The British Pharmacological Society's WDM Paton Memorial Lecture 2019: How doctors were informed about pharmaceutical products through advertising in the British Medical Journal from 1955/6 to 1985/6.

We have reviewed pharmaceutical advertisements in every available issue of the British Medical Journal (BMJ) in 12-month periods during 1955/6, 1965/6, 1975/6, and 1985/6. We have determined the amount of advertising, the therapeutic areas covered, and whether adverts reflected the large number of New Chemical Entities (NCEs) launched during that time. For each product we recorded the therapeutic indications, the marketing company, and the number of adverts appearing. The total number of products advertised fell from 340 in 1955/6 to 260 in 1965/6, 70 in 1975/6, and 16 in 1985/6. Advertisement numbers and companies advertising also fell. Antimicrobial drugs and cardiovascular drugs were the top products advertised over the 30 years, with respiratory, analgesic, and gastrointestinal drugs also in the top five. The number of different drugs advertised by individual companies fell from around eight per company in 1955/6 to one or two in 1985/6. There was good concordance between the most advertised therapeutic areas and NCEs entering the market. From the 1950s to the 1980s prescribers were extensively informed about pharmacological advances in therapeutics through BMJ advertisements. Many novel drugs that were advertised proved to be of lasting value. The Medicines Act 1968 introduced product licensing, regulations requiring demonstration of quality, efficacy, and safety, and restrictions on advertising. Subsequently many companies reduced their advertising or stopped altogether. Since advertising influences prescribing, and since antimicrobial drugs were the most commonly advertised products during 1955-86, we speculate that advertising, resulting in excess use, may have, at least partly, driven bacterial drug resistance.

[The history of antibiotics]. / Historien om antibiotika.

The development of chemical compounds for the treatment of infectious diseases may be divided into three phases: a) the discovery in the 1600s in South America of alkaloid extracts from the bark of the cinchona tree and from the dried root of the ipecacuanha bush, which proved effective against, respectively, malaria (quinine) and amoebic dysentery (emetine); b) the development of synthetic drugs, which mostly took place in Germany, starting with Paul Ehrlich's (1854-1915) discovery of salvarsan (1909), and crowned with Gerhard Domagk's (1895-1964) discovery of the sulfonamides (1930s); and c) the discovery of antibiotics. The prime example of the latter is the development of penicillin in the late 1920s following a discovery by a solitary research scientist who never worked in a team and never as part of a research programme. It took another ten years or so before drug-quality penicillin was produced, with research now dependent on being conducted in large collaborative teams, frequently between universities and wealthy industrial companies. The search for new antibiotics began in earnest in the latter half of the 1940s and was mostly based on soil microorganisms. Many new antibiotics were discovered in this period, which may be termed «the golden age of antibiotics¼. Over the past three decades, the development of new antibiotics has largely stalled, while antibiotic resistance has increased. This situation may require new strategies for the treatment of infectious diseases.

[Historical notes on the management of infection during the development of surgery]. / Apuntes históricos sobre el manejo de la infección en el desarrollo de la cirugía.

Surgery and medicine have not evolved in parallel. There have been discrepancies, bellicosity, contempt and even separate university studies during a long time. The Saint Cosme Brotherhood, founded to supervise the professional practice of barbers (short robe surgeon-barbers) in France in 1260, was opposed by the Faculty of Medicine in Paris. The conflicting interests of the university, Brotherhood and Barbers, that persisted until the 18 th century, impaired the progress of surgery. In the first half of the 19 th century, the advance of surgery continued facing pain, hemorrhage and infection. The control of the latter had to consider antisepsis, asepsis and finally the appearance of antimicrobial substances, sulfonamides and antibiotics that allowed surgeons to approach and solve major problems of the specialty.

The History of Biomarkers: How Far Have We Come?

Sepsis is one of the oldest and most elusive syndromes in medicine that is still incompletely understood. Biomarkers may help to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This will help to differentiate between systemic inflammation of infectious and noninfectious origin and aid therapeutic decision making, hence improve the prognosis for patients, guide antimicrobial therapy, and foster the development of novel adjunctive sepsis therapies. To reach this goal requires increased systematic investigation that includes twenty-first century scientific approaches and technologies and appropriate clinical evaluation.

Antibiotics: From the Beginning to the Future: Part 1.

The first written record of intervention against what later came to be known as an infectious disease was in the early seventeenth century by a Buddhist nun. She dried 3 to 4 wk old scabs from patients with mild smallpox and asked well people to inhale the powder. More than a century later in 1796, Edward Jenner described vaccination against smallpox by using cowpox that later was found to be caused by cowpox virus which is non-pathogenic for humans. Another century later in 1890, Robert Koch published the Koch's Postulates allowing the study of pathogenic bacteria and subsequently the study of agents to fight them. The first chemical cure for disease was reported by Paul Erhlich in 1909 in the form of an arsenic compound to treat syphilis. One hundred and ten years since then a lot has happened in the area of preventing and treating infectious diseases with significant contribution to increase in human lifespan. This is the only area of medicine in which treatment (antimicrobial agent) is used to eradicate a replicating biological agent inside the human host. The potential of this second biological agent to mutate under the selection pressure of antibiotics making them resistant was recognized in the 1940s. But the indiscriminate use of antibiotics for over 70 y has led to the present crisis of resistance in major pathogens with increased morbidity and mortality. In this review, we have incorporated all the possible avenues that might be useful in the future. However, none is more important than relearning the judicious use of antibiotics based on microbiology, pharmacology, and genetics.

[Hexa-sabbath. Foreign matter and vital substances, experts and the critical consumer in the FRG during the 1950s and 1960s]. / Hexa-Sabbat. Fremdstoffe und Vitalstoffe, Experten und der kritische Verbraucher in der BRD der 1950er und 1960er Jahre.

In the late Fifties and early Sixties the regulation of food additives represented a remarkable turning point in German consumer politics, establishing a debate about decision making and policy advice, altering the discourse of purity and contamination, and inaugurating a new political actor, the organized critical consumer. The amendment of the Food Law in December 1958 functioned as a negotiation process between representatives of science, industry and the state, which was institutionalized in the Senate Commissions of the German Research Foundation. While these Commissions for preservatives, foreign matter and colorants worked behind closed doors, a public discourse about the "toxic condition" of modern life and the negative role of the pharmaceutical and chemical industry gained strength. The debate about the admission of hexamethylenetetramine (hexa) took part at a crucial moment. Hexa was used as a preservative in the fish industry. But its anti microbial effectiveness was caused by the decomposition of hexa to formaldehyde. Despite the commission's verdict against hexa, the lobbying activities of the industry granted it a reprieve. In the media, the case of hexa was seen as a touchstone for the capacity of negotiated decision making and the ability of rational scientists to resist the demands of industry. Finally, in 1963 it was the new political actor of the organized critical consumer, heir and successor to the housewife federations as well as to "purists" advocating life reform, who, supported by the media, enforced the prohibition of hexa as a preservative.

La amenaza silenciosa de las resistencias bacterianas / The silent threat of bacterial resistance

Las resistencias bacterianas a antimicrobianos representan uno de los principales problemas en la actualidad, encontrándose dentro de las principales causas de muerte en todo el mundo. Latinoamérica y Argentina, lejos de ser una excepción,presentan incidencias crecientes de infecciones por gérmenes resistentes. Cada día, se conocen mejor los mecanismos de resistencia que presentan los bacilos gram negativos y algunos cocos positivos. El problema no surge sólo por el sobreuso de antimicrobianos en la medicina clínica. Su sobreutilización para maximizar los beneficios productivos en la pesca, la ganadería y la agricultura contribuyen a esta situación. Desde la perspectiva de la atención primaria de la salud,consideramos fundamental conocer todos los aspectos que forman parte de esta problemática para intentar mitigar el daño que las resistencias bacterianas generan a nivel global. Argentina se transformó en el primer país de la región y del continente en contar con una ley para prevenir y controlar la resistencia a los Antimicrobianos. Consideramos de vital importancia que se fomenten más y mejores políticas sanitarias de orden público para enfrentar este creciente desafío. (AU)

Nowadays, bacterial resistance to antimicrobials is one of the main problems, being one of the leading causes of death worldwide. Latin America and Argentina, far from being an exception, have an increasing incidence of infections by resistant germs. Every day, the resistance mechanisms of gram-negative bacilli and some positive cocci are better known. The problem does not arise only because of the overuse of antimicrobials in clinical medicine. Its overuse to maximize productive benefits in fishing, livestock, and agriculture also contributes to this issue. From the perspective of primary health care,it is essential to know all the aspects of this problem to mitigate the damage that bacterial resistance generates at a global level. Argentina became the first country in the region and the continent to have a law to prevent and control antimicrobial resistance. We consider it vitally important that more and better public health policies are promoted to face this growing challenge. (AU)

Elie Metchnikoff's and Paul Ehrlich's impact on infection biology.

The 100th anniversary of the Nobel Prize for Medicine to Paul Ehrlich and Elie Metchnikoff gives us a good opportunity to reflect on their research about infectious diseases. Elie Metchnikoff was not only the first to describe phagocytosis of invading pathogens by specialized blood cells - macrophages and neutrophils - he also was interested in the impact of normal flora on well-being and in pre- and probiotic diet and their influence on the normal flora. Paul Ehrlich not only developed the concept of the side-chain theory of antibody formation but also discovered the first chemotherapeutic agent against microbial pathogens through a combination of chemical modification of a lead substance and experimental animal screening on a broad-scale. Hence, they are not only the founders of immunology but also were the first to envisage infection biology as the result of an interplay between host and pathogen.

Ozone and its usage in general medicine and dentistry. A review article.

Ozone, an allotropic form of oxygen, is successfully used in the treatment of different diseases for more than a hundred years. It is highly valued for various effects, such as antimicrobial, antihypoxic, analgesic, immunostimulating etc. on biological systems. These mechanisms of action supported with a lot of case reports and scientific studies allow using it in different fields of medicine. This review of literature is another attempt to summarize different modalities of ozone application in dentistry. Further studies are necessary to standardize indications and treatment protocols of this promising medical agent.

Resistencia bacteriana, una crisis actual / Bacterial resistance, a current crisis

La resistencia bacteriana es una constante batalla que representa un problema de Salud Pública. Tan es así que la Organización Mundial de la Salud (OMS) la considera de sus prioridades en salud, debido al impacto que genera tanto en la salud (dado que proyecciones recientes indican que para 2050 se producirán más muertes por esta causa que las ocasionadas actualmente por elcáncer), como a su impacto económico (que, de acuerdo a un estudio reciente en el Reino Unido(1), costará a la economía mundialun estimado de 100 billones de dólares anualmente). La veloz aparición de bacterias multirresistentes y panresistentes es unfenómeno de índole mundial, cuestionando la eficacia antibiótica. Implementar protocolos y recomendaciones es vital, de igualforma que es necesario conciencias al personal sanitario, tomando como base el conocimiento de generación de resistencia y suimpacto a través de los años, potenciado por la actual pandemia de la COVID-19.(AU)

Bacterial resistance is a constant battle representing a Public Health trouble. So much, that the World Health Organization consi-derate Public Health as a priority in health, due to the impact that generates as much as in health (giving that recent projectionsindicate that by 2050 it’ll be produced more deaths because of this than the ones occasioned because of cancer) as its economicimpact (which, according to a recent study in the United Kingdom(1), it’ll cost the world’s economy an estimated of 100 trilliondollars). The quick appearance of multidrug-resistant and pandrug-resistant bacteria is a world nature phenomenon, questioningthe antibiotics efficiency. Implement protocols and recommendations is essential, just as essential and necessary as give aware-ness to health personnel, taking as base the knowledge of resistance generation and its impact through the years, empoweredby the actual pandemic of COVID 19.(AU)

A brief history of antibiotics and select advances in their synthesis.

The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against these pathogens, the war against them has not been won. And it may never be. Drug resistance is still menacing the society with many lives being lost due to deadly infections caused by continuously evolving strains spread beyond our means to eradicate them or prevent their spreading. Herein, the emergence and evolution of antibiotics is briefly reviewed, and a select number of total syntheses of naturally occurring antibiotics from the authors' laboratories are highlighted. The article concludes with a strong endorsement of the current efforts to intensify our fight against these dangerous pathogens with the hope that, this time, these initiatives will be sufficiently focused and serious enough so as to achieve our set goals of, at least, being prepared and ahead of them as part of our drive to improve humanity's healthcare and wellbeing.

Review article: the history of acute infectious diarrhoea management--from poorly focused empiricism to fluid therapy and modern pharmacotherapy.

BACKGROUND: Acute diarrhoea management has progressed from largely ineffective measures in the early years to a more effective physiologic approach in recent years. AIM: To review the history of acute diarrhoea management. METHODS: Citations in PubMed were reviewed on 'acute diarrhoea treatment' along with an extensive file maintained by the corresponding author. RESULTS: Freedom from diarrhoea was equated in early military conflicts with bravery and strength where diarrhoea-free soldiers had the 'guts' to fight. Until early 20th century, colonic irrigants, purgatives and emetic drugs were used to help eliminate undesired intestinal contents. Only a few early authorities suggested the need for replacement of fluids and salt, now standard treatment. Drugs aimed at diarrhoea symptom control have been broadly used for more than 100 years. The evolving history of one of those drugs, kaopectate is unappreciated. Once understanding the pathophysiology and infectious aetiology of acute diarrhoea, new oral fluids, pharmacologic agents designed to block specific secretory alterations and anti-infective drugs have been identified. CONCLUSIONS: Physiologic and antimicrobial approaches to controlling diarrhoea can lead to reduction of stool number and enteric complaints, important in industrialized areas, with the potential for decreasing threat of fatal illness among infants in developing regions.

History and Current Use of Antimicrobial Drugs in Veterinary Medicine.

This chapter briefly reviews the history and current use of antimicrobials in animals, with a focus on food animals in the more economically developed countries. It identifies some of the differences between human medical and food animal use, particularly in growth promotional and "subtherapeutic" use of medically-important antibiotics in animals. The public health impact of the extensive use of antibiotics in food animals for these purposes, differences internationally in such usage, and the major changes in current practices now underway in agricultural use are summarized. The emerging framing of the dimensions of antimicrobial resistance within a "One Health" framework is focusing global efforts to address the antimicrobial resistance crisis in a collaborative manner. The rapidly evolving development and application of practices of antimicrobial stewardship in animal is a critical part of the huge global effort to address antimicrobial resistance. The outcome is still uncertain.

The history of qing hao in the Chinese materia medica.

Artemisinin is currently used for treating drug-resistant malaria. It is found in Artemisia annua and also in A. apiacea and A. lancea. Artemisia annua and A. apiacea were known to the Chinese in antiquity and, since they were easily confused with each other, both provided plant material for the herbal drug qing hao (blue-green hao). This article shows, however, that since at least the eleventh century Chinese scholars recognized the difference between the two species, and advocated the use of A. apiacea, rather than A. annua for 'treating lingering heat in joints and bones' and 'exhaustion due to heat/fevers'. The article furthermore provides a literal translation of the method of preparing qing hao for treating intermittent fever episodes, as advocated by the eminent physician Ge Hong in the fourth century CE. His recommendation was to soak the fresh plant in cold water, wring it out and ingest the expressed juice in its raw state. Both findings may have important practical implications for current traditional usage of the plant as an antimalarial: rather than using the dried leaves of A. annua in warm infusions, it suggests that fresh juice extraction from A. apiacea may improve efficacy.

Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80.

This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first-generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on.

Defensins and other antimicrobial peptides: a historical perspective and an update.

Antimicrobial peptides are effectors of innate immunity in phagocytes, body fluids and epithelia. In mammals, defensins, peptides with a characteristic six-cysteine framework, are particularly abundant and widely distributed in various animal species and tissues. The first part of this review provides a historical overview of the ideas that led to the current state-of-the-art in antimicrobial peptides, and the second part is an update on mammalian defensins and their role in host defense to infections.

[Dyes, indispensable tools for the 19th century's biologic and therapeutic revolution]. / Les colorants, outils indispensables de la révolution biologique et thérapeutique du XIXe siècle.

Born from growing organic chemistry laboratories, dyes were extensively used par textile industry before to be applied in field of biology and therapeutics. Besides their interest for diagnostic techniques due to cell visualization (Virchow, Papanicolaou), dyes allowed scientists to propose scientific hypothesis founding, in conjunction with new microscopy tools, modern basis for biology : tissue constitution, cellular and sub cellular structure, s.o. One of the brightest illustrations of these progresses is the birth of neuronal theory which due to silver print of brain tissue allowed to see intimacy of cerebral structures et propose an operating scheme (Golgi, Cajal). Therapeutic progresses born from dyes chemistry are multiple. First concentrated on the research of antimalarial drugs (Ehrlich) following the use of methylene blue, then generally, anti-infectious drugs, they gave birth to various chimiotherapeutic families: antiseptics, antiparasitic drugs, antibacterial, among which one of the most spectacular illustrations remain sulphonamides preparation.

Cooperative development of antimicrobials: looking back to look ahead.

As foundations and governments mobilize to tackle antimicrobial resistance (AMR), several experiments in academic-industrial collaboration have emerged. Here, I examine two historical precedents, the Penicillin Project and the Malaria Project of the Second World War, and two contemporary examples, the Tuberculosis Drug Accelerator programme and the Tres Cantos Open Lab. These and related experiments suggest that different strategies can be effective in managing academic-industrial collaborations, and that such joint projects can prosper in both multisite and single-site forms, depending on the specific challenges and goals of each project. The success of these strategies and the crisis of AMR warrant additional investment in similar projects.