Critical insights to COVID‐19 disease and potential treatments using a systems analysis approach that integrates physiology, pharmacology, and clinical pharmacology

The power of pharmacology and its application by way of clinical pharmacology to provide invaluable insights into COVID19 disease is brought home vividly when exploring the infectivity and pathophysiology of SARSCOV2 in this pandemic. At its core, pharmacology utilizes and displays systems analysis to identify and correct aberrant physiology in disease or to provide much needed bridging intervention in a crisis. Pharmacology describes the impact of exogenous molecules upon living systems and to achieve this the discipline has over decades developed sophisticated measures to monitor absorption, distribution, excretion, and kinetics of interaction with the principal influenced tissues and receptors. SARSCOV2 is also an exogenous entity that displays some similar features as drugs of nasal or oral absorption, and which causes pathophysiologic responses in the human. Fortuitously, the application of spectacular advances in cell biology, structural biology, virology, and immunology to COVID19 disease has provided an invaluable background for this detailing of the pathogenesis of COVID19 from a pharmacological perspective. Employing wellestablished fundamental principles of pharmacology in COVID19 disease adds significantly to our knowledge base of COVID19 disease. Additionally, as highlighted earlier1 it is imperative to understand the pathogenic response in COVID19 disease when evaluating potential therapeutic interventions. It has also been argued in this Journal that globally we have missed significant opportunities to develop pharmacologically sound, physiologically appropriate, affordable, and effective therapeutic options with which to treat people who are unable to access effective vaccines or in whom despite vaccination are vulnerable to even a mild immune response to COVID19.2,3 The following thematic reviews specifically adopt a systems analysis approach using the pharmacological principles outlined above to further our insights into the role of SARSCOV2 in this pandemic. The sequence of these thematic reviews deserves comment. They have been deliberately arranged in an order that tracks the timebased development of the infection by SARSCOV2 following its species jump to the human, the tropism associated with nasopharyngeal infection and in individuals with serious disease to the progression to a dysregulated inflammatory state and in selected individuals the progression to ‘Long COVID’ with its differential host response. The Review by Head et al.4 focusses on the clash of two distinct evolutionary paths: that of the vulnerable complexity of the human with the lethal simplicity of SARSCoV2. In doing so it highlights the fundamental role played by thermodynamics in the spread of SARSCOV2 from the infection of a single cell through to the global population. In essence the SARSCoV2 hostdisease interface is a complex system that can be viewed from a pharmacological perspective. COVID19 can be seen as a unique synchrony of viral surface change with Gibbs free energy liberation upon target binding that drives thermodynamic spontaneity. In this way the authors have provided a rational basis for the time course of the pathophysiology, for it is this binding that permits viral tropism and distribution across populations. It is necessary that this thermodynamic spontaneity is repeated endlessly and an initial single host cell infection with subsequent spreads to bystander cells and to tissues. Head et al.4 also focused on the pivotal role of the mucosal layers in establishing a gradient with SARSCoV2 from the airway interface to the epithelial cell surface. It is an area that would appear important for designing any interventions to sequester this virus. Of major significance is the proposal that upper respiratory infection, favored by tropism, encourages SARSCoV2 selfassembly at scale and is a fundamental driver of global spread. In contrast, lower respiratory tract infection does not favor SARSCoV2 selfassembly at scale but critically drives COVID19 pathophysiology. It is this pathophysiology that is thoroughly explored by Lumbers et al.5 in their sequenced review. COVID19 has reminded us that coronaviruses are a particularly interesting example of increased virulence associated with the emergence of novel viruses, because of the very essential role that its receptor for cell entry plays in controlling inflammation and the immune response. SARS, SARSCov2, and HLN63 are three coronaviruses that use the angiotensinconverting enzyme receptor type II (ACE2) to enter cells. All three viruses cause morbidity and mortality via an overwhelming immune response, mediated at least in part by


Critical insights to COVID-19 disease and potential treatments using a systems analysis approach that integrates physiology, pharmacology, and clinical pharmacology
The power of pharmacology and its application by way of clinical pharmacology to provide invaluable insights into COVID-19 disease is brought home vividly when exploring the infectivity and pathophysiology of SARS-COV-2 in this pandemic. At its core, pharmacology utilizes and displays systems analysis to identify and correct aberrant physiology in disease or to provide much needed bridging intervention in a crisis. Pharmacology describes the impact of exogenous molecules upon living systems and to achieve this the discipline has over decades developed sophisticated measures to monitor absorption, distribution, excretion, and kinetics of interaction with the principal influenced tissues and receptors.
SARS-COV-2 is also an exogenous entity that displays some similar features as drugs of nasal or oral absorption, and which causes pathophysiologic responses in the human. Fortuitously, the application of spectacular advances in cell biology, structural biology, virology, and immunology to COVID-19 disease has provided an invaluable background for this detailing of the pathogenesis of COVID-19 from a pharmacological perspective. Employing wellestablished fundamental principles of pharmacology in COVID-19 disease adds significantly to our knowledge base of COVID-19 disease. Additionally, as highlighted earlier 1 it is imperative to understand the pathogenic response in COVID-19 disease when evaluating potential therapeutic interventions. It has also been argued in this Journal that globally we have missed significant opportunities to develop pharmacologically sound, physiologically appropriate, affordable, and effective therapeutic options with which to treat people who are unable to access effective vaccines or in whom despite vaccination are vulnerable to even a mild immune response to COVID-19. 2,3 The following thematic reviews specifically adopt a systems analysis approach using the pharmacological principles outlined above to further our insights into the role of SARS-COV-2 in this pandemic. The sequence of these thematic reviews deserves com-  ACE2 is a component of the renin-angiotensin system (RAS) which is classically viewed as a circulating endocrine system which through the actions of its major peptide, angiotensin II (Ang II) controls blood pressure and fluid and electrolyte homeostasis. Drugs that limit the actions of Ang II either by limiting its production or interfering with its interaction with the AT1 receptor have therefore been a mainstay in the treatment of hypertension and cardiac fibrosis. What is less widely appreciated is the role of local RAS in various organs and tissues, including fat tissue and vital organs. 6 However, the value of drugs that block the RAS in preventing organ damage is most evident in the heart and kidneys. The term "tissue RAS" may, however, limit our thinking. Aldosterone and its resultant endothelial damage, vasoconstriction and fluid retention is also implicated in fibrotic disease from COVID-19 infection.
It also appears that tissue angiotensin peptides and antialdosterone agents would seem to be a key focus of interest in discussing repurposing of drugs to treat inflammation induced by SARS-CoV-2 infection 5 rather than considering the RAS in its classi- Additionally, the enzyme ACE 2, a homologue of ACE, has two critical actions in blocking Ang II which are also potential key targets for therapeutics development. First, it catabolizes Ang II to Ang (1)(2)(3)(4)(5)(6)(7) and in doing so, it produces Ang (-1-7) which has opposing effects on tissues, cells, biochemical pathways etc, to those produced by Ang II.
Like ACE, ACE2 is widely distributed throughout almost every organ of the body and along the lining of blood vessels. Furthermore, ACE2 is a highly conserved protein having appeared early in evolution as it is found in chordates >100 million years ago. All examples of human viruses with broad host ranges use highly conserved cell receptors (i.e., with more than 90% amino acid sequence homology).
There are thus major consequences of destruction of ACE2 by SARS-CoV-2 including enhanced activity of tissue angiotensins and extremely widespread involvement of tissues and organs, and a multiplicity of effects causing inflammation that can be modi- In retrospect, it is clear that infection with SARS-CoV-2 (COVID-19) swept the world with amazing rapidity in contrast to the related SARS and MERS. Its major threat was to overwhelm universal health care systems particularly because of the number of older and comorbid patients affected, although it does not spare the young or healthy from developing severe forms of the disease requiring prolonged intensive care. Regardless of whether infection is asymptomatic or not, SARS-CoV-2 causes long-term sequelae (including so-called "long COVID") which is starting to appear to impose considerable health and economic burden for future generations. 7 Therefore, in this Journal, Jarrott et al. 8 has teased apart "Long COVID," both to develop a hypothesis for understanding the biological basis of the differential host response, and to guide clinical trials of pharmacological treatment strategies. It is noted that a significant proportion of people experience this "Long COVID"-a variety of troubling symptoms that appear to be associated with persistent low-level cytokine concentrations and low-grade general inflammation. Among other therapeutics that can affects these pathways, drugs that activate the intracellular transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) may increase the expression of enzymes to synthesize the intracellular antioxidant glutathione that will quench the free radicals that cause oxidative stress.
Interestingly, Jarrott suggests that the hormone melatonin, already a therapeutic in clinical use, has been identified as an activator of Nrf2 and it is discussed as a potential pharmacological treatment option, Readers of this Themed Review will see that the movement of SARS-CoV-2 within humans and across the human populations displays the key characteristics of a complex system that underpins COVID-19 disease. That is, it is a powerful motive for reflecting on potential for therapeutic development, as timing and dose is key.
Furthermore, this complex system is powerfully described by the thermodynamic considerations underpinning the physiological and | 3 of 3 EDITORIAL pharmacological properties of SARS-CoV-2, from infection of a single cell to its global spread in this pandemic. We must accept that the virus is the metaphorical center of our biological solar system and humans merely an opportunity for it to replicate at scale and to mutate.
Underlying this is the opportunity to find and exploit the weaknesses of the virus, as well as halt the inflammatory process, driven through Ang II becoming a vasoconstrictive endothelialitis. This knowledge will enable a scientific basis by which to choose the best drugs for clinical trialing and in the appropriate dosages and timing.
Collectively the three reviews provide a time-based portrayal of COVID-19 disease from its first entry to the human to its damaging deregulation of the inflammatory response to the devasting prolonged effects with "Long COVID." Based on a systems approach made possible by a pharmacological approach, the reviews integrate the important underpinning descriptive sciences, described for COVID-19 disease. In this way, a dynamic view of the viral infection, passage, and pathophysiology is obtained. Importantly these reviews addressed the issue of repurposed therapeutics in the context of the pathogenic responses to COVID-19 disease as previously highlighted. 1 This is made possible by the unique features of human physiology, pathology, and pharmacology; the disciplines that permit an integrated systems analysis approach to this disease. It will be important for the future to project system analysis with these disciplines to the forefront of responses to further unforeseen subsequent pandemics.