Potential Targets for Treatment of Coronavirus Disease 2019 (COVID-19): A Review of Qing-Fei-Pai-Du-Tang and Its Major Herbs.

COVID-19 has been declared a pandemic by WHO on March 11, 2020. No specific treatment and vaccine with documented safety and efficacy for the disease have been established. Hence it is of utmost importance to identify more therapeutics such as Chinese medicine formulae to meet the urgent need. Qing Fei Pai Du Tang (QFPDT), a Chinese medicine formula consisting of 21 herbs from five classical formulae has been reported to be efficacious on COVID-19 in 10 provinces in mainland China. QFPDT could prevent the progression from mild cases and shorten the average duration of symptoms and hospital stay. It has been recommended in the 6th and 7th versions of Clinical Practice Guideline on COVID-19 in China. The basic scientific studies, supported by network pharmacology, on the possible therapeutic targets of QFPDT and its constituent herbs including Ephedra sinica, Bupleurum chinense, Pogostemon cablin, Cinnamomum cassia, Scutellaria baicalensis were reviewed. The anti-oxidation, immuno-modulation and antiviral mechanisms through different pathways were collated. Two clusters of actions identified were cytokine storm prevention and angiotensin converting enzyme 2 (ACE2) receptor binding regulation. The multi-target mechanisms of QFPDT for treating viral infection in general and COVID-19 in particular were validated. While large scale clinical studies on QFPDT are being conducted in China, one should use real world data for exploration of integrative treatment with inclusion of pharmacokinetic, pharmacodynamic and herb-drug interaction studies.

Pandemics throughout the centuries.

Pandemics have ravished the globe periodically, often associated with war, at times commencing as fever and rash, beginning in recorded history in the crowded walled city of Athens during the Peloponnesian War as described in great detail by the Athenian historian and military general Thucydides in 430 BCE. As the world now faces the first major pandemic of the 21st century, we focus on the "plague" commencing in Athens in 430 BCE and the 2 pandemics of the more recent century, which killed more than one million, the Spanish flu of 1918 and the Asian flu of 1957. The latter linked with successful vaccine development thanks to the heroic efforts of microbiologist Maurice Hilleman. We now look back and then forward to the viral infection coronavirus disease 2019 now devastating the world.

An ancient viral epidemic involving host coronavirus interacting genes more than 20,000 years ago in East Asia.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors-pointing to which viruses have future pandemic potential. Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that likely started more than 20,000 years ago. These adaptive events were limited to the population ancestral to East Asian populations. Multiple lines of functional evidence support an ancient viral selective pressure, and East Asia is the geographical origin of several modern coronavirus epidemics. An arms race with an ancient coronavirus, or with a different virus that happened to use similar interactions as coronaviruses with human hosts, may thus have taken place in ancestral East Asian populations. By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to better predict the pandemics of the future. Importantly, adaptation to ancient viral epidemics in specific human populations does not necessarily imply any difference in genetic susceptibility between different human populations, and the current evidence points toward an overwhelming impact of socioeconomic factors in the case of coronavirus disease 2019 (COVID-19).

History and future of pandemics / Historia y futuro de las pandemias

Este artículo presenta una historia general de las epidemias históricas y de las nuevas enfermedades emergentes, señalando sus factores desencadenantes. Se afirma que las epidemias son inevitables, y que su riesgo aumenta en proporción al tamaño, la complejidad y el poder tecnológico de nuestras sociedades. La historia enseña que las epidemias han sido casi siempre desencadenadas por cambios en el ambiente ocasionados por las propias actividades humanas. Las enfermedades infecciosas son manifestación de una interacción ecológica entre la especie humana y otra especie de microorganismos. Y las epidemias son resultado del cambio en algún factor ambiental capaz de influir en esa interacción. Las catástrofes epidémicas son inevitables: en primer lugar, porque no podemos evitar formar parte de cadenas tróficas en las que comemos y somos comidos por los microbios; en segundo lugar, porque las infecciones son mecanismos evolutivos y factores reguladores del equilibrio ecológico, que regulan sobre todo el tamaño de las poblaciones; y, en tercer lugar, porque las intervenciones técnicas humanas, al modificar los equilibrios previos, crean equilibrios nuevos que son más vulnerables. De este modo las sociedades humanas son más vulnerables cuanto más complejas. Y los éxitos humanos en la modificación de condiciones ambientales conservan, o más bien aumentan, el riesgo de catástrofes epidémicas. Todas las necesarias medidas de vigilancia y control epidemiológico imaginables pueden disminuir los daños que producen las epidemias, pero nunca podrán evitarlas.

This article presents a general history of historical epidemics, and new emerging diseases, pointing out their triggers. It is claimed that epidemics are inevitable, and that their risk increases in proportion to the size, complexity, and technological power of our societies. History teaches that epidemics have almost always been triggered by changes in the environment caused by human activities themselves. Infectious diseases are manifestations of an ecological interaction between the human species and another species of microorganisms. And epidemics are the result of a change in some environmental factor capable of influencing that interaction. Epidemic catastrophes are inevitable: firstly, because we cannot help but be part of trophic chains in which we eat and are eaten by microbes; secondly, because infections are evolutionary mechanisms and regulatory factors of ecological balance, which regulate especially the size of populations; and thirdly, because human technical interventions, in changing previous balances, create new balances that are more vulnerable. In this way human societies are more vulnerable the more complex. And human successes in modifying environmental conditions retain, or rather increase, the risk of epidemic catastrophes. All necessary epidemiological surveillance and control measures imaginable can lessen the damage caused by epidemics, but they can never prevent them.

Pandemics: Historically Slow "Learning Curve" Leading to Biomedical Informatics and Vaccine Breakthroughs.

BACKGROUND: The worldwide tragedy of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic vividly demonstrates just how inadequate mitigation and control of the spread of infectious diseases can be when faced with a new microorganism with unknown pathogenic effects. Responses by governments in charge of public health, and all other involved organizations, have proved largely wanting. Data infrastructure and the information and communication systems needed to deal with the pandemic have likewise not been up to the task. Nevertheless, after a year of the worldwide outbreak, hope arises from this being the first major pandemic event in history where genomic and related biosciences - relying on biomedical informatics - have been essential in decoding the viral sequence data and producing the mRNA and other biotechnologies that unexpectedly rapidly have led to investigation, design, development, and testing of useful vaccines. Medical informatics may also help support public health actions and clinical interventions - but scalability and impact will depend on overcoming ingrained human shortcomings to deal with complex socio-economic, political, and technological disruptions together with the many ethical challenges presented by pandemics. OBJECTIVES: The principal goal is to review the history of biomedical information and healthcare practices related to past pandemics in order to illustrate just how exceptional and dependent on biomedical informatics are the recent scientific insights into human immune responses to viral infection, which are enabling rapid antiviral vaccine development and clinical management of severe cases - despite the many societal challenges ahead. METHODS: This paper briefly reviews some of the key historical antecedents leading up to modern insights into epidemic and pandemic processes with their biomedical and healthcare information intended to guide practitioners, agencies, and the lay public in today's ongoing pandemic events. CONCLUSIONS: Poor scientific understanding and excessively slow learning about infectious disease processes and mitigating behaviors have stymied effective treatment until the present time. Advances in insights about immune systems, genomes, proteomes, and all the other -omes, became a reality thanks to the key sequencing technologies and biomedical informatics that enabled the Human Genome Project, and only now, 20 years later, are having an impact in ameliorating devastating zoonotic infectious pandemics, including the present SARS-CoV-2 event through unprecedently rapid vaccine development. In the future these advances will hopefully also enable more targeted prevention and treatment of disease. However, past and present shortcomings of most of the COVID-19 pandemic responses illustrate just how difficult it is to persuade enough people - and especially political leaders - to adopt societally beneficial risk-avoidance behaviors and policies, even as these become better understood.

[From the Antonine Plague to the Cyprian Plague: Scopes and consequences of global plagues in the Roman Empire in the 3rd century AD.] / De la Peste Antonina a la Peste de Cipriano: Alcances y consecuencias de las pestes globales en el Imperio Romano en el siglo III d.C.

Between the 2nd and 3rd centuries the Roman Empire suffered two great plagues, the Antonine Plague, of which there is a bibliography, and the lesser known Plague of Cyprian. As an overview, both pandemics resemble the crisis that in 2020 the Coronavirus is generating in many aspects of human life. This article focuses on the impact that the Cyprian plague had in the context of the crisis of the third century, its mortality is estimated between 10-20% of the population in the affected places, finally its effects generated several of the necessary conditions for the transition from the ancient to the medieval world. It is about understanding how the cycle of plagues that went from the 2nd century to the 3rd century changed the appearance of the Roman world and what lessons history gives us 1700 years later.

Pandemics: past, present, future: That is like choosing between cholera and plague.

The major epidemic and pandemic diseases that have bothered humans since the Neolithic Age and Bronze Age are surveyed. Many of these pandemics are zoonotic infections, and the mathematical modeling of such infections is illustrated. Plague, cholera, syphilis, influenza, SARS, MERS, COVID-19, and new potential epidemic and pandemic infections and their consequences are described and the background for the spread of acute and chronic infections and the transition to endemic infections is discussed. The way we can prevent and fight pandemics is illustrated from the old and new well-known pandemics. Surprisingly, the political reactions through different periods have not changed much during the centuries.

Protection against severe infectious disease in the past.

Before the 20th century many deaths in England, and most likely a majority, were caused by infectious diseases. The focus here is on the biggest killers, plague, typhus, smallpox, tuberculosis, cholera, typhoid, dysentery, childhood infections, pneumonia, and influenza. Many other infectious diseases including puerperal fever, relapsing fever, malaria, syphilis, meningitis, tetanus and gangrene caused thousands of deaths. This review of preventive measures, public health interventions and changes in behavior that reduced the risk of severe infections puts the response to recent epidemic challenges in historical perspective. Two new respiratory viruses have recently caused pandemics: an H1N1 influenza virus genetically related to pig viruses, and a bat-derived coronavirus causing COVID-19. Studies of infectious diseases emerging in human populations in recent decades indicate that the majority were zoonotic, and many of the causal pathogens had a wildlife origin. As hunter-gatherers, humans contracted pathogens from other species, and then from domesticated animals and rodents when they began to live in settled communities based on agriculture. In the modern world of large inter-connected urban populations and rapid transport, the risk of global transmission of new infectious diseases is high. Past and recent experience indicates that surveillance, prevention and control of infectious diseases are critical for global health. Effective interventions are required to control activities that risk dangerous pathogens transferring to humans from wild animals and those reared for food.

Face Masks: Their History and the Values They Communicate.

Masks, now recommended and worn by a growing proportion of the world's population, have reflected various perceived meaning across time. This paper provides a brief history of the socio-cultural perceptions attached to wearing a mask by surveying how masks were perceived in ancient Greece and Rome, the origins of medical masks, and the ascribed socio-cultural meaning of masks during the COVID-19 pandemic. The use of a mask has historically diverse perceived meanings; currently, wearing a mask communicates a bipolar socio-cultural meaning and a nuanced, divisive symbology. To some, masks communicate a belief in medical science and a desire to protect one's neighbor from contagion. To others, a mask communicates oppression, government overreach, and a skepticism toward established scientific principles. It is the mask's ability to signal a deception, or extrapolated more broadly, a value system, that is highly relevant to current public health guidelines encouraging mask use to decrease the transmission of SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic. Public health officials and providers should utilize evidence-based health communication strategies when findings warrant a reversed recommendation of a symbol (such as masks) with a legacy of socio-cultural underpinnings that are deep-seated, complex, and emotional.

Are we Athens or Florence? COVID-19 in historical context.

We have been here before. In 430 BCE, a plague struck Athens, killing as much as 25% of the population. In 1347 CE, the bubonic plague afflicted western Europe for 4 years, killing as much as 50% of the population. The plague of Athens led to a collapse of their religion, cultural norms and democracy. In contrast, the bubonic plague led eventually to the Renaissance, a growth of art, science and humanism. As we contend with the COVID-19 global pandemic, will we become Athens or Florence?

[Reflections on the meaning of pain, suffering and death]. / Reflexiones sobre el sentido del dolor, el sufrimiento y la muerte.

The main aim of this paper is to define an answer, in a key time before COVID19, if it is indeed possible to do so, as to the difference between pain and suffering. In order to do so, we will refer to, although not exclusively, the reflexions of the German philosopher Robert Spaemann. To finish, the question of death will briefly be analysed.

Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential.

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary interstitial inflammatory disease of unknown etiology, and is also a sequela in severe patients with the Coronavirus Disease 2019 (COVID-19). Nintedanib and pirfenidone are the only two known drugs which are conditionally recommended for the treatment of IPF by the FDA. However, these drugs pose some adverse side effects such as nausea and diarrhoea during clinical applications. Therefore, it is of great value and significance to identify effective and safe therapeutic drugs to solve the clinical problems associated with intake of western medicine. As a unique medical treatment, Traditional Chinese Medicine (TCM) has gradually exerted its advantages in the treatment of IPF worldwide through a multi-level and multi-target approach. Further, to overcome the current clinical problems of oral and injectable intakes of TCM, pulmonary drug delivery system (PDDS) could be designed to reduce the systemic metabolism and adverse reactions of the drug and to improve the bioavailability of drugs. Through PubMed, Google Scholar, Web of Science, and CNKI, we retrieved articles published in related fields in recent years, and this paper has summarized twenty-seven Chinese compound prescriptions, ten single TCM, and ten active ingredients for effective prevention and treatment of IPF. We also introduce three kinds of inhaling PDDS, which supports further research of TCM combined with PDDS to treat IPF.

Public perception of laboratory animal testing: Historical, philosophical, and ethical view.

The use of laboratory animals in biomedical research is a matter of intense public debate. Recent statistics indicates that about half of the western population, sensitive to this discussion, would be in favor of animal testing while the other half would oppose it. Here, outlining scientific, historical, ethical, and philosophical aspects, we provide an integrated view explaining the reasons why biomedical research can hardly abandon laboratory animal testing. In this paper, we retrace the historical moments that mark the relationship between humans and other animal species. Then starting from Darwin's position on animal experimentation, we outline the steps that over time allowed the introduction of laws and rules that regulate animals' use in biomedical research. In our analysis, we present the perspectives of various authors, with the aim of delineating a theoretical framework within which to insert the ethical debate on laboratory animals research. Through the analysis of fundamental philosophical concepts and some practical examples, we propose a view according to which laboratory animals experimentation become ethically acceptable as far as it is guided by the goal of improving humans and other animal species (i.e., pets) life. Among the elements analyzed, there is the concept of responsibility that only active moral subjects (humans) have towards themselves and towards passive moral subjects (other animal species). We delineate the principle of cruelty that is useful to understand why research in laboratory animals should not be assimilated to a cruel act. Moreover, we touch upon the concepts of necessity and "good cause" to underline that, if biomedical research would have the possibility to avoid using animals, it would surely do that. To provide an example of the negative consequences occurring from not allowing laboratory animal research, we analyze the recent experience of Covid-19 epidemic. Finally, recalling the principle of "heuristics and biases" by Kahneman, we discuss why scientists should reconsider the way they are conveying information about their research to the general public.

Tutankhamun's Antimalarial Drug for Covid-19.

Drug repositioning is a strategy that identifies new uses of approved drugs to treat conditions different from their original purpose. Current efforts to treat Covid-19 are based on this strategy. The first drugs used in patients infected with SARS-CoV-2 were antimalarial drugs. It is their mechanism of action, i. e., rise in endosomal pH, which recommends them against the new coronavirus. Disregarding their side effects, the study of their antiviral activity provides valuable hints for the choice and design of drugs against SARS-CoV-2. One prominent drug candidate is thymoquinone, an antimalarial substance contained in Nigella sativa - most likely one of the first antimalarial drugs in human history. Since the outbreak of the pandemic, the number of articles relating thymoquinone to Covid-19 continuously increases. Here, we use it as an exemplary model drug, compare its antiviral mechanism with that of conventional antimalarial drugs and establish an irreducible parametric scheme for the identification of drugs with a potential in Covid-19.Translation into the laboratory is simple. Starting with the discovery of Nigella sativa seeds in the tomb of Pharaoh Tutankhamun, we establish a physicochemical model for the interaction of thymoquinone with both coronavirus and cells. Exploiting the predictive capability of the model, we provide a generalizable scheme for the systematic choice and design of drugs for Covid-19. An unexpected offshoot of our research is that Tutankhamun could not have died of malaria, a finding contrary to the mainstream theory.

[Epidemics: lessons from History]. / Épidémies: Leçons d'Histoire.

TITLE: Épidémies: Leçons d'Histoire. ABSTRACT: Jusqu'au milieu du XVIIIe siècle, l'espérance de vie était de 25 ans dans les pays d'Europe, proche alors de celle de la préhistoire. À cette époque, nos ancêtres succombaient, pour la plupart, à une infection bactérienne ou virale, quand la mort n'était pas le résultat d'un épisode critique, comme la guerre ou la famine. Un seul microbe suffisait à terrasser de nombreuses victimes. L'épidémie de SARS-CoV-2 est là pour nous rappeler que ce risque est désormais à nouveau d'actualité. Si son origine zoonotique par la chauve-souris est probable, la contamination interhumaine montre son adaptation rapide à l'homme et permet d'évoquer ainsi la transmission des épidémies, qu'elle soit ou non liée à des vecteurs, ces derniers pouvant représenter dans d'autres occasions un des maillons de la chaîne.

Learning from the past in the COVID-19 era: rediscovery of quarantine, previous pandemics, origin of hospitals and national healthcare systems, and ethics in medicine.

After the dramatic coronavirus outbreak at the end of 2019 in Wuhan, Hubei province, China, on 11 March 2020, a pandemic was declared by the WHO. Most countries worldwide imposed a quarantine or lockdown to their citizens, in an attempt to prevent uncontrolled infection from spreading. Historically, quarantine is the 40-day period of forced isolation to prevent the spread of an infectious disease. In this educational paper, a historical overview from the sacred temples of ancient Greece-the cradle of medicine-to modern hospitals, along with the conceive of healthcare systems, is provided. A few foods for thought as to the conflict between ethics in medicine and shortage of personnel and financial resources in the coronavirus disease 2019 era are offered as well.