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.

An overview of the safety pharmacology career of Dr. C.R. Hassler.

Each year the Safety Pharmacology Society (SPS) recognizes an investigator who has had a marked impact upon the discipline. The 2016 recipient of the SPS Distinguished Service Award (DSA) was Dr. Craig R. Hassler. Dr. Hassler is one of the founding members of the SPS and has been actively engaged in physiological research for over 46years. Dr. Hassler delivered a talk entitled "My 43Years at Battelle Memorial Institute" to meeting attendees. In this article an overview is provided of the illustrious career of Dr. Hassler along with an account of the numerous animal models that were developed at Battelle under his guidance over the years.

Pharmacology and psychiatry at the origins of Greek medicine: The myth of Melampus and the madness of the Proetides.

Melampus is a seer-healer of Greek myth attributed with having healed the young princesses of Argos of madness. Analysis of this legend and its sources sheds light on the early stages of the "medicalizing" shift in the history of ancient Greek medicine. Retrospective psychological diagnosis suggests that the descriptions of the youths' madness rose from actual observation of behavioral and mental disorders. Melampus is credited with having healed them by administering hellebore. Pharmacological analysis of botanical specimens proves that Helleborus niger features actual neurological properties effective in the treatment of mental disorders. The discussion aims at examining the rational aspects of the treatment of mental conditions in Greco-Roman antiquity.

PROFESSOR MIKHAIL P. NIKOLAEV AND RUSSIAN PHARMACOLOGY.

Various stages of life, scientific research and pedagogical activity of Prof. Mikhail P. Nikolaev are considered. The importance of his works in drug evaluation, endocrinological pharmacology, pharmacology of heart and vessels, pathological pharmacology, and discovery of drugs for organotherapy is shown. Prof. M. P. Nikolaev's effort in training research staff and teachers in pharmacology and his own teaching experience in medical and pharmaceutical universities are summarized. The activity of Prof. M. P. Nikolaev in military pharmacology is analyzed. The role of Prof. M. P. Nikolaev in establishing Russian journal Farmakologiya i Toksikologiya (Parmacology and Toxicology) and creating All-Union Scientific Society of Pharmacologists in the USSR is emnhasized.

[Contribution to the history of pharmacology (the late antique period)]. / Príspevek k dejinám farmakologie (období pozdní antiky).

Pharmacological literature in the Late Antique period followed the Roman tradition and widely used Scribonius Largus and excerpts from the writings of Pliny the Elder. Literature was created both in the western part of the Roman Empire and in North Africa in Carthage. Manuals have been written about medicinal plants (Herbarius of Pseudo-Apuleius, De herba vettonica of Pseudo-Musa), for drugs obtained from the animal kingdom (Liber medicinae of Sextus Placitus) or documents containing both (De medicina of Cassius Felix, De medicamentis of Marcellus Empiricus). The contribution of this literature is the mediation of ancient knowledge into the Middle Ages.

La digital: su historia y su rol actual / Digital: their history and their current role

Si bien las hojas de digital purpúrea (Digitalis purpurea) se empleaban desde el año 500 D.C., fue el Dr. WilliamWhitering, de Inglaterra, quien investigó sus propiedades y en 1785 escribió un libro que ingresó entre los clásicos de la historia de la medicina: An account of the foxglove and some of its medical uses, with practical remarks on dropsy and other diseases. Esta revisión repasa la historia de la digital, su mecanismo de acción, y los trabajos más recientes que revaloran los efectos de esta medicación, recomendada actualmente a menores dosis de digoxina que las clásicamente aceptadas, capaz de reducir las hospitalizaciones y mejorar la sobrevida, en especial en pacientes con grados avanzados de insuficiencia cardíaca y medicados con inhibidores de la enzima convertidora de angiotensina, beta-bloqueantes, antagonistas de la aldosterona y diuréticos. Quizás aún falta precisar su valor definitivo, pero es indudable que la digital marcó una etapa definitiva en los dominios de la Cardiología y que, junto a la amapola, la quina y la belladona, constituye el grupo de las cuatro principales plantas que han llevado alivio a las enfermedades del hombre(AU)

Although the leaves of Digitalis purpurea had been used since 500 D.C., it was the English physician William Withering who studied its properties. In 1785 he wrote the book called ôAn account of the foxglove and some of its medical uses: with practical remarks on dropsy and other diseasesö which became one of the classics in the history of medicine. This article reviews the history of digitalis, its mechanism of action, and recent studies which underline the importance of this medication. Digitalis is presently prescribed at lower doses than tradionally indicated; it is effective in reducing hospital stays, and improving survival, especially in patients with advanced stages of heart failure and receiving inhibitors of the angiotensin converting enzyme, beta-blockers, aldosterone antagonists, and diuretics.Even though its definitive value is yet to be determined, it is certain that digitalis has a role to play in the domains ofCardiology and belongs to the group of the four principal plants that have brought relief to human diseases, along with the poppy, Peruvian bark, and belladona (AU)

La digital: su historia y su rol actual / Digital: their history and their current role

Si bien las hojas de digital purpúrea (Digitalis purpurea) se empleaban desde el año 500 D.C., fue el Dr. WilliamWhitering, de Inglaterra, quien investigó sus propiedades y en 1785 escribió un libro que ingresó entre los clásicos de la historia de la medicina: An account of the foxglove and some of its medical uses, with practical remarks on dropsy and other diseases. Esta revisión repasa la historia de la digital, su mecanismo de acción, y los trabajos más recientes que revaloran los efectos de esta medicación, recomendada actualmente a menores dosis de digoxina que las clásicamente aceptadas, capaz de reducir las hospitalizaciones y mejorar la sobrevida, en especial en pacientes con grados avanzados de insuficiencia cardíaca y medicados con inhibidores de la enzima convertidora de angiotensina, beta-bloqueantes, antagonistas de la aldosterona y diuréticos. Quizás aún falta precisar su valor definitivo, pero es indudable que la digital marcó una etapa definitiva en los dominios de la Cardiología y que, junto a la amapola, la quina y la belladona, constituye el grupo de las cuatro principales plantas que han llevado alivio a las enfermedades del hombre

Although the leaves of Digitalis purpurea had been used since 500 D.C., it was the English physician William Withering who studied its properties. In 1785 he wrote the book called “An account of the foxglove and some of its medical uses: with practical remarks on dropsy and other diseases” which became one of the classics in the history of medicine. This article reviews the history of digitalis, its mechanism of action, and recent studies which underline the importance of this medication. Digitalis is presently prescribed at lower doses than tradionally indicated; it is effective in reducing hospital stays, and improving survival, especially in patients with advanced stages of heart failure and receiving inhibitors of the angiotensin converting enzyme, beta-blockers, aldosterone antagonists, and diuretics.Even though its definitive value is yet to be determined, it is certain that digitalis has a role to play in the domains ofCardiology and belongs to the group of the four principal plants that have brought relief to human diseases, along with the poppy, Peruvian bark, and belladona

From plant extract to molecular panacea: a commentary on Stone (1763) 'An account of the success of the bark of the willow in the cure of the agues'.

The application of aspirin-like drugs in modern medicine is very broad, encompassing the treatment of inflammation, pain and a variety of cardiovascular conditions. Although anecdotal accounts of willow bark extract as an anti-inflammatory drug have occurred since written records began (for example by Hippocrates), the first convincing demonstration of a potent anti-pyretic effect of willow bark containing salicylates was made by the English cleric Edward Stone in the late eighteenth century. Here, we discuss the route to optimizing and understanding the mechanism of action of anti-inflammatory drugs that have their origins in Stone's seminal study, 'An account of the success of the bark of the willow in the cure of agues'. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

[THE NASCENCY OF DRUG AND FIRST STEPS OF ITS DEVELOPMENT].

In this historical review article, the first examples of human attempts to use drugs for the solution of their health problems and the development of the concept of natural toxic (poisonous) substances in the history and prehistoric times, are discussed. It is regarded that, outside of the quelling of the hunger or quenching the thirst, some of our early an- cestors have coincidentally began to distinguish the different effects in some of the natural products in their environment, probably during their nutritional behavior. It is thought that in this way, the awareness for drugs and toxic substances have been raised. In our available sources related to this topic, the first instance in different societies that can be considered as drug seems to belong to different dates, and strikingly the earliest drug samples were found particularly in ancient Mesopotamia, Egypt, China and Indian civilizations. It was determined that primarily herbal resources were utilized for the first instance that can be considered as the first drug application in discussed societies. On the other hand, these first natural origin drug samples have been remained in the use of humankind in later centuries and some of them seems to be applied in a certain manner even today.

Clinical experience in late antiquity: Alexander of Tralles and the therapy of epilepsy.

Alexander of Tralles, writing in the late sixth century, combined his wide-ranging practical knowledge with earlier medical theories. This article shows how clinical experience is used in Alexander's works by concentrating on his therapeutic advice on epilepsy and, in particular, on pharmacology and the group of so-called natural remedies. I argue that clinical testing is used not only for the introduction of new medicines but also as an instrument for checking the therapeutic effect of popular healing practices. On another level, this article discusses Alexander's role as the author of a medical compendium; it suggests that by marking the cases of clinical testing with a set of recurrent expressions, Alexander leads his audience to reflect on his medical authority and personal contribution.

Los libros sobre las drogas americanas en la Biblioteca Histórica de la Farmacia Suiza / Books on American drugs in the historical library of the Switzerland pharmacy

Fundada en el año 2008, la Biblioteca Histórica de la Farmacia Suiza, situada en el instituto de Historia de la Medicina de la Universidad de Berna, tiene un fondo de más de 6000 obras. Entre ellas se encuentran algunos libros que se dedican a las drogas sudamericanas. Aparte de las obras de Nicolás Monardes, también existen otras de la farmacognosia europea de finales del siglo XIX y principios del XX. Este trabajo ilustra la importancia de la transferencia de conocimientos usando la Biblioteca Histórica helvética como ejemplo

Institute houses the Historical Library of the Swiss Pharmacy, founded in 2008, for the History of Medicine of the University of Berne provides an impressive collection of more than 6000 works. Among them are some books that deal with South American drugs. Besides the famous works by Nicolás Monardes and their translations, there are also a corpus of books representing the European pharmacognosy by the end of the 19th and the beginning of the 20th century. This paper is dedicated to the transfer of scientific knowledge reflected by the works in the Helvetic historical library

Veterinary pharmacology: history, current status and future prospects.

Veterinary therapeutics, based on the art of Materia Medica, has been practised for countless centuries, but the science of veterinary pharmacology is of very recent origin. This review traces the contribution of Materia Medica to veterinary therapeutics from the Egyptian period through to the Age of Enlightenment. The first tentative steps in the development of the science of veterinary pharmacology were taken in the 18th century, but it was not until the mid 20th century that the science replaced the art of Materia Medica. This review traces the 20th century developments in veterinary pharmacology, with emphasis on the explosion of knowledge in the 35 year period to 2010. The range of factors which have influenced the current status of the discipline are reviewed. Future developments are considered from the perspectives of what might be regarded as desirable and those innovations that might be anticipated. We end with words of encouragement for young colleagues intent upon pursuing a career in veterinary pharmacology.

Hormesis: Toxicological foundations and role in aging research.

The field of toxicology adopted the threshold dose response in the early decades of the 20th century. The model was rapidly incorporated into governmental regulatory assessment procedures and became a central feature of chemical evaluation and assessment. The toxicological community never validated the capacity of this model to make accurate predictions throughout the remainder of the 20th century. A series of recent investigations have demonstrated that the threshold and linear dose response model failed to make accurate predictions in the low dose zone. Such findings demonstrate a profound failure by the toxicology community on the central pillar of its discipline and one with profound public health, medical and economic implications. Ironically, the hormetic dose response, which was rejected by the toxicology community during the early decades of the 20th century, accurately predicted responses in the low dose zone in the same three large-scale validation assessments. Within the past two decades hormetic dose responses have been frequently reported in the experimental biogerontology literature, associated with endpoints associated enhancing healthy aging and longevity. The low dose stimulatory response of the hormetic dose response model represents the quantification of enhanced biological performance in the experimental facilitation of aging quality via multiple endpoints and mechanisms and in the extension of lifespan in such animal models research.

[Theory of toxic classification of traditional Chinese medicine and recommendations for revision of China pharmacopeia (volume 1)].

Toxic classification of traditional Chinese medicine, as a contribution of traditional Chinese medicine (TCM) to the recognition of medicinal toxicity and rational use of medicinal materials by Chinese people, is now a great issue related to safe medication, sustainable development and internationalization of Chinese medicine. In this article, the origination and development of toxic classification theory was summarized and analyzed. Because toxic classification is an urgent issue related to TCM industrialization, modernization and internationalization, this article made a systematic analysis on the nature and connotation of toxic classification as well as risk control for TCM industry due to the medicinal toxicity. Based on the toxic studies, this article made some recommendations on toxic classification of Chinese medicinal materials for the revision of China Pharmacopeia (volume 1). From the aspect of scientific research, a new technical guideline for research on toxic classification of Chinese medicine should be formulated based on new biological toxicity test technology such as Microtox and ADME/Tox, because the present classification of acute toxicity of mice/rats can not met the modern development of Chinese medicine any more. The evaluation system and technical SOP of TCM toxic classification should also be established, and they should well balance TCM features, superiority and international requirements. From the aspect of medicine management, list of toxic medicines and their risk classification should be further improved by competent government according to scientific research. In China Pharmacopeia (volume I), such descriptions of strong toxicity, toxicity or mild toxicity should be abandoned when describing medicine nature and flavor. This revision might help promote TCM sustainable development and internationalization, and enhance the competitive capacity of Chinese medicine in both domestic and international market. However, description of strong toxicity, toxicity or mild toxicity might be used when making cautions for the medicine, stating that the description is based on Chinese classic works. In this way, TCM traditional theory might be inherited and features of Chinese medicine maintained and reflected. Besides, modern findings should be added to the cautions, including dose-response relationship, toxic mechanism, and toxic elements. The traditional toxic descriptions and modern findings, as a whole, can make the caution clear and scientific, and then promote safe medication and TCM modernization and internationalization.

Medicinal use of earths and minerals from Hippocrates to Sir Hans Sloane and beyond.

In 1931 two pharmaceutical drawers containing mineral specimens, belonging to Sir Hans Sloane, the 18th century collector, Royal Physician, President of the Royal Society and of the Royal College of Physicians of London, were found in the Department of Botany of the Natural History Museum (NHM) of London. The drawers, each divided into 49 compartments, contained a total of 107 mineral pharmaceutical specimens, some labelled as mercury or white arsenic. Their registration, identification with the Sloane Manuscript Catalogues and subsequent transfer to the Mineralogy department of the NHM where one of these drawers is now on public display, had been documented by 1935. In antiquity therapeutic empiricism attributed medicinal properties to animal products, plants and minerals, including the soil of specific geographic locations. This communication traces the medicinal use of certain earths and minerals, listed in Sir Hans Sloane's manuscript catalogues, to classical antiquity with a reference to Arsenic compounds, which in our time are finding application in the treatment of acute promyelocytic leukaemia and to Terra Lemnia, a celebrated antidote of repute spanning twenty centuries, also included in the Sloane collections.

Early drug discovery and the rise of pharmaceutical chemistry.

Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history.