Kresimir Krnjevic (1927-2021) and GABAergic inhibition: a lifetime dedication.

After over seven decades of neuroscience research, it is now well established that γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Kresimir Krnjevic (1927-2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjevic was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology.

Developing Tools to Evaluate Non-linear Mixed Effect Models: 20 Years on the npde Adventure.

This article revisits 20 years of our work in developing evaluation tools adapted to non-linear mixed effect models. These hierarchical models involve a large number of assumptions concerning the structural evolution of the outcomes, the link between different outcomes, the variabilities in the parameters and model evaluation aims at assessing these various components, both to help guide the model building and to communicate on model adequacy for a given purpose. During our career, we have developed and extended simulation-based evaluation tools called normalised prediction discrepancies (npd) and normalised prediction distribution errors (npde), providing informative diagnostics through graphs and tests.

Animal Models in Pharmacology: A Brief History Awarding the Nobel Prizes for Physiology or Medicine.

BACKGROUND: The Nobel Prize of Physiology or Medicine (NPPM) has recognized the work of 222 scientists from different nationalities, from 1901 until 2020. From the total, 186 award researchers used animal models in their projects, and 21 were attributed to scientists and projects directly related to Pharmacology. In the most recent years, genetics is a dominant scientific area, while at the beginning of the 20th century, most of the studies were more related to anatomy, cytology, and physiology. SUMMARY: Mammalian models were used in 144 NPPM projects, being rodents the most used group of species. Moreover, 92 researchers included domestic species in their work. The criteria used to choose the species, the number of animals used and the experimental protocol is always debatable and dependent on the scientific area of the study; however, the 3R's principle can be applied to most scientific fields. Independently of the species, the animal model can be classified in different types and criteria, depending on their ecology, genetics, and mode of action. Key-Messages: The use of animal models in NPPM awarded projects, namely in Pharmacology, illustrates their importance, need and benefit to improve scientific knowledge and create solutions. In the future, with the contribute of technology, it might be possible to refine the use of animal models in pharmacology studies.

Between two stools? Pharmacologists nominated for Nobel prizes in "physiology or medicine" and "chemistry" 1901-1950 with a focus on John Jacob Abel (1857-1938).

Since the early stages of its academic professionalization, pharmacology has been an interdisciplinary field strongly influenced by the natural sciences. Using the Nobel Prize as a lens to study the history of pharmacology, this article analyzes nominations of pharmacologists for two Nobel Prize categories, namely "chemistry" and "physiology or medicine" from 1901 to 1950. Who were they? Why were they proposed, and what do the Nobel dossiers say about excellence in pharmacology and research trends? This paper highlights the evaluation of "shortlisted" candidates, i.e., those candidates who were of particular interest for the members of the Nobel Committee in physiology or medicine. We focus on the US scholar John Jacob Abel (1857-1938), repeatedly referred to as the "Founder of American Pharmacology." Nominated 17 times in both categories, Abel was praised by his nominators for both basic research as well as for his influential positions as editor and his work as chair at Johns Hopkins University. The Abel nominations were evaluated for the Nobel Committee in chemistry by the Swedish professor of chemistry and pharmaceutics Einar Hammarsten (1889-1968), particularly interested in Abel's work on hormones in the adrenal glands and in the pituitary gland. Eventually, Hammarsten did not view Abel's work prizeworthy, partly because other scholars had done-according to Hammarsten-more important discoveries in the same fields. In conclusion, analyses of Nobel Prize nominations help us to better understand various meanings of excellence in pharmacology during the twentieth century and beyond.

Geoffrey Burnstock - An accidental pharmacologist.

Geoffrey Burnstock, the founder of the field of purinergic signaling research passed away in Melbourne, Australia on June 3rd, 2020, at the age of 91. With his death, the world of biomedical research lost one of its most passionate, creative and unconventional thought leaders. He was an inspiration to the many researchers he interacted with for more than 50 years and a frequent irritation to those in the administrative establishment. Geoff never considered himself a pharmacologist having being trained as a zoologist and becoming an autonomic neurophysiologist based on his evolving interests in systems and disease-related research. By the end of his life he had: published some 1550 papers; been cited more than 125,000 times; had an h-index of 156 and had supervised over 100 Ph.D. students. His indelible legacy, based on a holistic, data-based, multidisciplinary, unconventional "outside the box" approach to research was reflected in two of the seminal findings in late 20th century biomedical research: the purinergic neurotransmitter hypothesis and the concept of co-neurotransmission, both of which were initially received by his peers with considerable skepticism that at times verged on disdain. Nonetheless, while raising hackles and threatening the status quo, Geoff persevered and prevailed, becoming a mentor for several generations of biomedical researchers. In this review we provide a joint perspective on Geoff Burnstock's legacy in research.

Women in the Pharmaceutical Sciences: Honoring Our Pioneers.

Graphical Abstract.

David S. Miller: Scientist, Mentor, Friend-a tribute and thank you.

David S. Miller was Acting Scientific Director of the Division of Intramural Research at the National Institute of Environmental Health Sciences, National Institutes of Health, and Head of the Intracellular Regulation Group in the Laboratory of Toxicology and Pharmacology before he retired in 2016. David received his Ph.D. in biochemistry from the University of Maine in 1973. David was a Group Leader at the Michigan Cancer Foundation before joining the NIEHS in 1985. His research covered a wide range from renal excretory transport mechanisms to regulation of transporters at the blood-CSF and blood-brain barriers, from fish, amphibians and birds to mammals. David was an outstanding scientist with irresistible enthusiasm for science and an incredible ability to think outside the box while being an exceptional mentor and friend.

The "Nobel Population" in Pharmacology: Nobel Prize laureates, nominees and nominators 1901-1953 with a focus on B. Naunyn and O. Schmiedeberg.

One way to investigate research trends in pharmacology over time is to study nominations for the Nobel Prize in physiology or medicine. Going beyond the laureates with strong links to pharmacology, this article pinpoints pharmacologist Nobel Prize nominees during the first half of the twentieth century with a particular focus on two co-founders of this journal: Oswald Schmiedeberg and Bernhard Naunyn. Using the Nobel nomination database which contains more than 5000 nominations in the category physiology or medicine from 1901 to 1953, we listed all scholars (Nobel nominees or nominators) who worked in a pharmacological institute. In addition, we collected nomination letters of Schmiedeberg and Naunyn in the archive of the Nobel committee for physiology or medicine in Stockholm to explore nomination networks and motives. The most often nominated pharmacologists from 1901 to 1953 were Alfred Newton Richards with 57 nominations, Rudolf Magnus (31), Edward Calvin Kendall (28), Otto Loewi (27), Sir Henry Hallett Dale (21) and Oswald Schmiedeberg (18). Surprisingly, the lion's share of the nominations was submitted by non-pharmacologists. We observed a decline in German nominations after World War II and an increase in US-American nominations, which indicates shifting centres and peripheries in pharmacological research. Furthermore, in our observed group of pharmacologists, there was no female nominee from 1901 to 1953. Nobel Prize nominations are to date an underused source to explore international scientific trends as well as scientific networks during the twentieth century.

Ibn Mandevaih Isfahani (949-983(?) AD), a physician from Isfahan's medical school.

There have arisen a number of prominent Iranian-Islamic physicians throughout the history of the fertile medicine landscape of Iran, some of whom are not very well known. Abu Ali Ahmad ibn Abd al-Rahman Mandevaih Isfahani (949-983(?) AD) was a great medical figure with scientific activities in the Hospital of Isfahan and al-Adudi Hospital of Baghdad in the golden age of Iranian-Islamic history, culture, and civilization during the reign of the Buyid dynasty and Abbasid Caliphate. He was also a prominent physician during the reign of Adud al-Dawla Deylami (949-983 AD). This present research has as its objectives the studying of the scientific life of ibn Mandevaih Isfahani and his works in this field. The works of this scientist and scholar reflect his skill and expertise in literature, philosophy, medicine, and medicine-related fields including ophthalmology and pharmacology.

Perspectives of Pharmacology over the Past 100 Years.

It is fitting that the 100th anniversary of the Handbook of Experimental Pharmacology celebrates not only its founding but also the founding of experimental pharmacology as both had their beginnings in Germany. Founded in 1919 by Arthur Heffter (1859-1925) as the "Handbuch der Experimentellen Pharmakologie" and renamed to its current title in 1937, the Handbook has continued to capture the emergence and developments of experimental pharmacology since the initial systematic work of Rudolf Buchheim and his student Oswald Schmiedeberg. Heffter, the first Chairman of the German Society of Pharmacology, was also responsible for isolating mescaline as the active psychedelic component from the peyote cactus, thereby initiating a series of studies along with an Institute that, much like the Handbook and the discipline of pharmacology, continues to discover and disseminate new findings to this day. These early endeavors to establish pharmacology as a viable and valuable contributor to the medical sciences met with considerable resistance and challenges. However, the persistence and dedication of these early pharmacologists placed pharmacology on a firm foundation from which to spread this discipline globally, leading ultimately to our current understanding of the principles of drug action and with an impact likely unanticipated by these founding scientists. Summarizing the beginnings of these efforts and their early spread to other countries provides an appropriate context in which to document the many contributions pharmacological research has made over the past 100 years and provide an opportunity to anticipate expectations around its future developments.

Hermann (Hugh) Blaschko (1900-1993): His fundamental contributions to biochemical pharmacology and clinical medicine.

Hermann (Hugh) Blaschko was a biochemical pharmacologist best known for discovering how adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine were synthesized, stored, and metabolized in adrenomedullary cells and sympathetic nerves. Blaschko's work not only supported the validity of the concept of neurochemical synaptic transmission but he also made fundamental contributions to the development of drugs used in clinical medicine to treat diseases such as depression, hypertension, and Parkinson's Disease.

Joshua Harold Burn (1892-1981): A visionary during the evolution of pharmacology as a biomedical discipline.

This article encapsulates the career of Joshua Burn, whose work encouraged new lines of experimentation and paved the way for fundamental advances in our knowledge of the autonomic nervous system. His legacy also endures in his efforts as Department Chairman to oversee a very supportive environment which led to the development of many successful scientists. By producing a body of work that enabled the discipline of pharmacology to contribute in a major way to the advancement of clinical medicine, Joshua Burn stands out as a unique figure in the annals of true scientific pioneers.