Patient-Oriented Problem-Solving (POPS) System in Pharmacology exercises. Nine of these exercises are now available to be downloaded from the ASPET website.

The POPS were originally developed in the 1980s as part of the movement to provide students with more problem-solving sessions. Framed by a pretest and posttest, groups of four students work

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on a patient-oriented problem. Each student in the group has access to a different set of information to solve the problem. The first POPS was published by the Upjohn Company in 1985. Twelve POPS were eventually developed between 1985 and 2000 but had not been revised since that time.

Several recent developments led to the POPS revision project. There has been a continued interest in giving students opportunities for active learning.

There is also a need for pharmacology-specific learning activities. Furthermore, there have been substantial changes in therapeutic guidelines, many new drugs are available, and the technology for delivering educational content is vastly different than when the exercises were last revised.

The POPS should serve the needs of those who teach pharmacology by providing a pharmacology-focused platform for active learning. The authors have made an effort to make the POPS useful for educating students in various health science professions and for interprofessional education.

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Description of the POPS System

History of the POPS System

The POPS System in Pharmacology is a series of exercises consisting of simulations of clinical problems. The exercises have been designed to be used in small group meeting sessions to supplement the teaching of pharmacology to first- or second-year students in the health professions.

Each exercise is designed for a group of four students, although modifications can be made for other group sizes. Prior to the group meeting, the students independently complete a pretest and review the learning objectives. During the group session, the students first discuss the answers to the pretest questions and then delve into the clinical scenario. Each student is given a portion of the information required to solve the problem.

Each student’s part contains answers to a subset of the pretest questions and information about one episode of the clinical problem. Thus, the students must exchange information and work together to arrive at potential solutions. After the group session, the students complete a posttest. The pretest and a posttest thus provide a mechanism for measuring individual learner achievement.

The original POPS System, Patient-Oriented Problem-Solving System in Immunology, was developed in 1974 by Drs. Parker A. Small, Susan M. Johnson, and Eldon J. Ullmer at the University of Florida. Pharmacology POPS exercises were subsequently developed by a team of 11 pharmacology faculty from six eastern medical schools. The exercises were supported by the Upjohn Company, with six topic areas published and distributed in 1985. Three of the original six exercises were later updated and rewritten. Six additional topics were added to the original six topics, and were made available as paper booklets that were obtained, free of charge, by contacting Upjohn Company Medical Services Liaisons. Upjohn merged with Pharmacia in 1995, then with Monsanto and Searle in 2000, and the joint companies became part of Pfizer in 2002.

A description of the development and evaluation of the original six pharmacology POPS System exercises has been published (Burford HJ, Ingenito AJ, Williams PB. Development and evaluation of patient-oriented problem-solving materials in pharmacology (1990) Academic Medicine 65(11):689693). This paper contains details on the educational validation of the exercises along with data establishing that the exercises improve learning of the subject materials.

In the 1990s, the rights to the POPS exercises were transferred to the Association of Medical School Pharmacology Chairs (AMSPC). A formal proposal was developed in 2014 by Dr. Mark Simmons to revise all of the exercises in cooperation with ASPET and the AMSPC. This process has been greatly facilitated by Dr. Catherine Fry, who joined ASPET during the summer of 2014 and serves as the director of education. Drs. Fry and Simmons serve as co-editors of the series.

During 2015 the updated exercises were completed and sent out for peer review. The first five revised exercises were rolled out at a Division for Pharmacology Education symposium at the ASPET Annual Meeting at EB2016 in San Diego, CA.

Purpose of the POPS System The POPS system is designed to help students learn how to apply basic science knowledge to the solution of clinical problems. The exercises encourage students to find information necessary for solving problems by using sources (e.g., textbooks, online resources, and peers) that are available to health care professionals throughout their careers. The format of the exercises requires students to work together and thus: 1) increase their ability to evaluate their colleagues’ opinions, thought processes, and diagnoses; 2) improve their communication skills; and 3) increase their skills in interpersonal and interprofessional relations.

Practical applications of pharmacological principles to therapeutics often involve the exercise of clinical judgment, wherein opinions between practitioners may differ. Often there are no absolute rights or wrongs. It is hoped that these exercises will provide some insight into the notion of controversy in clinical judgment.

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Currently Available POPS Exercises The topics covered in the currently available POPS exercises are: Title Antimicrobial Chemotherapy Cancer Chemotherapy Chemotherapeutic Challenges Complications of Analgesic Therapy* Drug Therapy of Congestive Heart Failure Drug Use in the Elderly* Heavy Metal Toxicity* Pharmacokinetics Applied to the Treatment of Asthma Treatment of Psychosis Therapy of Diabetes Mellitus Treatment of Cardiac Arrhythmias Treatment of Essential Hypertension

Authors Claudine El-Beyrouty, Brian Roslund, and Bhavik Shah Dennis Peffley Katharina Brandl, Sarah Lerchenfeldt, and Amit K. Tiwari Mark J. Hernandez and Drew Zimmer Rob Rockhold A. Laurel Gorman and Mariana B. Dangiolo Robert Theobald, Jr. David C. McMillan Gagani Athauda, Autumn Ning, and Timothy Holley Jayne S. Reuben June Yun Mark A. Simmons

* Pending final revisions

The revised exercises are available on the ASPET website at http://bit.ly/2axzQij. Faculty can download

the appropriate files along with an Instructor’s Manual that provides guidance in implementing the exercises.

Graduate Students and Postdoctoral Scientists: Apply to Join the ASPET Mentoring Network The ASPET Mentoring Network: Coaching for Career Development is a program designed to supplement the training that graduate students and postdoctoral trainees receive through their university programs.

The ASPET Mentoring Network will focus on developing skills needed to succeed scientifically, professionally, psychologically, and socially, including discussions about experiences and pressures faced by groups that are underrepresented in the sciences. As a professional development experience, the program uses a coaching model to help participants develop success skills for a variety of careers.

Graduate students and postdoctoral scientists accepted into the 2017-2018 program will attend several events in association with Experimental Biology 2017 in Chicago, IL. These will include training and an informal reception on Friday, April 21; a halfday program on Saturday, April 22; and the Graduate Student-Postdoctoral Colloquium on Saturday

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afternoon. During this time, trainees will meet faculty coaches, other students and postdocs, and become part of a 6-person coaching group. Each trainee will also meet individually with their coach during the EB2017 meeting and participate in virtual group meetings throughout the year. Group events will be tailored to the specific needs of each coaching group, but may focus on work/life balance, interview skills, communication, networking, and other topics frequently identified as important to growth as a professional.

Who Is Eligible?

Graduate students and postdoctoral scientists who are members of ASPET are eligible to apply. If you’re not a member, it’s easy to join! Please visit https:// www.aspet.org/membership/.

What Support Is Provided?

Applicants accepted into the program will receive a $1000 travel award to defray travel and housing

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costs to attend EB2017, complimentary registration, and meals during the program. Applicants are encouraged to present an abstract at EB2017, but it is not required to be eligible to apply. Please note that if you are accepted into the program, you will not be eligible to receive any other ASPET travel awards for EB2017.

What Do Previous Participants Have to Say about the Program?

The inaugural cohort of ASPET’s Mentoring Network shared the following feedback about the 2016 program:

ASPET Mentoring Network participants attending the ASPET Business Meeting at EB2016.

Our group instantly connected with each other, and it was amazing to see how much we all had in common. We support each other and plan monthly goals, which motivates us to achieve them. Most importantly, sharing each other’s experiences helps us gain valuable insights.

– Suleman Hussain, graduate student, University of Texas Health Science Center at San Antonio One memorable feature of the ASPET Mentoring Network is that it provides an open forum in which to discuss the ways our lives fit in and around science. Even though our discussions have been adeptly facilitated by established pharmacologists as mentors, of value to me has been the opportunity to interact with and learn from my peers. Despite many of us being in different pharmacology-focused fields, it is these relationships that will be most valuable as we all transition towards becoming independent scientists. I recommend participating in this program enthusiastically and without reservation.

– Cam McCarthy, postdoctoral scientist, Augusta University ASPET’s Mentoring Network is a valuable platform, not only to pursue career guidance from well-established scientists but also to develop scientific collaborations with peers. I am finding my dedicated coaching group very helpful for designing my outlook towards future opportunities and challenges. I am really happy to have become part of this excellent program.

– Amreen Mughal, graduate student, North Dakota State University Participating in the ASPET Mentoring Network has significantly expanded my network in the ASPET community and has provided me with wonderful mentors and fellow mentees that support each other both professionally and personally. I’ve enjoyed hearing stories and getting career advice from a diverse group of people who are at different stages of their careers with varied experiences.

– Sophia Kaska, graduate student, Michigan State University Seeking sincere mentorship from experts in the field is crucial for achieving success. ASPET’S Mentoring Network program has provided me a unique lifelong opportunity to cultivate a strong mentor-mentee relationship and seek guidance on anything and everything for successful professional development. Moreover, the program has brought together trainees who face similar challenges during early scientific careers, which allows us to network with each other, along with mentors and find common solutions to any challenges we face.

– Naeem Patil, postdoctoral scientist, Vanderbilt University Medical Center

How Do I Apply?

The application for the ASPET Mentoring Network can be found at https://www.aspet.org/Education/ ASPET_Mentoring_Network/ and is due by Friday, November 18, 2016.

For more information contact Dr. Catherine L. Fry at cfry@aspet.org.

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ASPET’s Newest Funding Opportunity, Pharmacology Industry Internships for PhD Students (PIIPS)

Established through the BIG IDEAS I initiative, the Pharmacology Industry Internships for PhD Students (PIIPS) program provides a unique funding opportunity to create institutional programs that will provide PhD students with experience in industrial settings, such as the pharmaceutical/biotechnology or government regulatory sectors, while enrolled in graduate school.

The objectives of the PIIPS program include:

• Increase opportunities for PhD students enrolled in graduate programs with an emphasis on pharmacology to participate in industrial internships during their graduate training.

• Develop and foster university–industry partnerships facilitating diversity in graduate training and career options related to pharmacology.

• Facilitate opportunities for PhD students to make informed decisions about careers in the pharmaceutical and biotechnology sectors as well as other allied disciplines such as the FDA and Contract Research Organizations.

• Increase participation by industrial organizations in graduate student internships.

The first applications to this program were invited over the summer, and we thank those who applied.

Funding announcements will be made by November 1, 2016. We are excited to offer this new program and look forward to working with the funded institutions.

SURF Alumni: Share Your Stories for the 25th Anniversary!

Since 1992, ASPET has been proud to fund undergraduate pharmacology research through our Summer Undergraduate Research Fellowship (SURF) program.

We look forward to commemorating the 25th anniversary of SURF in 2017! For the anniversary, we will unveil a new SURF webpage, anniversary booklet, and other celebratory materials. We are inviting alumni of the program to share their “SURF stories”, representing a range of participation years, career outcomes, and geographic regions. ASPET The Pharmacologist • September 2016

would like to know: What did the fellowship mean to you? Did the experience shape your career path or provide you with new opportunities?

Fellows from both the institutional and individual programs are invited to respond. Participation is voluntary, and your story may be chosen to include in our anniversary materials. If we do select your story for use in any of our materials, we will inform you.

Please use the following link to contribute: https:// www.surveymonkey.com/r/SURFstories.

Any questions may be directed to Dr. Catherine L. Fry at cfry@aspet.org.

We look forward to hearing from you!

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Journals News Peer Review Week 2016

Reprinted from https://peerreviewweek.wordpress.com/help-us-promote-peerreview-week

ASPET journals are proud to take part in Peer Review Week 2016, which is September 19-25. Peer Review Week is a global event, celebrating the indispensable role peer review plays in the quality of scientific publishing. The theme of this second annual Peer Review Week is “Recognition for Review,” which will examine how those involved in all types of review should be acknowledged for their contributions.

ASPET recently initiated a reviewer acknowledgment program, thanking reviewers for their contributions to ASPET’s four wholly owned journals, Pharmacological Reviews, Journal of Pharmacology and Experimental Therapeutics, Drug Metabolism and Disposition, and Molecular Pharmacology.

Peer Review Week 2016 will include interviews, webinars, and social media activities set up to improve understanding of peer review and its impact on scholarly publishing. A list of peer review resources is available at http://www.preval.org/prw/.

ASPET’s editors noted the importance of peer review to scientific publishing:

“Peer review is the gold standard by which science is evaluated.

Only scientists working in or close to the field of study can judge adequately the rigor, novelty and impact of a publication. One of the advantages of publishing in a society journal is that the editors and editorial board are experts in the field, almost all of whom have ongoing research programs of their own.”

Edward T. Morgan, Editor, Drug Metabolism and Disposition “The integrity of the scientific process depends heavily on the rational assessment of those critical thought processes presented in the scientific literature. Without the objectivity and significant time commitment from dedicated editors and reviewers, the system would be inviable. As scientists we know that peer review can sometimes be flawed, but just as ’democracy is the worst form of government, except for all the others’ (ascribed to Churchill, 1947), it remains the best of all alternatives.”

Kenneth Tew, Editor, Journal of Pharmacology and Experimental Therapeutics “Peer review remains a cornerstone of scientific publishing and an essential component of the scientific endeavor. The careful and objective reviews provided both improve the quality of the scientific studies as well as ensure that scientific reports can be read with confidence that they are technically, analytically, and logically sound.

The willingness for reviewers to fit these tasks into their already full workdays and maintain an objective focus is invaluable.”

Stephen Traynelis, Editor, Molecular Pharmacology ”Independent peer review of original scientific contributions to pharmacology journals is essential to move the pharmacological sciences forward by fostering publication of tests of clearly defined hypotheses that are rigorously tested and thoughtfully discussed. This needs reinforcing in today’s scientific publishing environment, where there is a proliferation of journals that are not requiring careful review prior to publication. Pharmacology journals that maintain a tradition of independent and critical review need to be recognized as separate and distinct from those that do not.”

Darrell R. Abernethy, Editor-in-Chief, Pharmacology Research & Perspectives

ASPET is grateful to all who serve as reviewers for our journals. Those interested in serving as reviewers should register with our online manuscript system. Including a complete list of expertise terms is critical to finding the best match between a manuscript and qualified peer reviewers.

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Kathryn E. Meier Named Next Editor of Molecular Pharmacology ASPET’s Board of Publications Trustees has selected Dr. Kathryn E. Meier to succeed Dr. Stephen F. Traynelis as the next editor of Molecular Pharmacology. Dr. Meier will fully assume the editorship in January 2017 when Dr. Traynelis’ term will end. Dr. Meier’s appointment as editor culminates a selection process that began in March of this year.

Dr. Meier received a BA in biology, cum laude, from the University of California, San Diego, and a PhD in pharmacology from the University of Wisconsin, Madison. She was an NIH predoctoral trainee with the Department of Pharmacology, School of Medicine, University of Wisconsin and an NIH postdoctoral fellow in the Division of Pharmacology, Department of Medicine, University of California, San Diego, where Dr. Paul Insel was her mentor.

She has held positions with the Howard Hughes Medical Institute in the Department of Pharmacology, University of Washington, and with the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and the Hollings Cancer Center at the Medical University of South Carolina. Since 2003, she has been with Washington State University in the Department of Pharmaceutical Sciences (professor), where she has held several administrative positions (chair, Pharmaceutical Sciences; interim assistant dean for curriculum and research affairs; director, Program in Nutrition and Exercise Physiology). Since

2013, Dr. Meier has been associate dean for graduate education for the College of Pharmacy at Washington State University.

Dr. Meier’s laboratory studies the molecular pharmacology of signal transduction, with a recent focus on GPCR receptor-mediated mechanisms by which omega-3 fatty acids inhibit the growth of certain cancers. Her research has generated over 80 articles and book chapters and nearly 100 published abstracts.

Dr. Meier has been an ASPET member since 1994. She has been a member of the Division for Molecular Pharmacology, serving as secretary/ treasurer, and was a member of the Short Course/ Continuing Education Committee. Dr. Meier will complete her term on ASPET’s Board of Publications Trustees at the end of 2016. She has served as the ASPET representative to the FASEB Publications and Communications Committee. She is also a member of the American Association for the Advancement of Science and the American Physiological Society.

Prospective Molecular Pharmacology authors should note that the manuscript submission process will not change with the change in editors. All submissions will continue to be handled through the journal’s online manuscript system (http://submitmolpharm.aspetjournals.org).

More information about Dr. Meier’s background is included in the announcement published in the Molecular Pharmacology October issue at http://bit.ly/2bqI25l.

New Editorial Board Members The Board of Publications Trustees is pleased to welcome Dr. David Taylor at East Carolina University and Dr. Jack Yalowich at Ohio State University to the JPET Editorial Advisory Board.

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Membership News Participate in the Member-Get-A-Member Campaign When new members are asked, “How did you hear about ASPET?,” the number one answer is through a colleague, mentor, or friend. Members, like you, are already recruiting new members to ASPET. Why not get credit for your efforts and possibly win prizes?

Participate in the ASPET Member-Get-A-Member program to be entered into a raffle to win an American Express gift card. The more members you recruit, the higher the gift card amount!

By helping us recruit new members, you will be contributing to the growth and sustainability of ASPET. 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.

How the Program Works:

Prizes

1. Tell your colleagues, students, and friends about the benefits of ASPET membership. See a full listing of member benefits.

2. Encourage them to fill out an application form online.

3. Tell the applicant that they must enter your name and email address in the “Sponsor Name/Email” field on the application form.

4. Tell the applicant that they must enter the marketing code “MGM” in the field that asks, “Where did you hear about ASPET?” 5. Once they are approved for membership and their dues payment has been made, you will receive credit for your recruitment efforts.

6. The more members you recruit, the higher the prize drawing in which you will be entered.

7. Every MGM participant will be recognized for their recruitment efforts on our website and in The Pharmacologist.

8. Prize drawings will be picked in February 2017.

• Recruit 1-2 new members to be entered into the $25 American Express gift card drawing.

• Recruit 3-4 new members to be entered into the $50 American Express gift card drawing.

• Recruit 5+ new members to be entered into the $75 American Express gift card drawing.

Helpful Tips • Student membership in ASPET is FREE for the first year. Get your friends and students to apply for membership.

• Start with your department – check to see if your friends, colleagues, and students in your department are members. If not, ask them to apply!

• Contact the ASPET membership department if you need any recruitment materials such as membership brochures, flyers, and application forms.

If you have any questions about this program, please email the membership department or call 301-634-7060.

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ASPET Commemorates the Following Members for Their 50 Years with the Society Mario D. Aceto, PhD Martin W. Adler, PhD Amir Askari, PhD Floyd E. Bloom, MD Charles R. Boshart, PhD Warren S. Chernick, DSc Lincoln Chin, PhD Samuel A. Cucinell, MD Rose Dagirmanjian, PhD Lloyd E. Davis, PhD, DVM Maurice B. Feinstein, PhD John J. Fudema, PhD William F. Geber, PhD

Theodore Goodfriend, MD Lowell M. Greenbaum, PhD Albert Grossman, PhD Donald C. Harrison, MD David M. Jacobowitz, PhD Norman B. Javitt, MD, PhD Sarah C. Kalser, PhD Irwin J. Kopin, MD Josep G. Llaurado, MD, PhD Benedict Lucchesi, MD, PhD Robert H. McDonald, MD John H. Mennear, PhD Jose M. Musacchio, MD

Roger F. Palmer, MD Alan M. Poisner, MD Thaddeus P. Pruss, PhD Joseph D. Robinson, MD Robert L. Russell, PhD Harry Salem, PhD Emil R. Smith, PhD Solomon H. Snyder, MD Edwin Uyeki, PhD Roberto Vargas, MD, PhD Horacio Vidrio, MD Richard M. Welch, PhD Richard J. Wurtman, MD

A special thanks to everyone who participated in the 2016 ASPET Member Survey for Strategic Planning Priorities. The survey explored six specific areas including: • ASPET strategic priorities—actions and outcomes that unify members in common purpose • Changing pharmacology identity—issues shaping the future of the discipline and profession • Change drivers—trends and issues affecting scientists, institutions, and organizations • Potential member programs and services—new or expanded ways to meet your needs • Your membership experience—how you value different aspects of your ASPET membership • ASPET scientific journals—factors that influence your decision to publish your research in ASPET journals By sharing your perspectives on these areas, you have greatly helped the ASPET Council in planning for the future strategic direction of the Society. We look forward to sharing the results and outcomes of the survey and strategic planning process soon.

S p o t t h e D i ffe re n c e .

Answer key for puzzle on the back cover.

1. The light on the second row in the ceiling is gone.

2. The Exit sign is now red.

3. The purple journal standing up on the table to the right side of the photo is flipped upside down.

4. The first circle on the large ASPET sign is now peach instead of green.

5. Some of the circles are removed from the Shop ASPET poster.

6. The price tag on the white ASPET shirt (second from left) has been removed.

7. The ASPET logo on the stuffed donkey (middle one in first row on table) is gone.

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New Members REGULAR MEMBERS Wendell S. Akers, Lipscomb Univ Coll of Pharmacy, TN Ashley Amirhamzeh, CA John W. Calvert, Emory Univ, GA Joo Youn Cho, Seoul National Univ Coll of Med & Hospital, South Korea Elizabeth A. Dierks, Bristol-Myers Squibb, NJ John W. Elrod, Temple Univ, PA Brett C. Ginsburg, Univ of Texas HSC William Gordon, GNF, CA Sumanta K. Goswami, Univ of California Leslyn A. Hanakahi, Univ of Illinois, Chicago Tracy M. Handel, Univ of California, San Diego Niresh Hariparsad, Vertex Pharmaceuticals, MA Elizabeth A. Heller, Univ of Pennsylvania Yoshikazu Imanishi, Case Western Reserve Univ, OH Denise M. Inman, Northeast Ohio Med Univ Jagdish K. Jaiswal, The Univ of Auckland, New Zealand Melanie S. Joy, Univ of Colorado Sch of Pharmacy Simon Kaja, Loyola Univ Chicago, IL Kyung Bo Kim, Univ of Kentucky Weidong G. Lai, Eisai Inc., MD Xue-Jun Li, Univ of Illinois Bo T. Lindmark, AstraZeneca R&D, Gothenburgh, Sweden Moses O. Oyewumi, Northeast Ohio Med Univ Xiufeng Pang, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal Univ Keshab R. Paudel, Trinity Sch of Medicine, St Vincent and the Grenadines Girish Ramaswamy, Univ of Pennsylvania Monsheel Sodhi, Univ of Illinois David Webb, Univ of Edinburgh, United Kingdom

POSTDOCTORAL MEMBERS Ebunoluwa R. Asenuga, PhD, Univ of Benin, Edo State, Nigeria Shannon R. Blume, Children’s Hospital of Philadelphia, PA Mirza Bojic, Univ of Zagreb, Croatia Wen An Pan, Univ of California, San Diego Farhana Sakloth, Virginia Commonwealth Univ Peter O. Ughachukwu, Chukwuemeka Odumegwu Ojukwu Univ, Nigeria

GRADUATE STUDENT MEMBERS Temitayo E. Adeyeoluwa, Univ of Ibadan, Nigeria Ammar M. Ahmedani, African City of Technology, Sudan Hasan Aldewachi, Sheffield Hallam Univ, United Kingdom Adam D. Ambrosetti, Samford Univ McWhorter Sch of Pharmacy, AL Edwin J. Arauz, Univ of Florida/ Center for Environmental & Human Toxicology Sunil Bhurtel, Yeungnam Univ, South Korea Chris Bolden, Univ of Arkansas for Med Sciences Allison D. Brackley, Univ of Texas HSC at San Antonio Maisa Correa de Oliveira, Southern Methodist Univ, TX Philip M. Cox, Johns Hopkins Univ Sch of Med, MD Michael Crosby, Univ of Toronto, Canada Amanda H. DeBrot, Univ of Alabama at Birmingham David L. Ebenezer, Univ of Illinois at Chicago Mohammad Ebrahimi Kalam, North Carolina A&T State Univ Huijie (Jade) Feng, Michigan State Univ

Rachel J. Fenske, Univ of Wisconsin, Madison Philip T. Gallo, Rutgers Univ, NJ Taylor A. Gentile, Temple Univ Lewis Katz Sch of Med, PA Jingwen Huang, Florida State Univ Nicole M. Nieves Aviles, Univ Central del Caribe, Puerto Rico Jonathan M. Ploeger, Univ of Minnesota Christopher E. Ruth, Univ of Arkansas Thomas Solomon, James L Winkle Coll of Pharmacy, OH Jennifer J. Terpstra, Univ of Arizona Pierre Thibeault, Univ of Western Ontario, Canada Miriam Zegeye, Imperial College London, United Kingdom Yitong Zhao, Florida State Univ

UNDERGRADUATE STUDENT MEMBERS Maxine A. Abustan, Univ of Rhode Island Phillip J. Adams, Clemson Univ, SC Serena Agrawal, Univ of Texas HSC San Antonio Valeryia Aksianiuk, Univ of Pennsylvania Sri Sai Swetha Atluri, Univ of Arizona Jogen Atone, Trinity Univ, TX Malachi Barnett, Florida Inst of Technology Brianna L. Bauer, The College of Wooster, OH Shruti Bidani, Univ of Pittsburgh, PA Emily Bonacquisti, Univ at Buffalo, NY Jordan T. Brooks, Walla Walla Univ, WA Darlyn T. Caraballo-Pérez, Univ of Puerto Rico at Arecibo Michael A. Chepanoske, Washington & Jefferson Coll, PA Alexandra B. Choate, Univ of Texas at Austin Erin Choi, Rutgers Univ, NJ Brendan J. Connolly, Johns Hopkins Univ, MD

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Leandrew A. Dailey, Fort Lewis College, CO Kiana E. Dash, Hampton Univ, VA Rachel Davidson-Knapp, Univ of Arizona Ana Defendini, Univ of Puerto Rico Rio Piedras Campus Emily A. Diaz, Hofstra Univ, NY Jennifer Diaz, Univ of Illinois Paula Dorcenat, Bethune Cookman Univ, FL Sydney L. Drury, York Coll of Pennsylvania Mary C. Egwim, Tufts Univ, MA Nader C. Elkhechen, Univ at Buffalo (SUNY), NY Bailey J. Englund, Augustana Coll, IL Taylor P. Enrico, Colby Coll/Case Western Reserve Univ, OH Ashton D. Faler, The Univ of Findlay, OH Zalman Faltushanskiy, Loyola Univ Medl Center, IL Reed S. Geisler, Cornell Univ, NY Carly M. Gerhardt, Michigan State Univ Elaine M. Gersz, Muhlenberg Coll, PA James D. Gesualdi, Rowan Univ, NJ Julisa G. Gonzalez, San Diego City Coll, CA Sara I. Graves, Gustavus Adolphus Coll, MN Cassidy A. Guida, Stony Brook Univ, NY Lisa C. Gutgesell, Missouri Univ of Science & Technology Malika Hassel, Aurora Univ, IL Daniel G. Hicks, Univ of Arkansas for Med Sciences Miriam Hill-Odom, Xavier Univ of Louisiana Kirk A. Hofman, Univ at Buffalo (SUNY), NY Amanda A. Hoskins, Univ of Kentucky Erin Hunt, Fordham Univ, NY Dillion Hutson, Tulane Univ, LA Alexander F. Infante, Univ of Illinois at Chicago Bojan Isakov, Univ of Arizona Emily N. Johnson, Univ of Texas HSC San Antonio Jasmine K. Johnson, The Univ of Arkansas at Pine Bluff Yvette Kayirangwa, Spelman Coll, GA Brian Kim, Univ of Illinois at Chicago

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Scott E. King, Washington & Jefferson Coll, PA Wendy R. Klein, George Mason Univ, VA Elizabeth A. Knauss, Muskingum Univ, OH Brandon H. Koo, Rensselaer Polytechnic Inst, NY Christina R. Kresser, Univ of North Carolina at Chapel Hill Sydney M. Lammers, Univ of Kentucky Eli A. Lavender, Sewanee: The Univ of the South, TN Henry Lee, Univ of California, San Diego Sanggil Lee, Seoul National Univ, South Korea Jennifer Li, Stony Brook Univ (SUNY), NY Fatima Lima, Univ of Michigan Jennifer Liu, Univ of California, Santa Cruz Jacob Z. Longenecker, Ferris State Univ, MI Hannah Y. Lu, Univ of Texas HSC San Antonio Zhuoyan Lu, Vanderbilt Univ, TN Atri G. Maharaj, Stony Brook Univ (SUNY), NY Allison K. Mak, Vanderbilt Univ, TN Riya Malhotra, Michigan State Univ Daniel T. Manjooran, Univ of Pittsburgh, PA Joel R. Marty, Western Michigan Univ Grace A. McCarthy, Washington & Jefferson Coll, PA Patton C. McClelland, Carleton Coll, MN Hilda Mejia Pena, Univ of California, San Diego Maria C. Miggs, Univ of North Carolina at Chapel Hill Brian M. Miller, Univ of Pittsburgh, PA Mark M. Mizrachi, Stony Brook Univ (SUNY), NY Jomar Morales Mercado, Univ Metropolitana, Puerto Rico Jordan C. Moretta, Univ of Florida Riley D. Mullins, The Ohio State Univ Kayla V. Myers, Boston Univ, MA Nihal Narsipur, Rutgers Univ Ernest Mario Sch of Pharmacy, NJ Sarah S. Oh, Rutgers Univ, , NJ Ji Young Park, Rutgers Univ, NJ Darren C. Peel, Michigan State Univ Ashley E. Peppriell, SUNY Geneseo, NY

Carlos A. Perez-Heydrich, Univ of North Carolina at Chapel Hill John D. Pina, Univ of Kentucky Alexa M. Pinsky, Univ of Michigan Matthew J. Pleshinger, The Coll of Wooster, OH Demisha D. Porter, King Univ, TN Richard R. Potter, Univ of Pittsburgh, PA Timothy X. Qi, Univ of North Carolina at Chapel Hill Katherine A. Qualls, Univ of Mary Washington, VA Elizabeth H. Quaye, Univ at Buffalo (SUNY), NY Katherine A. Rogers, Univ of Texas HSC San Antonio Sergio I. Salazar, San Diego City Coll, CA Francisco G. Sanchez-Conde, Grinnell Coll, IA Ciara G. Sanon, Univ of Florida Brian R. Schuler, Univ of Findlay, OH Brianna L. Scotland, Virgin Islands Alaa M. Shahare, Univ of Arkansas for Med Sciences Ami Shiddapur, Univ of North Carolina at Chapel Hill Jaden D. Shirkey, Case Western Reserve Univ, OH Jerry Sicalo, Washington State Univ Andrew M. Silberfeld, Univ of Pittsburgh, PA Mackenzie P. Snyder, Univ of Virginia Luke N. Soucie, Northern Michigan Univ Nneka I. Southwell, Rochester Inst of Technology, NY Victoria K. Spadafora, Pennsylvania State Univ Katya M. Sracic, Univ of Virginia Ian T. Stukes, Sandy Springs Friends School, MD Mary H. Swaney, Penn State Univ, PA Trinny Tat, Univ of Arizona Rick D. Tenorio, Univ of California, San Diego Michael P. Trahan, BUAMS, AR Matthew T. Tran, Hendrix College, AR Latia M. Tucker, Hampton Univ, VA Meghan B. Turner, Univ of Kentucky Sebastian S. Velazquez, Univ of Puerto Rico, Rio Piedras Campus

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Amanda M. Wahl, St. John Fisher College, NY Nathan W. Wainscott, Univ of Louisville Christopher A. Wallace, Walla Walla Univ, WA Helen Y. Wang, Rutgers Univ, NJ Meghan N. Watkins, Whitworth Univ, WA

Natasha V. Wells, Univ of North Carolina at Pembroke Dayna Wilmot, MIT, MA Jessica M. Xiao, Rutgers Univ Ernest Mario School of Pharmacy, NJ Hyeon Jeong Yang, Rutgers Univ, NJ Natalia A. Zaliznyak, Yale Univ, CT Nathalie P. Zavala, Stony Brook Univ (SUNY), NY

Daniel Zeitouni, Univ of North Carolina at Chapel Hill Eric M. Zhang, Northeastern Univ, MA Laetitia X. Zhang, Johns Hopkins Univ, MD

RENEW YOUR MEMBERSHIP FOR 2017 Thank you for your membership in ASPET this year. With your support, ASPET was excited to introduce several new programs including activities to enhance undergraduate student engagement at our annual meeting and the Pharmacology Industry Internships for PhD students program. We are looking forward to another exciting year as we finish up our Society’s strategic planning process and as we gear up for our 2017 annual meeting in Chicago. Be sure to renew your membership to take advantage of all the member benefits ASPET has to offer.

To Renew: Visit www.aspet.org and log in to the member homepage. If you have any questions about your membership renewal or need assistance logging in, contact membership@aspet.org.

Be one of the first 1,000 members to renew and be entered in a raffle drawing for a $50.00 American Express gift card!

Thank you for your continued support!

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Members in the News Achievements, Awards, Promotions, and Scientific Breakthroughs Dr. Mark Hernandez Dr. Mark Hernandez has accepted a nomination to serve on the Board of Directors for the International Association of Medical Science Educators (IAMSE). IAMSE is a nonprofit professional development society organized and directed by health professions educators whose goals include promoting excellence and innovation in teaching, student assessment, program evaluation, instructional technology, human simulation, and learner-centered education. Dr. Hernandez is looking forward to his continued service to ASPET’s Division for Pharmacology Education, and also his new role on IAMSE’s Board of Directors.

Dr. Mark Hernandez Alabama College of Osteopathic Medicine

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Division News Division for Translational and Clinical Pharmacology The ASPET Division for Translational and Clinical Pharmacology (TCP) offers numerous opportunities aimed at career development for young scientists. Some of the recent initiatives include: • Informational interviews with successful scientists in academia and industry (published on the ASPET website.) (https://www.aspet.org/ISTCP/Resources/).

• “Meet-the-Experts” Luncheon and Early Career Faculty Showcase at the ASPET Annual Meeting at Experimental Biology.

• Careers in Translational and Clinical Pharmacology site visits. (http://bit.ly/1OAeuOg).

• Pharmaceutical industry internship in medical affairs at Ferring Pharmaceuticals.

Please visit the informational interview series on the TCP division website to know what experts have to say regarding their journey to a successful career path in academia and industry.

Our “Meet-the-Experts” Luncheon has been a very successful event at the ASPET Annual Meeting at Experimental Biology 2015 and 2016. Trainees have benefited from networking with established scientists in academia and industry, and have cultivated successful mentee-mentor relationships for career advancement.

Selections have been made for the one day site visit opportunity to Janssen Pharmaceuticals (Monica Javidnia, Naeem Patil, Sukhada Bhave and Narasimha Midde) and a USDA facility (Farhana Sakloth and Blessy George) for 2016. In a future issue of The Pharmacologist, we will report on individual trainee experiences. In the meantime, Dr. Phillip Saccone has recently completed a medical affairs internship at Ferring Pharmaceuticals for six months. Please read below for his personal experience regarding this exciting internship opportunity.

Stay tuned for further exciting opportunities from the TCP division, and we encourage all trainees for their active participation. If you feel our activities are of interest to you, please contact our communications officer, Dr. Naeem Patil at naeem.patil@vanderbilt.edu.

My Experience as an Industry Intern: Mentorship Matters

By Phillip Saccone, PhD During my time in graduate school, I received two particularly salient pieces of advice that, in retrospect, have made the greatest impact on both my graduate training and professional career: engage multiple mentors and develop these relationships symbiotically. Such associations empower you to refine your interests, and unlock, or sometimes create opportunities when the right circumstances are

presented. My journey to Ferring Pharmaceuticals, and subsequent transition from intern to full-time employee was precisely the result of this kind of engagement.

At the University of Michigan, I was fortunate to be mentored by Dr. James Woods, who encouraged my independence and autonomy, and whose enthusiasm for science attracted a diverse group of people to the lab. Training in such an environment exposed me to opportunities beyond the traditional academic path, and gave me the confidence to pursue non-conventional prospects.

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Three days after defending my thesis, I was in the lobby of Ferring Pharmaceuticals waiting to meet my new boss, Dr. Thomas Beveridge, who founded the nascent internship program. My position was on the Clinical Sciences team, within the Medical Affairs department, which focuses on educating researchers and practitioners about Ferring products. At the time, I had no idea what that entailed or how my research background, which was not in the company’s therapeutic space, would enable me to contribute.

However, it was the perspective of Dr. Beveridge, as well as that of the team leader, Dr. Dennis Marshall, that taught me the traits you inherit from earning your PhD (independence, critical thinking, creativity, persistence, meticulousness, perseverance) lend themselves to learning just about anything, and that the “business” of medical affairs could be cultivated on the job. Under their mentorship, I kept that perspective in the forefront of my mind, and got to work.

My first assignment was to coordinate the writing of an expert scientific review with multiple leaders in the field of prostate cancer, including a Nobel Laureate. I approached the project like any other scientific inquiry: I read up on the

literature, synthesized information from multiple sources, integrated the work of collaborators, and shepherded through a working draft in relatively short order. Once the manuscript was complete, the team received very positive feedback, and Dr. Beveridge made sure my individual contributions were recognized. This acknowledgment bolstered my credibility within other areas of the company, which in turn created other opportunities.

Next, I assisted Dr. Beveridge in performing due diligence on a new medicine the company was interested in acquiring. After working closely with him to prepare product-specific materials for the company leadership, I was asked to take on similar (albeit smaller) projects independently that were related to business development. After a few months, it was clear that the bandwidth of the team was expanding, which enabled Drs. Beveridge and Marshall to find additional ways for our group to help the company.

With the internship coming to a close, they asked if a new position could be created within Medical Affairs so that I could join the team. It was an unexpected, but wonderful conclusion to my first industry experience.

When reflecting back on such an outcome, some people choose to focus on crediting their abilities and/or their good fortune (and it certainly seems like many opportunities depend on both). From my perspective, the relationships that people create, and their ability to culture a healthy mentormentee relationship, formally or informally, is the mortar that marries hard work and happenstance. You invest in other people, and they invest right back in you. I am grateful to the people at Ferring for creating an opportunity for a young professional, and I’m happy they found value in my contributions. I look forward to being at a point in my career where I can provide that type of guidance for someone else.

(From Left) Dr. Thomas Beveridge, Dr. Phillip Saccone, and Dr. Dennis Marshall

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Chapter News 2016 New York Pharmacology Society (NYPS) Annual Meeting in Review The fifth annual NYPS meeting highlighting “Receptors in Sensory Systems” held at the University of Rochester, Hilton Garden Inn, on Tuesday, May 17, 2016 continued the great success of the chapter! There were over 80 attendees including students, faculty, and industry scientists representing Cornell University, D’Youville College, University at Buffalo, University of Rochester, and industry research organizations.

Kirill A. Martemyanov, PhD of The Scripps Research Institute in Florida, delivered the NYPS annual meeting’s keynote address and Wallace O. Fenn Lecture entitled “G Protein Signaling in the Retina and Beyond.” Dr. Martemyanov, a recent Cogan Award recipient NYPS keynote speaker from the Association Kirill A. Martemyanov, PhD for Research in Vision and Ophthalmology, described his research on retinal signaling in which his lab has identified several key components critical to the selective connectivity of rod and cone photoreceptors with different classes of downstream bipolar cells.

Additional invited thematic speakers were Tiffany

Schmidt, PhD of Northwestern University Department of Neurobiology and Slav Bagriantsev, PhD of Yale University Department of Cellular and Molecular Physiology. Dr. Schmidt described her research discoveries that distinct, identifiable subtypes of retinal ganglion cells establish different synaptic connections within the retina. Dr. Bagriantsev spoke of his recent research identifying signaling properties of large-diameter mechanoreceptive neurons in tactile foraging animals.

Presidential Graduate Student Symposium speakers included six advanced graduate students from regional universities and research institutes: Jennifer Martin of the University at Buffalo, Liwei Wang of the University of Rochester, Mallorey Himmel of the University at Buffalo, Ezen Choo of Cornell University, Justin Siemian of the University at Buffalo, and Mallory Scott of the University of Rochester. Early Career Scientist presentations were made by Craig Nash of the University of Rochester and Diara Santiago-Gonzalez of the University at Buffalo. There were more than 40 graduate students in attendance and 18 graduate students presented original research posters.

Outgoing NYPS President Paul J. Kammermeier, PhD of the University of Rochester gave final remarks and welcomed the new President Jun-Xu Li, PhD of the University at Buffalo. Further details can be found at www.aspet.org/NYPS/.

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2016 Great Lakes Chapter Annual Meeting in Review In July 2016, the Great Lakes Chapter of the American Society for Pharmacology and Experimental Therapeutics (GLC ASPET) hosted its annual meeting to foster interactions among pharmacologists in the Great Lakes region and to provide a forum for undergraduate and graduate students, as well as postdoctoral fellows to present their research. The meeting had a very exciting program, including an afternoon scientific symposium focused on “Basic and Translational Advances in Neurological Disease: From Signaling to Therapeutics” that featured five nationally and internationally recognized researchers in the area of neuroscience.

Alfred George, MD, chair, Department of Pharmacology of Northwestern University, Feinberg School of Medicine, discussed “Therapeutic Targeting of Ion Channels in Genetic Epilepsy.”

Epilepsy, a common neurological disorder, has been associated with channelopathies, particularly those involving voltage-gated sodium (Nav) channels. Dr. George provided data supporting ion

2016 GLC Annual Meeting

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channels as good drug targets and evidence that pharmacological targeting of aberrant channel function with novel agents can be beneficial in epilepsy treatment.

Anthony West, PhD, Department of Neuroscience, Chicago Medical School at Rosalind Franklin University, presented on the “Role of cGMP Signaling in Neurodegenerative Disorders and Development of Targeted Therapeutics.” Dr. West reviewed the current and developing treatment strategies for Huntington’s disease and Parkinson’s disease, as well as recent data suggesting therapeutic benefits of targeting various components of the soluble guanylyl cyclasecGMP signaling in the striatum.

Tammy Dellovade, PhD, from the Cambridge AbbVie Foundational Neuroscience Center provided a review of the “Translational Challenges with Animal Models of Neurological Diseases.” Dr. Dellovade stressed the lack of predictive models for Alzheimer’s disease (AD) as one of the major challenges in drug discovery and development for AD and the critical need for biomarkers to optimize patient selection in clinical trials evaluating new therapeutic agents for AD. Robert Vassar, PhD, Department of Cell and Molecular Biology, Northwestern University, discussed “BACE1: The Beta-secretase Enzyme in Health and Alzheimer’s disease”, an enzyme he discovered and a prime AD target for which various inhibitors are currently evaluated in the clinic. Dr. Vassar provided a comprehensive review of BACE1 properties in disease states and its possible mechanism and role in the pathogenesis of AD, as well as the current status of the clinical trials evaluating BACE1 inhibitors.

Natalie Tronson, PhD, Department of Psychology, University of Michigan, closed the scientific symposium with a review of her work on “Sex Differences, Inflammation, and Memory.” In particular, she described her data generated from two murine models of systemic inflammation that are used to evaluate the impact and mechanisms of illness on memory function.

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S p o t t h e D i ffe re n c e .

The original photo is on top. Find the seven differences between the original photograph and the altered photograph on the bottom. Answer key on page 168.

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