Remdesivir for severe acute respiratory

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COVID-19: An evaluation of the
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Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19:

An evaluation of the evidence

Yu-chen Cao, Qi-xin Deng, Shi-xue Dai

PII: S1477-8939(20)30116-2
DOI: https://doi.org/10.1016/j.tmaid.2020.101647
Reference: TMAID 101647

To appear in: Travel Medicine and Infectious Disease

Received Date: 5 March 2020

Revised Date: 17 March 2020
Accepted Date: 26 March 2020

Please cite this article as: Cao Y-c, Deng Q-x, Dai S-x, Remdesivir for severe acute respiratory
syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence, Travel Medicine and
Infectious Disease (2020), doi: https://doi.org/10.1016/j.tmaid.2020.101647.

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Remdesivir for Severe Acute Respiratory Syndrome Coronavirus 2

causing COVID-19: an evaluation of the evidence

Yu-chen Cao1*, Qi-xin Deng1*, Shi-xue Dai2, M.D.

*: The two authors are equal in contribution to this review.

1 The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong,

China

2 Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong

Academy of Medical Sciences, South China University of Technology, Guangzhou 510080,

Guangdong, China

Corresponding Author: Shi-xue Dai, MD & PhD, Associate Professor of Medicine.

Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong

Academy of Medical Sciences, South China University of Technology, Guangzhou 510080,

Guangdong, China. Email: shixuedai@hotmail.com

1
Abstract

The novel coronavirus infection that initially found in Wuhan at the end of 2019 has attracted

great attention. So far, the number of infectious cases has increased globally to more than 100

thousand and defined as a pandemic situation, but there are still no "specific drug" available.

Relevant reports have pointed out the novel coronavirus has 80% homology with SARS. In the

difficulty where new synthesized drug cannot be applied immediately to patients, “conventional

drug in new use” has become a feasible solution. The first medication experience of the recovered

patients in the US has led remdesivir to be the "specific drug". China has also taken immediate

action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics

for Corona Virus Disease 2019 (COVID-19). We started from the structure, immunogenicity, and

pathogenesis of coronavirus infections of the novel coronavirus. Further, we analyzed the

pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting

experiments on COVID-19.

Keywords: severe acute respiratory syndrome coronavirus 2, Corona Virus Disease 2019,

remdesivir, phase III clinical trial

Introduction

The novel coronavirus 2019 (2019-nCoV), officially named severe acute respiratory

syndrome coronavirus 2 (SARS-CoV-2), is a newly-emerged human infectious coronavirus. It

initially originated in a seafood market in Wuhan, a city with a population of 11 million. Since

2
December 2019, it has spread rapidly in China in a short period of time. As of 17 March 2020,

there have been 81116 confirmed cases and 3231 deaths. It has spread to other countries, such as

Korea, Japan, Italy, Singapore, and Iran, with a total of 85296 cases confirmed. Due to it is a

newly-emerged virus, researchers have taken quick actions to isolate the virus and perform gene

sequencing, making identifying treatments possible. Even so, it takes time to develop new drugs

and vaccines, as well as to explore biotherapeutics, thus it is unlikely to be applied to patients with

urgent need. Therefore, "conventional drug in new use" becomes a viable solution. The

SARS-CoV-2 is 80% homologous with the acute respiratory syndrome-associated coronavirus

(SARS-CoV), which also broke out in China in 2002, and some enzymes are even more than 90%

homologous.[1] Consequently, we are expecting to find drugs for the treatment of COVID-19 from

the experience of SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV). Some drugs,

such as ribavirin, interferon, lopinavir, and corticosteroids, have been used in patients with SARS

or MERS,[2] within the selection range of “conventional drug in new use”. Through clinical

treatment of the COVID-19, it has been found that neuraminidase inhibitors (oseltamivir,

peramivir, zanamivir), ganciclovir, acyclovir, ribavirin are ineffectual and not recommended for

clinical application.[3] When we set our sights on the broad-spectrum antiviral drugs, we found that

a drug unlisted, remdesivir, has demonstrated strength in trials related to MERS-CoV and Ebola

virus infection. In the United States, the first patient with COVID-19 has shown significant

improvement in clinical symptoms within 24 hours of treatment with remdesivir. This case has

convinced the public that remdesivir could become a new "specific drug" for COVID-19. This

article starts from the structure, immunogenicity, and pathogenesis of infection of the

SARS-CoV-2, and then analyzes the feasibility of conducting trials and putting into clinical use of

3
COVID-19 from the pharmacological characteristics and successful cases of remdesivir.

1 Structure and immunogenicity of SARS-CoV-2

SARS-CoV-2 is an enveloped, single, and positive stranded RNA virus. The virus particles

are round or oval in shape, with a diameter about 60~140nm. Based on sequence analysis, it

shows that the novel coronavirus belongs to Beta coronavirus Lineage β, Sarbecovirus, where

SARS-CoV and MERS-CoV are included. However, it forms a new clade different from

SARS-CoV and MERS-CoV, and becomes the seventh member of the coronavirus family to infect

humans.[4]

SARS-CoV-2 shows the typical beta coronavirus organization: 5’ untranslated region (UTR),

replication enzyme coding region, S gene, E gene, M gene, N gene, 3’ UTR, and several

unidentified nonstructural open reading frames (Figure 1).[4] The replication enzyme coding region

mainly expresses and encodes two large genes: ORF1a and ORF1b, which encode 16

nonstructural proteins (nsp1 ~ nsp16) that are highly conserved throughout the coronavirus. S

gene, M gene, E gene, and N gene respectively encode four main structural proteins: spike (S),

membrane (M), envelope (E), and nucleocapsid (N) proteins. The S protein is the receptor binding

site, which is on the viral surface; The M protein shapes the virions, promotes membrane

curvature, and is responsible for the transport of nutrients across cell membranes; the E protein

plays a role in the assembly and release of virus, and is involved in viral pathogenesis; the N

protein can bind virus RNA genome and maintain its stability.[5] Among them, S protein plays a

key role in virus recognizing and binding to host cell surface receptors, and mediating the fusion

of virus envelope and cell membrane.[6] Through the analysis of the whole genome sequence of

SARS-CoV-2, it shares 40% sequence similarity with MERS-CoV and 80% sequence similarity

4
with SARS-CoV, indicating that SARS-CoV-2 is more compatible with SARS-CoV.[7] In addition,

by performing systematic structural simulations and immunogenicity scans of the S proteins of all

coronaviruses, as well as calculating the immunogenic distance between SARS-CoV-2 and other

coronavirus subtypes, it can be concluded that the immunogenicity of the S protein of

SARS-CoV-2 is closer to that of SARS-CoV.[8] It is known that SARS-CoV enters target cells by

binding the S protein to the ACE2 receptor on the cell surface, which is triggered by the cell serine

protease TMPRSS2.[9] In view of the 76% amino acid similarity between SARS-CoV-2 and

SARS-CoV,[10] we can speculate that the novel coronavirus may have a similar function to

SARS-CoV, which has been preliminary proved in bioinformatics prediction methods as well as in

vitro tests.[9]

Previous studies have shown that 4 of the 5 key amino acids of the S protein on the surface of

SARS-CoV-2 that binds to angiotensin-converting enzyme 2 (ACE2) receptor on the target cells

have changed. It was suspected it may affect the affinity of the S protein to ACE2 receptor, and in

turn affect the spread of the virus among the public.[10] However, through calculation methods of

molecular structure simulation, the interaction between the S protein of SARS-CoV and the ACE2

receptor has perfectly maintained in a holistic manner.[11] At present, it has been proved that the

binding affinity between the extracellular domain of the S protein of SARS-CoV-2 and ACE2

receptors is about 10-20 times higher than that of SARS-CoV, which may facilitate

human-to-human transmission of SARS-CoV-2.[12]

2 The pathogenic mechanisms of COVID-19

COVID-19 is a respiratory syndrome caused by SARS-CoV-2 infection. In general,

COVID-19 is an acute resolved disease, and the most common symptoms at onset are fever, dry

5
cough, and fatigue, partly with nausea, diarrhea, or other gastrointestinal symptoms. Compared

with SARS and MERS, COVID-19 has milder clinical symptoms and lower fatality,[13, 14] but it

can also be fatal. Severe patients may develop diffuse alveolar injury, progressive respiratory

failure, and acute respiratory distress syndrome (ARDS) and so on.

Similar to SARS-CoV, the receptor binding domain (RBD) of S protein on the surface of

SARS-CoV-2 binds to the ACE2 receptor on the cell surface to facilitate the virus entering the

host cell; then the virus exposes its RNA, translates its RNA replicase, and forms an RNA

replicase-transcriptase complex. Through transcription and replication, the complex forms RNA

negative strands that will be translated for the structural proteins of the virus later. Then the

structural proteins and RNA in the cytoplasm assemble into new viral particles, which are released

from infected cells by exocytosis to infect other cells (Figure 2). Each infected cell produces

thousands of novel viral particles that spread to bronchi, eventually reach the alveoli, and

extrapulmonary organs, causing pneumonia and targeted organic infections. However, the ACE2

receptor is not only expressed in the respiratory organs. It has been reported that, by using the

RNA-seq method to express ACE2 receptors in human tissues, the number of ACE2 receptors

expressed in the gastrointestinal tract (high in esophagus, small intestine, and colon, but low in

stomach), kidneys, and testes is nearly 100 times higher than that in the lung,[15] suggesting that

these tissues may also be the target organs for SARS-CoV-2 invasion. It may explain why some

patients with COVID-19 developed other system injuries clinically besides respiratory system

injuries. Furthermore, it have been found that SARS-CoV-2 nucleic acid detection is positive in

the feces of some patients, indicating that there may be live virus in the feces, and the digestive

system may be a potential route for COVID-19.[16]

6
 In COVID-19, in addition to the direct damages caused by the virus, the indirect immune

injuries caused by the injured tissues also attract great concern, which may be related to the

severity and fatality of the disease. Previous studies have shown that pulmonary inflammation and

extensive lung injury in patients with SARS are associated with an increase in proinflammatory

cytokines (such as IL-1β, IL-6, IL-12, IFN-γ, IP-10, and MCP-1) in serum.[17] And it has been

reported that the MERS-CoV infection induced elevated proinflammatory cytokine concentrations

(such as IFN-γ, TNF-α, IL-15, and IL-17) in serum.[18] We note that patients with COVID-19 also

have high levels of IL-1β, IFN-γ, IP-10, and MCP-1 in their serum, leading to activation of the

Th1 cell responses. Furthermore, the concentrations of GCSF, IP-10, MCP-1, MIP-1A, and TNF-α

in ICU patients were higher than those in non-ICU patients, indicating that cytokine storms were

associated with disease severity. Apart from this, SARS-CoV-2 infection also activates the

secretion of cytokines (such as IL-4 and IL-10) in Th2 cell responses that suppress inflammation,

which is different from SARS-CoV infection.[17] Further researches are needed to investigate the

responses of Th1 and Th2 in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19.

Currently, the pathogenesis of COVID-19 is unclear. The first pathologic autopsy of a patient

with COVID-19 demonstrated that the lungs of the patient reviews diffuse alveolar injury and

pulmonary hyaline membrane formation, consistent with ARDS. The overall pathological

manifestations of the lungs were similar to SARS and MERS. Flow cytometry signified that the

number of CD4+ and CD8+ T lymphocytes in peripheral blood was greatly reduced, but their state

was overactivated. Other than this, CCR4+ and CCR6+ Th17 lymphocytes with highly

proinflammatory effects increased in CD4+ T lymphocytes; CD8+ T lymphocytes had a high

concentration of cytotoxic granules, of which 31.6% were perforin positive, 64.2% were particle

7
lysin positive, and 30.5% were both particle lysin and perforin positive. It manifests that the

severe immune injury in this patient may be closely linked to the overactivation of T lymphocytes

characterized by the increase of Th17 lymphocytes and the high cytotoxicity of CD8+ T

lymphocytes.[19]

We presume that the failure to develop a full adaptive immune response to COVID-19 could

be due to: The progression of pneumonia was too rapid to allow the available establishment of

adaptive immune responses. Likewise, the counts of peripheral CD4+ and CD8+ T lymphocytes

were substantially reduced, leading to insufficient immune defenses. Furthermore, Peripheral T

lymphocytes are in an over-activated state, manifested by increase of Th17 and high cytotoxicity

of CD8+ T lymphocytes, accounting for to a certain degree of immune injury in patients. This over

activation not only failed to establish an immune response, but also caused tissue injuries, mostly

manifested as severe injury in the lungs, and some patients died of multiple organ failure. This

situation further accelerates the deterioration and shortens the course of the disease, hampering the

establishment of fully adaptive immune response. The immunopathological injuries caused by the

over activation also provides us with an idea for treating COVID-19, for example, we can

probably apply the IL-17 inhibitor (secukinwmab) directed against Th17 cell activation, but it still

need more exploration. Also, vaccines are also one of the solutions to make up for the lack of

adaptive immune response.

The latest study terms that the changes of viral nucleic acid in patients with COVID-19 is

similar to that in patients with influenza, but different from those with SARS. Viral load can be

detected not only in symptomatic patients but also in asymptomatic patients, pointing out the

potential for virus transmission in asymptomatic or mildly symptomatic patients. These findings

8
are coherent with reports evidencing that the virus transmission may have occurred early in

infectious processes, illustrating that case detection and isolation may require a different strategy

from that required to control SARS-CoV.[20]

3 Structure, pharmacokinetics, and RCTs of remdesivir

Remdesivir (GS-5734) is a nucleoside analogs drug (Figure 3B) with extensive antiviral

activity and effective treatment of lethal Ebola and Nipah virus infections in nonhuman

primates.[21] As an RNA-dependent RNA polymerase (RdRp) inhibitor, it can inhibit the

replication of multiple coronaviruses in respiratory epithelial cells. A recent study reported that

remdesivir competes with natural counterpart ATP. Once remdesivir added into the growing chain

(i position), it cannot cause an immediate stop. On the contrary, it will continue to extend three

more nucleotides down to stop the strand at (i + 3) position (Figure 2).[22]

In the Ces1c (-/-) mouse SARS model, the preventive treatment trial of remdesivir achieved

satisfactory results. Administering 1 day after the onset of the disease, lung virus titers decreased

significantly, with improvements on pulmonary function. Administering 2 days after the onset, the

pulmonary virus titer can be obviously reduced, but the survival rate of mice is still relatively low.

This study implied that when the pulmonary injuries reach the maximum, simply reducing the

virus titer can no longer suppress the strong immune responses in mice, also showing that

administering before the peak of virus replication can significantly improve symptoms of the

infected mice. In a rhesus monkey model infected with MERS-CoV, treating with remdesivir
[23]

24h before infection can completely prevent symptoms caused by MERS-CoV, strongly inhibit

viral replications in the respiratory tract, and prevent the formation of pulmonary lesions.

Administering remdesivir 12 hours after infection provides clear clinical benefits, reducing

9
clinical symptoms, lung virus replication, and lung lesions.
[24]

Pharmacokinetic experiments in cynomolgus monkeys showed the first-pass effect of oral

remdesivir resulted in a low bioavailability of the drug. Intramuscular injection of 3 mg/kg had a

50% survival rate compared with the control group. Administering intravenously at a dose of 10

mg/kg, remdesivir rapidly decomposed into the original drug (nucleoside phosphate) in rhesus

monkeys. Within two hours, remdesivir quickly distributed in peripheral blood mononuclear cells

(PBMCs), and soon afterwards activated to nucleoside triphosphate to reach a peak, with a

survival rate of 100%.[25] As for pharmacokinetic studies in vivo, after the intravenous infusion of

the remdesivir solution formulation at a single dose of 3 to 225 mg for two hours, it showed

dose-linear pharmacokinetics. Intravenous infusion of 150 mg of a remdesivir solution repeated

one hour per day showed a linear pharmacokinetics over a period of 14 days. After intravenously

injecting 75 and 150 mg of remdesivir solution formulations over two hours, the pharmacokinetic

profile was similar to that of a lyophilized formulation. Intravenous infusion of 75 mg of drug

over 30 minutes provides similar levels of parent drug exposure to the same dose over two hours

(Table 1). After the intravenous infusion, remdesivir will enter the cellular metabolism to form

active GS-443902 (Figure 3C), but the frequencies of PBMCs exposure of GS-443902 is higher

than those of intravenous infusion of remdesivir 150 mg within two hours. Studies in PBMCs

show that the half-life of GS-443902 is more than 35h.[26] In the case of daily administration, the

active substance of the drug GS-443902 will accumulate in vivo. As a result, in large-scale clinical

trials, after the first dose of 200 mg is administered, the subsequent dose is adjusted to 100 mg to

ensure the proper blood concentration in vivo.[27]

Intravenous infusions in previously phase I clinical trials have good safety and

10
pharmacokinetic properties. Also, no cytotoxicity, hepatorenal toxicity, or no serious adverse

reactions related to metering have been observed in climbing experiments. Subjects were tolerant

in studies that repeated 150 mg intravenously daily for 7 to 14 days. Remdesivir did not show any

renal injuries in a multi-dose study.[26] Phase II clinical trials were conducted in Ebola

virus-infected patients. In clinical trials of anti-Ebola drugs, the fatality rate of patients in the

experimental group using remdesivir was 53%, and the efficacy was significantly worse than that

of the two monoclonal antibodies MAb114 (fatality rate 35%) and REGN-EB3 (fatality rate

33%).[27] The 53% fatality rate was not significantly different from the average 50% fatality rate of

Ebola virus infection, and as a result, phase II clinical trials were stopped. Nevertheless, in

consideration of Ebola's high lethality and monoclonal antibodies with more obvious therapeutic

effects, when there are merely 175 patients injected remdesivir, we cannot assume remdesivir of

no avail. The small sample size is not enough to deny the effect of remdesivir. Moreover, receptors

of Ebola virus are widely distributed in vivo, not only to the respiratory tract, but also to the

digestive tract, urinary tract, and blood system, etc., causing mortally hemorrhagic fever; in

addition, Ebola virus persists in the eyes and central nervous system for long[28]. Once remdesivir

entering body, it will be quickly distributed to the testis, epididymis, eyes, and brain, but relatively

less in eyes and brain.[29] All these indicate that the wide range of spread of Ebola virus in the high

lethality tissues make remdesivir control Ebola ineffectively. The Wuhan Virus Research Institute

conducted in vitro experiments on COVID-19 of remdesivir and found that remdesivir was the

fastest-acting and most powerful antiviral agent. In the primary culture of human airway epithelial

cells in vitro, SARS-CoV’s IC50 = 0.069 µM, MERS-CoV’s IC50 = 0.074 µM, and the

dose-dependent effect on virus inhibition,[2] which is speculatively related to the fact that

11
remdesivir triphosphate cannot be removed by nsp14-ExoN.[30] It has been conjectured the loss of

function of exonuclease may be involved with the three additional nucleotides added after the

incorporation of remdesivir into the extended strand.[22]

In vitro and animal models, remdesivir has demonstrated activity against both SARS and

MERS that also belong to coronaviruses, and theoretically provides support its effectiveness in

treating COVID-19.

4 Successful cases of remdesivir in treating COVID-19

Presently, there have been successful cases of remdesivir in the treating COVID-19. The New

England Journal of Medicine reported the entire course of rehabilitation of the first patient with

COVID-19 in the United States. The patient once visited Wuhan but was neither directly exposed

to Wuhan Seafood Market nor had direct contact with the diagnosed patients. He returned to

Washington on 15 January 2020. On 19 January, due to cough and fever for four days, he went to

the hospital for emergency treatment, and was then diagnosed with COVID-19. His condition was

stable from the second to the fifth day of admission (the sixth to ninth day of onset). On the

evening of the fifth day of admission, the blood oxygen saturation decreased to 90%. The

condition continued to worsen, and chest radiographs on the sixth day of admission (tenth day of

onset) showed typical characteristics of COVID-19. In view of the continuous aggravation of the

patient’s clinical symptoms, the physicians gave a chartered medication (Compassionate Use) to

remdesivir on the evening of the 6th day of admission, and began to give intravenous to the patient

on the evening of the seventh day of admission (the eleventh day of onset), without adverse

reactions. Vancomycin was discontinued that night and cefepime was discontinued the following

day. On the eighth day of admission (the twelfth day of onset), the patient’s clinical symptoms

12
were improved, and the oxygen saturation increased to 94%. Although the patient was still

hospitalized as of 30 January 2020, all symptoms had been resolved except for cough and

occasional running nose.[31]

It is worth noting that from the data in the article, it can be found the viral load of patients has

decreased before remdesivir injection (Table 2), which is not described in detail in the original

report. It’s known that the viral infection is self-limiting, and the patient is a mild to moderate

infectious case with a controlled fever in time, thus it is possible that his recovery is related to the

role of self-defense mechanisms and supportive treatment as well. It cannot be inferred that the

improvement of patients’ condition after taking the drug is definitely connected to remdesivir.

Whether there is a link between the improvement of the symptoms and the drug is worth further

consideration.

Clinical symptoms, especially respiratory symptoms, have been improved significantly

within 24 hours, bringing hope for the treatment of patients with severe COVID-19. For

COVID-19 no specific medication is available, remdesivir is expected to be a "specific drug".

However, for the acute infectious diseases, reducing the number of viral copies in the body is the

key point. Also, the efficacy of the drug should be focused on the pharmacokinetics and kinetics

data of COVID-19 in the ongoing phase III clinical trials.

5 Feasibility of trials on remdesivir on COVID-19

The outbreak of SARS-CoV-2 in Wuhan constituted an epidemic threat in China. The World

Health Organization announced it a public health emergency of international concern on 30

January 2020. During the outbreak, the number of confirmed cases in China showed an

exponential growth. The people and the government of the country tried their best to fight the

13
epidemic with soaring combat mood. The nation’s enthusiasm to fight the epidemic provides the

trials on COVID-19 a favorable environment. At the same time, Article 23 of China’s new Drug

Administration Law, which came into effect on 1 December 2019, has enabled the

"Compassionate Use" to develop adaptively in China. Two clinical trials on remdesivir have

passed the most stringent ethical review of the 74 projects. On 5 February 2020 the trial has

officially launched with experimental drugs provided by Gilead Sciences for free in China by

professor Chen Wang, an academician of Chinese Academy of Engineering, an internationally

renowned respiratory expert who successfully suggested Chinese Government building “Fang

Cang” hospitals to cure more than 10 thousand mild or prepatent COVID-19 patients[32]. Due to

the large number of confirmed cases of COVID-19 in China with no effective drugs, it is easy to

collect clinical samples for trials theoretically. However, the rigor of the included samples

hindered recruitment. As public attach more attention on prevention and treatment, fewer patients

meet stringent inclusion criteria, resulting in a slow recruitment process. Another reason is that

there are plenty of drugs in the clinical trials, speeding up the patients’ leaving hospital.

Nevertheless, it has been reported that more severe patients have been recruited, which provides

favorable conditions for the trial of the severe group, and as a result, at least, it can be rapidly

applied to the clinical treatment of severe patients in the near future. The need of treatment on

COVID-19 is urgent, so if the results of clinical trials prove it has the potential to benefit the

treatment, according to China’s "Compassionate Use", remdesivir will be more immediately used

in patients with severe illness. Meanwhile, the opening of green channels under special

circumstances to speed up the review and approval process of the drug approval center will

undoubtedly help save the lives of critical patients and promote the developing of “specific drugs”.

14
In the absence of clinical trial results, it is still difficult to put remdesivir into large scale clinical

use[33]. With the political support, the rapid development of clinical trials on remdesivir is

imperative.

A drug, GS-441524 (compound A, Figure 3A) for treating feline infectious peritonitis (FIP)

caused by coronavirus infection in cats has been tested in cats. Its safety and effectiveness in

treating FIP have been proven,[34] with FDA’s approval. It can be seen from the structure that

remdesivir is phosphorylated from GS-441524, with identical target RdRp (Figure2). It is

noteworthy that though coronavirus reproduces more than 20 generations in GS-441524 yields

resistance, the resistant virus is still sensitive to high concentrations of remdesivir and the fitness

of the resistant virus has reduced to the same level as wild-type MERS-CoV,[35] which avoids

resistant mutant coronaviruses from producing resistant supervirus. At the beginning of

developing remdesivir, Gilead Science selected a large number of nucleosides or their prodrugs to

conduct in vitro growth inhibition experiments on Ebola-infected human microvascular

endothelial cells in the laboratory and found compound A showed inhibitory activity (EC50=0.78

μM), and the compound A was GS-441524. Thereafter, on the basis of Compound A, after

examining the activity and toxicity of compounds surrounding Compound A, modifying the

prodrug, and optimizing amino acids and acyl groups, the cynomolgus monkey performs a

pharmacokinetic test to select a structure such as GS-5734 (Figure 3B).[25] Although in phase II it

was not as effective as competitive drugs and clinical trials were terminated, remdesivir showed

good safety and pharmacokinetics in both phases I and II clinical trials. COVID-19 has once again

brought remdesivir to the stage of clinical trials. Whether the results of phase III clinical trial will

make its comeback to the stage is worthy of expectation.

15
 Phase II clinical trials have demonstrated human tolerance to remdesivir. Of the 175 patients

in the phase II clinical trial administering remdesivir, 9 were reported to have serious adverse

reactions, 8 of whom were considered not related to drugs, and 1 with severe hypotension was

thought to be drug-related, but still not confirmed.[27] The GS-441524, a drug used to treat FIP, has

shown a high degree of safety in feline trials as well. The focal injection site reactions only

showed in immediate pain with vocalization, occasional growling, and postural changes lasting for

30–60s. These initial reactions were relieved after the owners became more adept at administering

the injection. Except for a cat with a slight increase in urea nitrogen and SDMA of the third round

of treatment, no other symptoms of systemic poisoning were observed.[34] Relevant research

signified that through a large number of synthesis and structure-activity analysis, the toxicity was

greatly reduced after GS-411524 was synthesized into GS-5734 (remdesivir).[36] The safety of

remdesivir in human is further speculated.

Coronaviruses must replicate nucleic acids to generate new progeny virus after entering

human cells. SARS-CoV-2 is known to be single stranded RNA virus, so RdRp must be used to

replicate nucleic acids. Remdesivir, a nucleotide analogues, act as RdRp inhibitor, can provide a

scheme for blocking RNA replication. Related studies have found that it plays a role in the final

stage of entering the cell, which is consistent with its expected mode of action. Wuhan Virus

Research Institute carried out a vitro inhibition test and found that remdesivir can block virus

infection at very low micromolar concentration of Vero E6 cells infected with virus, and the cell

selectivity is high (EC50 = 0.77 μM, CC50 > 100 μM, SI > 129.87).[2] In an anti-Ebola infection

experiment on cynomolgus monkeys, intravenous injection of 10 mg/kg of remdesivir, the drug

can exist in the blood for a long time and can inhibit to Ebola virus with a percentage of 100.[25]

16
Wuhan Virus Research Institute’s research that applied remdesivir to Vero E6 cells with an EC90=

1.76 μΜ, lower than that of the monkey model, draw to a speculation that it could also play a role

in SARS-CoV-2 infected monkeys. Based on the effectiveness in previous researches, although

there are many unknowns and limits of remdesivir, the phase III clinical trials on SARS-CoV-2 are

not only a fight against this epidemic, but also of strategic importance to reserve more effective

antiviral drugs for the future.

Conclusion

Strategic reservation for antiviral drugs will avoid the difficulty of medicine unavailable

when an outbreak comes again. Remdesivir’s situational and political superiority, as well as its

previous research results and application effects make it imperative to carry out the clinical trials

focusing on the SARS-CoV-2. Given that SARS-CoV-2 is an RNA virus that is easy to mutate, the

rapid starting of clinical trials is undoubtedly a right choice to prevent the resistance mutation due

to blind medication. It has been covered in the World Health Organization (WHO)

Director-General’s opening remarks at the media briefing on COVID-19 on 20 February 2020 that

the two clinical trials on remdesivir of therapeutics prioritized by the WHO R&D Blueprint are

expected preliminary results in three weeks. On February 24, the WHO cast a vote of confidence

for Gilead Sciences' experimental antiviral drug, remdesivir, indicating that remdesivir has great

potential and may be the best candidate for the treatment of COVID-19. Whatever the progress of

the clinical trials is, we are expecting that the clinical trials of remdesivir, a starring drug, would

bring outstanding breakthroughs to the treatment of COVID-19, or more promisingly, other virus

infection in the future.

17
Contributors：
：

All authors contributed to the conception of the Review. YC Cao and QX Deng reviewed the

literature and drafted the manuscript. SX Dai critically reviewed the manuscript. All authors

contributed to the revision of the manuscript.

Conflicts of interest:

The authors report no conflicts

Acknowledgements:

This review was funded by the National Natural Science Foundation of China (NSFC, No.

81300370), a General Program (No. 2017M622650) and a Special Support Program (No.

2018T110855) from China Postdoctoral Science Foundation (CPSF), as well as by the Natural

Science Foundation of Guangdong (NSFG, 2018A030313161).

18
Table 1 Drug concentrations in plasma and the concentration of pharmacologically active

substances in PBMCs in healthy people

Table 2 Viral load in the first course of rehabilitation in the United States

Figure 1 The RNA diagram of SARS-CoV-2

The structure of spike protein is downloaded from RCSB PBD

(http://www.rcsb.org/pdb/home/home.do, accessed Feb 25); The model that S protein receptor

binding domain (RBD) bind to ACE2 is downloaded from National Microbiology Data Center

(http://nmdc.cn/?from=groupmessage&isappinstalled=0#/, accessed Feb 25).

Figure 2 SARS-CoV-2 invasion process and how remdesivir works

1 SARS-CoV-2 enters target cells by binding the S protein to the ACE2 receptor on the cell

surface; 2 Remdeivir, the nucleotide analogues, act as RdRp inhibitors ,can provide a scheme for

blocking RNA replication; 3 Once remdesivir added into the growing chain (I position), is cannot

cause an immediate stop. On the contrary, it will continue to extend three more nucleotides down

to stop the strand at (i + 3) position; 4 Remdesivir triphosphate cannot be removed by

nsp14-ExoN.

Figure 3 Structure of remdesivir and its precursors and metabolites

The original structure of the drug is derived from DRUGBANK (https://www.drugbank.ca,

accessed Feb 25)

19
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coronavirus (2019-nCoV) in vitro.[J]. Cell research,2020.

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Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and

respiratory diseases,2020,43:E2.

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2019[J]. The New England journal of medicine,2020,382(8):727-733.

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2019-nCoV and SARS virus[J]. Journal of Genetics and Genomics,2020.

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probable bat origin[J]. Nature,2020,579(7798):270-273.

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Prefusion Conformation[J]. bioRxiv,2020:2020-2022.

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in Wuhan, China[J]. Lancet (London, England),2020,395(10223):497-506.

[14] Chan J F, Yuan S, Kok K, et al. A familial cluster of pneumonia associated with the 2019 novel

coronavirus indicating person-to-person transmission: a study of a family cluster[J]. Lancet (London,

England),2020,395(10223):514-523.

[15] Fan C, Li K, Ding Y, et al. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis

Damage After 2019-nCoV Infection[J]. medRxiv,2020:2020-2022.

[16] Zhang H, Kang Z, Gong H, et al. The digestive system is a potential route of 2019-nCov infection:

a bioinformatics analysis based on single-cell transcriptomes[J]. bioRxiv,2020:2020-2021.

[17] Wong C K, Lam C W K, Wu A K L, et al. Plasma inflammatory cytokines and chemokines in

severe acute respiratory syndrome[J]. Clinical & Experimental Immunology,2004,136(1):95-103.

[18] Mahallawi W H, Khabour O F, Zhang Q, et al. MERS-CoV infection in humans is associated with

a pro-inflammatory Th1 and Th17 cytokine profile[J]. Cytokine,2018,104:8-13.

[19] Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory

distress syndrome[J]. The Lancet. Respiratory medicine,2020:S2213-S2600.

[20] Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of

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Infected Patients[J]. N Engl J Med,2020.

[21] Mk L, F F, Jm G, et al. Remdesivir (GS-5734) protects African green monkeys from Nipah virus

challenge.[J]. Science translational medicine,2019,11(494).

[22] Cj G, Ep T, Jy F, et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA

polymerase from Middle East respiratory syndrome coronavirus.[J]. The Journal of biological

chemistry,2020.

[23] Tp S, Ac S, Sr L, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir,

ritonavir, and interferon beta against MERS-CoV.[J]. Nature communications,2020,11(1):222.

[24] de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734)

treatment in the rhesus macaque model of MERS-CoV infection[J]. Proc Natl Acad Sci U S A,2020.

[25] Warren T, Jordan R, Lo M, et al. Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus

Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus

Disease (EVD) in Infected Non-human Primates[J]. 2015,139(3):311-320.

[26] Appendix 4. Summaries of evidence from selected experimental therapeutics, as of October

2018[J].( https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?u

a=1 accessed in 17 March,2020)

[27] S M, Le D, Rt D, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.[J].

The New England journal of medicine,2019,381(24):2293-2303.

[28] L B, Ds C, Km J, et al. The Pathogenesis of Ebola Virus Disease.[J]. Annual review of

pathology,2017,12:387-418.

[29] Tk W, R J, Mk L, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in

rhesus monkeys.[J]. Nature,2016,531(7594):381-385.

22
[30] Jordan P C, Stevens S K, Deval J. Nucleosides for the treatment of respiratory RNA virus

infections[J]. Antivir Chem Chemother,2018,26:1631083325.

[31] Kim J Y, Choe P G, Oh Y, et al. The First Case of 2019 Novel Coronavirus Pneumonia Imported

into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures[J]. J

Korean Med Sci,2020,35(5):e61.

[32] Chen S, Yang J, Yang W, et al. COVID-19 control in China during mass population movements at

New Year[J]. The Lancet,2020,395(10226):764-766.

[33] Ja A, Ah A, Za M. Remdesivir as a possible therapeutic option for the COVID-19.[J]. Travel

medicine and infectious disease,2020:101615.

[34] Pedersen N C, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog

GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis[J]. J Feline Med

Surg,2019,21(4):271-281.

[35] Ml A, El A, Ac S, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is

Mediated by the Viral Polymerase and the Proofreading Exoribonuclease.[J]. mBio,2018,9(2).

[36] A C, Ol S, T B, et al. Synthesis and antiviral activity of a series of 1'-substituted

4-aza-7,9-dideazaadenosine C-nucleosides.[J]. Bioorganic & medicinal chemistry

letters,2012,22(8):2705-2707.

23
Table 1 Drug concentrations in plasma and the concentration of pharmacologically active
substances in PBMC in healthy people
75mg 150mg
Time (min)
30 120 120
Drug in plasma (μM) 0.09 0.13 0.23
GS-443902 in PBMC(μM) 0.031 0.014 0.023
Table 2 Viral load in the first course of rehabilitation in the United States
4th day onset 7th day onset 11th day onset
Nasopharyngeal swab Ct*，18-20 Ct，23-24 Ct，33-34
Oropharyngeal swab Ct，21-22 Ct，32-33 Ct，36-40
（*：Higher Ct means lower viral load）
Figure 1 The RNA diagram of SARS-CoV-2
The structure of spike protein is downloaded from RCSB PBD
(http://www.rcsb.org/pdb/home/home.do, accessed Feb 25); The model that S protein receptor
binding domain (RBD) bind to ACE2 is downloaded from National Microbiology Data Center
(http://nmdc.cn/?from=groupmessage&isappinstalled=0#/, accessed Feb 25).
Figure 2 SARS-CoV-2 invasion process and how remdesivir works
1 SARS-CoV-2 enters target cells by binding the S protein to the ACE2 receptor on the cell surface; 2 Remdeivir, the nucleotide analogues, act as RdRp
inhibitors ,can provide a scheme for blocking RNA replication; 3Once remdesivir added into the growing chain (i position), is cannot cause an immediate stop. On
the contrary, it will continue to extend three more nucleotides down to stop the strand at (i + 3) position; 4 Remdesivir triphosphate cannot be removed by
nsp14-ExoN.
Figure 3 Structure of remdesivir and its precursors and metabolites
The original structure of the drug is derived from DRUGBANK (https://www.drugbank.ca,
accessed Feb 25)
Another random document with
no related content on Scribd:
12. “A horse and a sword | from my hoard will I
give,
And a ring gives Bragi to boot,
That hatred thou makst not | among the gods;
So rouse not the great ones to wrath.”

Loki spake:

13. “In horses and rings | thou shalt never be rich,

Bragi, but both shalt thou lack;
Of the gods and elves | here together met
Least brave in battle art thou,
(And shyest thou art of the shot.)”

Bragi spake:

14. “Now were I without | as I am within, [157]

And here in Ægir’s hall,
Thine head would I bear | in mine hands away,
And pay thee the price of thy lies.”

Loki spake:

15. “In thy seat art thou bold, | not so are thy
deeds,
Bragi, adorner of benches!
Go out and fight | if angered thou feelest,
No hero such forethought has.”
Ithun spake:

16. “Well, prithee, Bragi, | his kinship weigh,

Since chosen as wish-son he was;
And speak not to Loki | such words of spite
Here within Ægir’s hall.”

Loki spake:

17. “Be silent, Ithun! | thou art, I say, [158]

Of women most lustful in love,
Since thou thy washed-bright | arms didst wind
About thy brother’s slayer.”

Ithun spake:

18. “To Loki I speak not | with spiteful words

Here within Ægir’s hall;
And Bragi I calm, | who is hot with beer,
For I wish not that fierce they should fight.”

Gefjun spake:

19. “Why, ye gods twain, | with bitter tongues

Raise hate among us here?
Loki is famed | for his mockery foul,
And the dwellers in heaven he hates.”

Loki spake:
20. “Be silent, Gefjun! | for now shall I say
Who led thee to evil life;
The boy so fair | gave a necklace bright,
And about him thy leg was laid.”

[159]

Othin spake:

21. “Mad art thou, Loki, | and little of wit,

The wrath of Gefjun to rouse;
For the fate that is set | for all she sees,
Even as I, methinks.”

Loki spake:

22. “Be silent, Othin! | not justly thou settest

The fate of the fight among men;
Oft gavst thou to him | who deserved not the gift,
To the baser, the battle’s prize.”

Othin spake:

23. “Though I gave to him | who deserved not the

gift,
To the baser, the battle’s prize;
Winters eight | wast thou under the earth,
Milking the cows as a maid,
(Ay, and babes didst thou bear;
 Unmanly thy soul must seem.)”

[160]

Loki spake:

24. “They say that with spells | in Samsey once

Like witches with charms didst thou work;
And in witch’s guise | among men didst thou go;
Unmanly thy soul must seem.”

Frigg spake:

25. “Of the deeds ye two | of old have done

Ye should make no speech among men;
Whate’er ye have done | in days gone by,
Old tales should ne’er be told.”

Loki spake:

26. “Be silent, Frigg! | thou art Fjorgyn’s wife,

But ever lustful in love;
For Vili and Ve, | thou wife of Vithrir,
Both in thy bosom have lain.”

[161]

Frigg spake:
27. “If a son like Baldr | were by me now,
Here within Ægir’s hall,
From the sons of the gods | thou shouldst go not
forth
Till thy fierceness in fight were tried.”

Loki spake:

28. “Thou wilt then, Frigg, | that further I tell

Of the ill that now I know;
Mine is the blame | that Baldr no more
Thou seest ride home to the hall.”

Freyja spake:

29. “Mad art thou, Loki, | that known thou makest

The wrong and shame thou hast wrought;
The fate of all | does Frigg know well,
Though herself she says it not.”

Loki spake:

30. “Be silent, Freyja! | for fully I know thee,

Sinless thou art not thyself; [162]
Of the gods and elves | who are gathered here,
Each one as thy lover has lain.”

Freyja spake:
31. “False is thy tongue, | and soon shalt thou find
That it sings thee an evil song;
The gods are wroth, | and the goddesses all,
And in grief shalt thou homeward go.”

Loki spake:

32. “Be silent, Freyja! | thou foulest witch,

And steeped full sore in sin;
In the arms of thy brother | the bright gods caught
thee
When Freyja her wind set free.”

Njorth spake:

33. “Small ill does it work | though a woman may

have
A lord or a lover or both;
But a wonder it is | that this womanish god
Comes hither, though babes he has borne.”

[163]

Loki spake:

34. “Be silent, Njorth; | thou wast eastward sent,

To the gods as a hostage given;
And the daughters of Hymir | their privy had
When use did they make of thy mouth.”
Njorth spake:

35. “Great was my gain, | though long was I gone,

To the gods as a hostage given;
The son did I have | whom no man hates,
And foremost of gods is found.”

Loki spake:

36. “Give heed now, Njorth, | nor boast too high,

No longer I hold it hid;
With thy sister hadst thou | so fair a son,
Thus hadst thou no worse a hope.”

Tyr spake:

37. “Of the heroes brave | is Freyr the best

Here in the home of the gods; [164]
He harms not maids | nor the wives of men,
And the bound from their fetters he frees.”

Loki spake:

38. “Be silent, Tyr! | for between two men

Friendship thou ne’er couldst fashion;
Fain would I tell | how Fenrir once
Thy right hand rent from thee.”

Tyr spake:
39. “My hand do I lack, | but Hrothvitnir thou,
And the loss brings longing to both;
Ill fares the wolf | who shall ever await
In fetters the fall of the gods.”

Loki spake:

40. “Be silent, Tyr! | for a son with me

Thy wife once chanced to win;
Not a penny, methinks, | wast thou paid for the
wrong,
Nor wast righted an inch, poor wretch.”

Freyr spake:

41. “By the mouth of the river | the wolf remains

[165]
Till the gods to destruction go;
Thou too shalt soon, | if thy tongue is not stilled,
Be fettered, thou forger of ill.”

Loki spake:

42. “The daughter of Gymir | with gold didst thou

buy,
And sold thy sword to boot;
But when Muspell’s sons | through Myrkwood ride,
Thou shalt weaponless wait, poor wretch.”
Byggvir spake:

43. “Had I birth so famous | as Ingunar-Freyr,

And sat in so lofty a seat, [166]
I would crush to marrow | this croaker of ill,
And beat all his body to bits.”

Loki spake:

44. “What little creature | goes crawling there,

Snuffling and snapping about?
At Freyr’s ears ever | wilt thou be found,
Or muttering hard at the mill.”

Byggvir spake:

45. “Byggvir my name, | and nimble am I,

As gods and men do grant;
And here am I proud | that the children of Hropt
Together all drink ale.”

Loki spake:

46. “Be silent, Byggvir! | thou never couldst set

Their shares of the meat for men;
Hid in straw on the floor, | they found thee not
When heroes were fain to fight.”

Heimdall spake:
47. “Drunk art thou, Loki, | and mad are thy deeds,
Why, Loki, leavst thou this not? [167]
For drink beyond measure | will lead all men
No thought of their tongues to take.”

Loki spake:

48. “Be silent, Heimdall! | in days long since

Was an evil fate for thee fixed;
With back held stiff | must thou ever stand,
As warder of heaven to watch.”

Skathi spake:

49. “Light art thou, Loki, | but longer thou mayst

not
In freedom flourish thy tail;
On the rocks the gods bind thee | with bowels torn
Forth from thy frost-cold son.”

Loki spake:

50. “Though on rocks the gods bind me | with

bowels torn
Forth from my frost-cold son, [168]
I was first and last | at the deadly fight
There where Thjazi we caught.”

Skathi spake:
51. “Wert thou first and last | at the deadly fight
There where Thjazi was caught,
From my dwellings and fields | shall ever come
forth
A counsel cold for thee.”

Loki spake:

52. “More lightly thou spakest | with Laufey’s son,

When thou badst me come to thy bed;
Such things must be known | if now we two
Shall seek our sins to tell.”

Then Sif came forward and poured mead for Loki in a

crystal cup, and said:

53. “Hail to thee, Loki, | and take thou here

The crystal cup of old mead;
For me at least, | alone of the gods,
Blameless thou knowest to be.”

[169]

He took the horn, and drank therefrom:

54. “Alone thou wert | if truly thou wouldst

All men so shyly shun;
But one do I know | full well, methinks,
Who had thee from Hlorrithi’s arms,—
 (Loki the crafty in lies.)”

Beyla spake:

55. “The mountains shake, | and surely I think

From his home comes Hlorrithi now;
He will silence the man | who is slandering here
Together both gods and men.”

Loki spake:

56. “Be silent, Beyla! | thou art Byggvir’s wife,

And deep art thou steeped in sin;
A greater shame | to the gods came ne’er,
Befouled thou art with thy filth.”

Then came Thor forth, and spake:

57. “Unmanly one, cease, | or the mighty hammer,

Mjollnir, shall close thy mouth; [170]
Thy shoulder-cliff | shall I cleave from thy neck,
And so shall thy life be lost.”

Loki spake:

58. “Lo, in has come | the son of Earth:

Why threaten so loudly, Thor?
Less fierce thou shalt go | to fight with the wolf
When he swallows Sigfather up.”
Thor spake:

59. “Unmanly one, cease, | or the mighty hammer,

Mjollnir, shall close thy mouth;
I shall hurl thee up | and out in the East,
Where men shall see thee no more.”

Loki spake:

60. “That thou hast fared | on the East-road forth

To men shouldst thou say no more; [171]
In the thumb of a glove | didst thou hide, thou
great one,
And there forgot thou wast Thor.”

Thor spake:

61. “Unmanly one, cease, | or the mighty hammer,

Mjollnir, shall close thy mouth;
My right hand shall smite thee | with Hrungnir’s
slayer,
Till all thy bones are broken.”

Loki spake:

62. “A long time still | do I think to live,

Though thou threatenest thus with thy hammer;
Rough seemed the straps | of Skrymir’s wallet,
When thy meat thou mightest not get,
 (And faint from hunger didst feel.)”

Thor spake:

63. “Unmanly one, cease, | or the mighty hammer,

Mjollnir, shall close thy mouth; [172]
The slayer of Hrungnir | shall send thee to hell,
And down to the gate of death.”

Loki spake:

64. “I have said to the gods | and the sons of the

gods
The things that whetted my thoughts;
But before thee alone | do I now go forth,
For thou fightest well, I ween.

65. “Ale hast thou brewed, | but, Ægir, now

Such feasts shalt thou make no more;
O’er all that thou hast | which is here within
Shall play the flickering flames,
(And thy back shall be burnt with fire.)”

And after that Loki hid himself in Franang’s waterfall

in the guise of a salmon, and there the gods took
him. He was bound with the bowels of his son Vali,
but his son Narfi was changed to a wolf. Skathi took
a poison-snake and fastened it up over Loki’s face,
and the poison dropped thereon. Sigyn, Loki’s wife,
sat there and held a shell under the poison, but when
the shell was full she bore away the poison, and
meanwhile the poison dropped on Loki. Then he
struggled so hard that the whole earth shook
therewith; and now that is called an earthquake. [151]

[Contents]

NOTES
[152]

Prose. Ægir: the sea-god; Snorri gives Hler as another of his names,
but he is not elsewhere called Gymir, which is the name of the giant,
Gerth’s father, in the Skirnismol. On Ægir cf. Grimnismol, 45, and
Hymiskvitha, 1. Frigg: though Othin’s wife is often mentioned, she
plays only a minor part in the Eddic poems; cf. Voluspo, 34,
Vafthruthnismol, 1, and Grimnismol, introductory prose. Thor: the
compiler is apparently a trifle confused as to Thor’s movements; the
“journey in the East” here mentioned cannot be the one described in
the Hymiskvitha, nor yet the one narrated by Snorri, as Loki was with
Thor throughout that expedition. He probably means no more than
that Thor was off killing giants. Sif: concerning Thor’s wife the chief
incident is that Loki cut off her hair, and, at the command of the
wrathful Thor, was compelled to have the dwarfs fashion her a new
supply of hair out of gold; cf. Harbarthsljoth, 48. Bragi: the god of
poetry; cf. Grimnismol, 44 and note. Ithun: the goddess of youth; cf.
note on Skirnismol, 19. Ithun is not mentioned by name in any other
of the Eddic poems, but Snorri tells in detail how the giant Thjazi
stole her and her apples, explaining the reference in Harbarthsljoth,
19 (q. v.). Tyr: the god of battle; cf. Hymiskvitha, 4, and (concerning
his dealings with the wolf Fenrir) Voluspo, 39, note. Njorth: the chief
of the Wanes, and father of Freyr and Freyja; cf. (concerning the
whole family) Skirnismol, introductory prose and note, also Voluspo,
21 and note. Skathi: Njorth’s wife was the daughter of the giant
Thjazi; cf. Harbarthsljoth, 19, note, and Grimnismol, 11. Vithar: the
silent god, the son of Othin who avenged his father by slaying the
wolf Fenrir; cf. Voluspo, 54, Vafthruthnismol, 51, and Grimnismol, 17.
Loki: the mischief-making fire-god; in addition to the many
references to his career in the Lokasenna, cf. particularly Voluspo,
32 and 35, and notes. Byggvir and Beyla: not mentioned elsewhere
in the poems; Freyr’s conspicuous servant is Skirnir, hero of the
Skirnismol. Fimafeng (“The Swift Handler”) [153]and Eldir (“The Man
of the Fire”): mentioned only in connection with this incident.
Glittering gold: Ægir’s use of gold to light his hall, which was often
thought of as under the sea, was responsible for the phrase “flame of
the flood,” and sundry kindred phrases, meaning “gold.” [154]

6. Lopt: like Lothur (cf. Voluspo, 18) another name for Loki; cf.
Hyndluljoth, 43, and Svipdagsmol, 42.

7. In the manuscript this stanza begins with a small letter, and

Heinzel unites it with stanza 6. [155]

8. Bragi: cf. note on introductory prose. Why Loki taunts him with
cowardice (stanzas 11–13–15) is not clear, for poetry, of which Bragi
was the patron, was generally associated in the Norse mind with
peculiar valor, and most of the skaldic poets were likewise noted
fighters.

9. There exists no account of any incident in which Othin and Loki

thus swore blood-brotherhood, but they were so often allied in
enterprises that the idea is wholly reasonable. The common process
of “mingling blood” was carried out quite literally, and the promise of
which Loki speaks is characteristic of those which, in the sagas,
often accompanied the ceremony; cf. Brot af Sigurtharkvithu, 18 and
note.

10. In stanzas 10–31 the manuscript has nothing to indicate the

identity of the several speakers, but these are uniformly clear
[156]enough through the context. Vithar: cf. note on introductory
prose. The wolf’s father: Loki; cf. Voluspo, 39 and note.

13. Sijmons makes one line of lines 4–5 by cutting out a part of each;
Finnur Jonsson rejects 5 as spurious.

14. The text of line 4 is somewhat obscure, and has been

[157]variously emended, one often adopted suggestion making the
line read, “Little is that for thy lies.”

15. Adorner of benches: this epithet presumably implies that Bragi is

not only slothful, but also effeminate, for a very similar word, “pride of
the benches,” means a bride.

16. Ithun: Bragi’s wife; cf. note on introductory prose. The goddesses
who, finding that their husbands are getting the worst of it, take up
the cudgels with Loki, all find themselves confronted with undeniable
facts in their own careers; cf. stanzas 26 (Frigg), 52 (Skathi) and 54
(Sif). Gefjun and Freyja are silenced in similar fashion. Wish-son:
adopted son; Loki was the son of the giant Farbauti and the giantess
Laufey, and hence was not of the race of the gods, but had been
virtually adopted by Othin, who subsequently had good reason to
regret it. [158]

17. We do not even know who Ithun’s brother was, much less who
slew him.

19. Gefjun: a goddess, not elsewhere mentioned in the poems, who,

according to Snorri, was served by the women who died maidens.
Beyond this nothing is known of her. Lines 3–4 in the manuscript are
puzzling, and have been freely emended.
20. Nothing is known of the incident here mentioned. There is a good
deal of confusion as to various of the gods and goddesses, and it
has been suggested that Gefjun is really Frigg under another name,
with a little of Freyja—whose attributes were frequently confused
with Frigg’s—thrown in. Certainly Othin’s [159]answer (stanza 21,
lines 3–4) fits Frigg perfectly, for she shared his knowledge of the
future, whereas it has no relation to anything known of Gefjun. As for
the necklace (line 3), it may be the Brisings’ necklace, which appears
in the Thrymskvitha as Freyja’s, but which, in some mythological
writings, is assigned to Frigg.

21. Snorri quotes line 1; cf. note on stanza 29.

23. There is no other reference to Loki’s having spent eight years

underground, or to his cow-milking. On one occasion, however, he
did bear offspring. A giant had undertaken to build the gods a
fortress, his reward being Freyja and the sun and moon, provided
the work was done by a given time. His sole helper was his horse,
Svathilfari. The work being nearly done, and the gods fearing to lose
Freyja and the sun and moon, Loki [160]turned himself into a mare,
and so effectually distracted Svathilfari from his task that shortly
afterwards Loki gave birth to Othin’s eight-legged horse, Sleipnir. In
such contests of abuse a man was not infrequently taunted with
having borne children; cf. Helgakvitha Hundingsbana I, 39–45. One
or two of the last three lines may be spurious.

24. Samsey: perhaps the Danish island of Samsö. Othin was the god
of magic, but there is no other reference to his ever having disguised
himself as a witch.

25. Frigg: Othin’s wife; cf. note to introductory prose.

26. Fjorgyn: Othin; cf. Voluspo, 56 and note. Vili and Ve: Othin’s
brothers, who appear merely as, with Othin, the sons of Bur and
Bestla; cf. Voluspo, 4. The Ynglingasaga says that, during one of
Othin’s protracted absences, his two brothers took Frigg as their
mistress. Vithrir: another name for Othin. [161]

27. On the death of Baldr, slain through Loki’s cunning by the blind
Hoth, cf. Voluspo, 32 and note.

29. Freyja: daughter of Njorth and sister of Freyr; cf. note on

introductory prose. Snorri, in speaking of Frigg’s knowledge of the
future, makes a stanza out of Lokasenna, 21, 1; 47, 2; 29, 3–4, thus:
“Mad art thou, Loki, | and little of wit, / Why, Loki, leavst thou this
not? / The fate of all | does Frigg know well, / Though herself she
says it not.”

30. According to Snorri, Freyja was a model of fidelity to her

husband, Oth. [162]

32. Before each of stanzas 32–42 the manuscript indicates the

speaker, through the initial letter of the name written in the margin.
Thy brother: Freyr; there is no other indication that such a relation
existed between these two, but they themselves were the product of
such a union; cf. stanza 36 and note.

33. Njorth: father of Freyr and Freyja, and given by the Wanes as a
hostage, in exchange for Hönir, at the close of the first war; cf.
Voluspo, 21 and note, also Skirnismol, introductory prose and note.
Babes: cf. stanza 23 and note. Bugge suggests that this clause may
have been a late insertion. [163]

34. Daughters of Hymir: we have no clue to who these were, though

Hymir is doubtless the frost-giant of the Hymiskvitha (q.v.). Loki’s
point is that Njorth is not a god, but the product of an inferior race
(the Wanes).

35. The son: Freyr.

36. Thy sister: the Ynglingasaga supports this story of Njorth’s

having had two children by his sister before he came among the
gods. Snorri, on the other hand, specifically says that Freyr and
Freyja were born after Njorth came to the gods.

37. Tyr: the god of battle; cf. notes on Hymiskvitha, 4, and Voluspo,
39. Freyr; concerning his noble qualities cf. Skirnismol, introductory
prose and note. [164]

38. Snorri mentions Tyr’s incompetence as a peacemaker. Fenrir:

the wolf, Loki’s son; cf. Voluspo, 39.

39. Hrothvitnir (“The Mighty Wolf”): Fenrir, who awaits in chains the
final battle and death at the hands of Vithar. The manuscript has a
metrical error in line 3, which has led to various emendations, all with
much the same meaning.

40. Thy wife: there is no other reference to Tyr’s wife, nor do we

know who was the son in question. [165]

41. The mouth of the river: according to Snorri, the chained Fenrir
“roars horribly, and the slaver runs from his mouth, and makes the
river called Vam; he lies there till the doom of the gods.” Freyr’s
threat is actually carried out; cf. concluding prose.

42. The daughter of Gymir: Gerth, heroine of the Skirnismol, which

gives the details of Freyr’s loss of his sword. Muspell’s sons: the
name Muspell is not used elsewhere in the poems; Snorri uses it
frequently, but only in this same phrase, “Muspell’s sons.” They are
the dwellers in the fire-world, Muspellsheim, led by Surt against the
gods in the last battle; cf. Voluspo, 47 and 52 and notes. Myrkwood:
here the dark forest bounding the fire-world; in the Atlakvitha (stanza
3) the name is used of another boundary forest.

43. Byggvir: one of Freyr’s two servants; cf. introductory prose.

Ingunar-Freyr: the name is not used elsewhere in the poems, or by
Snorri; it may be the genitive of a woman’s name, Ingun, the
unknown sister of Njorth who was Freyr’s mother (cf. stanza 36), or a