La duda vacunal en España (1801), Ruiz de Luzuriaga en defensa de la vacunación / Vaccine hesitancy in Spain (1801), Ruiz de Luzuriaga responses in defense of vaccination

La rápida difusión del método jenneriano se cimentó en la sencillez para practicarlo, en su aparente eficacia para combatir las viruelas y en su oportunidad epidemiológica, ya que apareció en el momento de mayor recrudecimiento de la enfermedad. El impulso inicial para su propagación, que originó un reconocido movimiento de protección de la salud poblacional, no estuvo exento de controversia. A la vez que se iban sumando defensores de la vacuna, aparecían opiniones contrarias que utilizaban críticas diversas para desprestigiarla. La más común era divulgar sus supuestos fracasos utilizando los medios de comunicación de la época, para lo que se aireaban casos ocurridos en los hijos de personalidades notables de la sociedad. Ignacio María Ruiz de Luzuriaga (1763-1822), en calidad de secretario de la Real Academia de Medicina Matritense asumió un papel catalizador, convirtiéndose en protagonista de la historia inicial de la vacunación en España. Ha sido considerado como introductor, divulgador y ardiente defensor de la vacuna, tal como se desprende del análisis de la abultada correspondencia que generó entre 1801 y 1802, catalogada como "Papeles sobre la vacuna". Estos documentos, conservados en la biblioteca de la Academia, muestran su actividad como propagador del método y de su capacidad para dar respuesta a las dudas e inquietudes relacionadas con sus posibles efectos adversos, evitando que se pusiera en peligro la continuidad de las vacunaciones

The rapid diffusion of the jennerian method was founded in simplicity to practice, in its apparent effectiveness in combating smallpox and its epidemiological opportunity, as it appeared at the time of greatest recrudescence of the disease. The initial impulse for it's propagation, which originated a recognized movement to protect population health, was not without controversy. At the same time that defenders of the vaccine were added, opposite opinions appeared that used diverse critics to discredit it. The most common was to reveal their alleged failures using the media of the time, so cases were reported that occurred in the children of notable people in society. Ignacio María Ruiz de Luzuriaga (1763-1822), as secretary of the Royal Academy of Medicine he assumed a catalytic role, becoming the protagonist of the initial history of vaccination in Spain. It has been considered as an introducer, disseminator and ardent defender of the vaccine, as can be seen from the analysis of the bulky correspondence generated between 1801 and 1802 cataloged as "Papeles sobre la vacuna". These documents, preserved in the Academy library, show their activity as a propagator of the method and its capacity to respond to the doubts and concerns related to their possible adverse effects, avoiding jeopardizing the continuity of vaccines

Adverse events following adenovirus type 4 and type 7 vaccine, live, oral in the Vaccine Adverse Event Reporting System (VAERS), United States, October 2011-July 2018.

BACKGROUND: In March 2011, the U.S. Food and Drug Administration licensed adenovirus type 4 and type 7 vaccine, live, oral (Barr Labs, Inc.) (adenovirus vaccine) for use in military personnel 17 through 50 years of age. The vaccine was first universally administered to U.S. military recruits in October 2011. We investigated adverse event (AE) reports following the adenovirus vaccine submitted to the Vaccine Adverse Event Reporting System (VAERS). METHODS: We searched the VAERS database for U.S. reports among persons who received adenovirus vaccine during October 2011 through July 2018 including participants in a military observational study. We reviewed all serious reports and accompanying medical records. We compared the proportion of serious reports in a proxy military recruit population and reviewed all reports of suspected allergic reactions following adenovirus vaccination. RESULTS: During the analytic period, VAERS received 100 reports following adenovirus vaccination; 39 (39%) were classified as serious and of these, 17 (44%) were from the observational study. One death was reported. Males accounted for 72% of reports. Median age of vaccinees was 19 years (range 17-32). The most frequently reported serious AEs were Guillain Barré syndrome (GBS) (n = 12) and anaphylaxis (n = 8); of these, two GBS and all the anaphylaxis reports were reported in the observational study. Reports documented concurrent receipt of multiple other vaccines (95%) and penicillin G (IM Pen G) or other antibiotics (50%). CONCLUSIONS: The reporting rate for serious AEs was higher than with other vaccines administered in the comparison military recruit population (39% vs 18%); however, we identified no unexpected or concerning pattern of adenovirus vaccine AEs. Co-administration of vaccines and IM Pen G was commonly reported in this military population. These exposures may have contributed to the GBS and anaphylaxis outcomes observed with the adenovirus vaccine. Future adenovirus vaccine safety studies in a population without these co-administrations would be helpful in clarifying the vaccine's safety profile.

An historical overview over Pharmacovigilance.

Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio of drugs, improving patient's safety and the quality of life. In this commentary we report the milestones of pharmacovigilance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific journals, up to today's modern and ultra-structured electronic registries. The historical phases also help us to understand why pharmacovigilance helped us to achieve such important results for man's health and for pharmacology itself, and to identify the challenges that await Pharmacovigilance in future years.

Therapeutic disasters that hastened safety testing of new drugs.

New drugs were not required to undergo premarket safety testing in the United States until 1938, when a therapeutic disaster-the Elixir Sulfanilamide tragedy-prompted Congress to pass a bill mandating this now-routine process. History repeated itself nearly 25 years later, when another therapeutic disaster-the thalidomide tragedy-led to passage of new amendments in 1962 to ensure drug efficacy and greater drug safety. As is typical with historical events, critical information was gained that led to novel approaches for understanding, predicting, diagnosing, and managing drug-induced toxicities. Continued refinement of current, along with development of new, approaches will mitigate future drug-related catastrophes, with the goal of avoiding them entirely.

The history of pharmacovigilance.

This article reviews the main historical events before the 21st century and explained their consequences in the current pharmacovigilance legislation.

Historical aspects of immunization and vaccine safety communication.

It has been a long journey starting from the beginnings of variolation [3] leading up to the greatest success in the history of immunization: the eradication of smallpox [39]. Today, vaccines are an acknowledged important medical advance [40]. Nevertheless, immunization has been the subject of public controversy on several occasions [15, 24, 31]. This article shall provide a short overview of some aspects of the early stages of immunization in Western countries, including some examples of vaccine safety controversies in the past.

The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment.

Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia.

[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.

Medical science and the military: the Allies' use of amphetamine during World War II.

Although amphetamine was thoroughly tested by leading scientists for its effects in boosting or maintaining physical and mental performance in fatigued subjects, the results never provided solid grounds for approving the drug's use, and, in any case, came too late to be decisive. The grounds on which amphetamine was actually adopted by both British and American militaries had less to do with the science of fatigue than with the drug's mood-altering effects, as judged by military men. It increased confidence and aggression, and elevated "morale."

'Sexual chemistry' before the pill: science, industry and chemical contraceptives, 1920-1960.

The history of contraceptives met the history of drugs long before the invention of the contraceptive pill. In the first half of the twentieth century, numerous pharmaceutical laboratories, including major ones, manufactured and marketed chemical contraceptives: jellies, suppositories, creams, powders and foams applied locally to prevent conception. Efforts to put an end to the marginal status of these products and to transform them into 'ethical' drugs played an important role in the development of standardized laboratory tests of efficacy of contraceptive preparations; debates on the validity of such tests; evaluation of the long-term toxicity of chemical compounds; and the rise of collaborations between activists, non-profit organizations and the pharmaceutical industry. Chemical contraceptives were initially associated with quack medicine, shady commercial practices and doubtful morality. Striving to change the status of contraceptives and to promote safe and efficient products that reduced fertility in humans shaped some of the key features of the present-day production and regulation of pharmaceuticals.

The legal standards for the radioactive or non radioactive drugs research and approval in the European Community and in Germany after the thalidomide catastrophe.

The drug thalidomide was contained in the blockbuster Contergan, which has been used as a non- prescription sedative drug and a potent treatment for occurring morning sickness in pregnant women during the 1950s and the early 1960s. This therapeutic use has led to one of the most prominent disasters in the history of drug development due to peripheral neuritis and malformations, e.g. phocomelia, in babies whose mothers had taken thalidomide within their pregnancies. Moreover, this catastrophe initiated a change of paradigm in Germany as well as in Europe with regard to drug safety and the regulatory setting. This article describes the history of the use of thalidomide and the regulatory framework of drug approval at that time as well as changes after the Contergan disaster including considerations to radiopharmaceuticals. Additionally, aspects of drug safety in the different development phases of pharmaceuticals as well as radiopharmaceuticals, i.e. pre-clinical and clinical phases, are characterised. However, many drugs have been withdrawn from the market after approval due to changes with regard of their risk-benefit balance after the occurrence of adverse drug reactions. Thus, pharmacovigilance activities are also mentioned in this review article. Last, obstacles and future perspectives in the arena of drug research and development also considering the use of radiopharmaceuticals are delineated.

EMS in Viracept--the course of events in 2007 and 2008 from the non-clinical safety point of view.

Viracept (nelfinavir) is an HIV protease inhibitor supplied by Roche outside the US, Canada and Japan. Viracept was first introduced by Roche in 1998. Although newer protease inhibitors have become available for the treatment of HIV, it is viewed as a useful medicine for patients who are intolerant to ritonavir (since it does not require ritonavir boosting), pregnant women, and patients in resource-limited settings, since the formulation is heat-stable and does not require refrigeration. The relatively high prevalence of HIV in some of the third world countries means that it was also a product of choice for young women of childbearing age, pregnant and nursing women and young children. On 18 May 2007 F. Hoffmann-La Roche received first reports of a "bad smell" of blisterpacked Viracept tablets and one adverse drug report of nausea and vomiting from patients in Spain. Subsequently, ethyl methanesulfonate (EMS), an established mutagen, carcinogen and teratogen was identified as the potential source of the bad smell. On 6 June 2007, Viracept was globally recalled as the extent of the contamination exceeded the guidances for permissible levels set by regulatory authorities by more than 1000-fold and hence human risk was not readily assessable. In the following, a compilation of the course of events from a non-clinical point of view is presented. This compilation only partially reflects the complexity of the case and the interactions between all parties between May/June 2007 and September 2008 and hence necessarily remains partly a subjective compilation of the authors of this article. This compilation serves also as an introduction into this Special Issue of Toxicology Letters. The data on the cause and levels of contamination, likely duration of intake and affected patient population can be found in the subsequent contributions. Most importantly, we share in other parts of this Special Issue with the scientific community the data and risk assessment arguments that supported the conclusion by the company and regulatory authorities that the levels of contamination with EMS posed no health risk to affected patients.

[Controversial expertise. The "Scientific Advisory Committee for Drug Safety" and its role in drug regulation in the Federal Republic of Germany, 1968-1976]. / Umstrittene Expertise. Der Beirat "Arzneimittelsicherheit" in der bundesdeutschen Arzneimittelregulierung 1968-1976.

The article focuses on the "Scientific Advisory Committee for Drug Safety" of the Federal Ministry of Health. Highlighting the role this committee played in West Germany's policy on medicinal drugs, it shows how drug regulation during this period shifted from expert committees to a larger public consisting of media, pressure groups of alternative medicine and politicians.