Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19.

The emergence of SARS-CoV-2, and the ensuing global pandemic, has resulted in an unprecedented response to identify therapies that can limit uncontrolled inflammation observed in patients with moderate to severe COVID-19. The immune pathology behind COVID-19 is complex and involves the activation and interaction of multiple systems including, but not limited to, complement, inflammasomes, endothelial as well as innate and adaptive immune cells to bring about a convoluted profile of inflammation, coagulation and tissue damage. To date, therapeutic approaches have focussed on inhibition of coagulation, untargeted immune suppression and/or cytokine-directed blocking agents. Regardless of recently achieved improvements in individual patient outcomes and survival rates, improved and focussed approaches targeting individual systems involved is needed to further improve prognosis and wellbeing. This review summarizes the current understanding of molecular and cellular systems involved in the pathophysiology of COVID-19, and their contribution to pathogen clearance and damage to then discuss possible therapeutic options involving immunomodulatory drug delivery systems as well as summarising the complex interplay between them.

Scalable nanoprecipitation of niclosamide and in vivo demonstration of long-acting delivery after intramuscular injection.

The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate.

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.

Physicians' Attitudes Towards Treating Patients in the Context of COVID-19 Pandemic in Pakistan.

Background and objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the cause of a worldwide outbreak of respiratory illness, which has been declared as coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO). The outbreak has posed a huge challenge to countries around the world and has resulted in a global lockdown. The pandemic has especially overburdened the healthcare sector, resulting in a shortage of personnel and equipment. Along with many other manifestations, it has resulted in stress and anxiety for the physicians as well. Furthermore, many healthcare workers have been reluctant in treating COVID-19 patients. This study aimed to explore the concerns of physicians in the context of the COVID-19 pandemic and to evaluate the reasons for their reluctance to treat the patients. Methodology This descriptive cross-sectional study included 235 physicians from seven hospitals of Pakistan who were actively working amid the COVID-19 pandemic. Data were collected from March 1, 2020, to May 30, 2020, using a structured online questionnaire. Participants were approached via non-probability convenient sampling. Two hundred and eight respondents were included in the data analysis. SPSS Statistics version 23.0 (IBM Corp., Armonk, NY) was used for data entry and analysis. Results A striking 83.7% (n=174) of the respondents expressed their reluctance to treat patients with COVID-19. Concerns they raised included one or more of the following four reasons; lack of proper personal protective equipment (PPE), fear of self-infection, excessive workload, and fear of transmitting the infection to their family members. Of note, 92% (n=161) of the respondents reported a lack of PPE while 74.1% (n=129) reported fear of transmitting the infection to their family members as reasons for their reluctance. The vast majority of the participants reported the need for psychological training to treat the patients' anxiety (95.2%, n=198). Many participants were afraid that their own anxiety might be affecting the quality of care patients were receiving (67.3%, n=140). Hence, most of the participants reported that psychological counseling should be provided (93.3%, n=194). Participants with family members older than 60 years were found to be reluctant to treat patients due to the risk of transmitting the infection to them (69.7%, n=145, p=0.001). Therefore, a major proportion of the participants (96.2%, n=200) felt that the hospitals should provide a place for them to rest and temporarily isolate themselves to avoid coming into contact with their family members. Conclusions We conclude that a major proportion of physicians is reluctant to treat their patients due to multiple factors. The grave situation of the pandemic has taken a toll on their mental health, which could be affecting the quality of care that the patients receive. Their concerns should be addressed to not only provide them with support and improve their working environment but also to ensure that they are fully equipped to provide state-of-the-art care to the patients in these grave times.

The SARS-CoV-2 Pandemic and the Role of Honey and its Products as an Emerging Therapeutic Regime: A Review

The outbreak of pneumonia that broke out in Wuhan, in December 2019, later rapidly spread to the rest of the world. This was identified as Coronavirus disease 2019 (COVID-19) [officially renamed severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)] caused by a zoonotic beta Coronavirus entitled 2019 novel Coronavirus (2019-nCoV). The aim of this study was to summarize the biological features of SARSCoV-2, its clinical features and the possible antiviral effect of honey against SARS-CoV-2. For this purpose, recently published literature, official documents and selected up-to-date preprint studies were reviewed. The initial source of SARS-CoV-2 is still unknown but a possible animal-to-human transmission is indicated. Human spread of SARS-CoV-2 is due to droplet spread. The infected individual may present as symptomatic or asymptomatic, this varies from patient to patient mainly depending upon his/her immunity. To combat the current pandemic various modalities are under study, an important and harmless way of treatment might be the use of honey. Various studies have demonstrated antiviral effects of honey. Propolis and honey have shown promising anti-viral effect against SARS-CoV-2. Thus, the combined effect of honey and its products might open a door for developing a safe and highly efficient natural drug against COVID-19 infection. [ABSTRACT FROM AUTHOR] Copyright of Biomedica is the property of Knowledge Bylanes and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)