Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)

Sanders, James M.; Monogue, Marguerite L.; Jodlowski, Tomasz Z.; Cutrell, James B

doi:10.1001/jama.2020.6019

Cited by 2,363 publications

(3,091 citation statements)

References 78 publications

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“…management. The implications of drug interactions have already been raised for this reason with lopinavir/ritonavir use for COVID-19 [60] and are likely to be exacerbated with the higher ritonavir dose needed for tipranavir. Moreover, tipranavir has a black box warning from the FDA for fatal and nonfatal intracranial haemorrhage as well as severe hepatotoxicity [61][62][63].…”

Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are 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 lung, in order to maximise the potential for success of proposed human clinical trials.

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Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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“…Lastly, several notable mechanistic classes demonstrated lack of any activity or were significantly enriched among molecules that trended toward amplifying the disease phenotype. ACE inhibitors and angiotensin receptor blockers (ARBs) have been the subject of interest given their widespread use and reported viral entry into the cell via the ACE2 receptor 26 . These classes showed no significant activity.…”

mentioning

confidence: 99%

Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2

Heiser

McLean

Davis

et al. 2020

Preprint

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To identify potential therapeutic stop-gaps for SARS-CoV-2, we evaluated a library of 1,670 approved and reference compounds in an unbiased, cellular image-based screen for their ability to suppress the broad impacts of the SARS-CoV-2 virus on phenomic profiles of human renal cortical epithelial cells using deep learning. In our assay, remdesivir is the only antiviral tested with strong efficacy, neither chloroquine nor hydroxychloroquine have any beneficial effect in this human cell model, and a small number of compounds not currently being pursued clinically for SARS-CoV-2 have efficacy. We observed weak but beneficial class effects of -blockers, mTOR/PI3K inhibitors and Vitamin D analogues and a mild amplification of the viral phenotype with -agonists.

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“…There is a need to determine which of the antiviral agents that have already been synthesized and tested through the first and second phase of approval, which prove sufficiently effective to block the virus entry and/or stop or slow down its multiplication to gain time for the innate and adapted reaction of the whole immune system. Within this approach, a list of agents have already been tested, including the combination of chloroquine or hydroxychloroquine with azithromycin, oseltamivir, lopinavir/ritonavir, darunavir, favipiravir, remdesivir, and ivermectin [15,[121][122][123][124]. With different, either unspecific or targeted mechanisms of action, each of them had been successfully used against other viruses or parasites.…”

Section: Therapeutic Optionsmentioning

confidence: 99%

COVID-19 — Toward a comprehensive understanding of the disease

et al. 2020

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The evidence on the pathophysiology of the novel coronavirus SARS-CoV-2 infection is rapidly growing. Elucidating why some patients suffering from COVID-19 are getting so sick, while others are not, has become an informal imperative for researchers and clinicians around the globe. The answer to this question would allow rationalizing the fear surrounding this pandemic. Understanding of the pathophysiology of COVID-19 relies on unraveling of interplaying mechanisms, including SARS-CoV-2 virulence, human immune response, and complex inflammatory reactions with coagulation playing a major role. An interplay with bacterial co-infections, as well as the vascular system and microcirculation affected throughout the body should also be examined. More importantly, a comprehensive understanding of pathological mechanisms of COVID-19 will increase the efficacy of therapy and decrease mortality. Herewith, the authors present a combined viewpoint based on the current state of knowledge on COVID-19: beginning from the virus, its transmission, and mechanisms of entry into the human body, through the pathological effects on the cellular level, up to immunological reaction, systemic and organ presentation. Last but not least, currently available and possible future therapeutic and diagnostic options are briefly commented on. (Cardiol J 2020; 27, 2: 99-114)

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Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)

Cited by 2,363 publications

References 78 publications

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2

COVID-19 — Toward a comprehensive understanding of the disease

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