Response to the emerging novel coronavirus outbreak
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m406 (Published 31 January 2020) Cite this as: BMJ 2020;368:m406Read our latest coverage of the Coronavirus outbreak
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Dear Editor,
The notion that angiotensin receptor blockers (ARBs) like Losartan can prevent COVID-2019 infection has started to circulate, and in some cases we also witnessed its prescription for this reason, although no basis of evidence is available to date.
This notion started from a comment by Phadke and Saunik [1], who suggested the use of ARBs like Losartan since it has been demonstrated that SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) receptors to enter its host.
In their comment there is an evident mistake, and, as Akamatsu stated in another comment [2], ARBs act on Angiotensin 2 receptors (AT2), which are not the same as ACE receptors. Akamatsu suggests then the possible use of ACE-inhibitors as potentially effective drugs to prevent COVID-2019 infection, although this class of drugs may worsen respiratory symptoms like cough.
But even this statement is incorrect, since the ACE2 receptor, which is different from the ACE receptor and was discovered in the 2000s, is insensitive to classical ACE inhibitors [3].
Therefore, there is no indication, and no pharmacological base, to prescribe or suggest ARBs or ACE inhibitors for COVID-2019 infection.
This practice, besides being useless to prevent COVID-2019 infection, may be harmful, leading to inappropriate drug treatments and risk of adverse events, or may instill dangerous over-confidence against the infection risk.
Therefore, the practice of prescribing ARBs or ACE-inhibitors for the prevention of COVID-2019 infection should be discouraged.
References
1) https://www.bmj.com/content/368/bmj.m406/rr-2
2) https://www.bmj.com/content/368/bmj.m406/rr-7
3) Patel, V. B., Zhong, J. C., Grant, M. B., & Oudit, G. Y. (2016). Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circulation research, 118(8), 1313-1326
Competing interests: No competing interests
Dear Editor
Mr Dahaj (rapid response) suggests that the ability of Naproxen to inhibit this corona virus should be investigated.
May I enter a caveat please? Patients who suspect they are suffering from this virus and home-test themselves should not be encouraged to self-treat themselves. Naproxen is known to cause Stevens-Johnson Syndrome.
Competing interests: No competing interests
Dear Editor
With the ongoing spread of COVID-19 virus all around the world and with knowing this concept that not all potential suggested-for-trials drugs against this virus are available in countries like Iran, a rather available and the over-the-counter drug, Naproxen as a promising treatment or prevention agent may be suggested besides the supportive management.
COVID-19 virus is an enveloped, positive-sense, single-stranded RNA beta-coronavirus [1]. Naproxen, a non-steroidal anti-inflammatory drug, has previously been revealed to exert antiviral activity against influenza A virus by impeding nucleoprotein (NP) binding to RNA in a study by Nathalie Lejal et al [2]. Furthermore, Weinan Zheng et al [3] indicated that naproxen is a potential broad, multi-mechanistic anti-influenza virus therapeutic, as it inhibits influenza B virus replication both in vivo and in vitro. Additionally, the NP of influenza B virus (BNP) has a higher binding affinity to naproxen than influenza A virus NP (ANP). Specifically, naproxen targets the NP at residues F209 (BNP) and Y148 (ANP). This interaction antagonizes the nuclear export of NP normally mediated by the host export protein CRM1.
Based on the fact that the COVID-19 virus is single-stranded RNA virus and Naproxen has an antiviral activity via inhibiting nucleoprotein (NP) binding to RNA in the replication process of RNA-viruses like influenza A/B, the use of Naproxen as a probable agent for control of widespread novel coronavirus infection may be assumed.
Published literature relating to the effect of Naproxen on the COVID-19 virus is limited. Clinicians may consider the use of Naproxen for treatment of the infected host cell and spread of infection besides using its anti-inflammatory feature in patients with more severe symptoms. Clinical trials and research may reveal this efficiency.
References:
1. Zumla, A., Chan, J., Azhar, E. et al. Coronaviruses — drug discovery and therapeutic options. Nat Rev Drug Discov 15, 327–347 (2016). https://doi.org/10.1038/nrd.2015.37
2. Lejal, N., Tarus, B., Bouguyon, E., et al. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother 57, 2231–2242 (2013). https://doi.org/10.1128/AAC.02335-12
3. Zheng, W., Wenhui, F., Shuang, Z. al. Naproxen exhibits broad anti-influenza virus activity in mice by impeding viral nucleoprotein nuclear export. Cell reports 27, 1875-1885 (2019). https://doi.org/10.1016/j.celrep.2019.04.053
Competing interests: No competing interests
Dear Editor
This informative editorial makes no reference to the widespread use of screening for possible fever using non-contactable forehead thermometers. Almost daily on the TV news one can see the skin temperature of the forehead being quickly measured outdoors. The President of China was recently filmed having a temperature measurement made at his wrist as were people before getting on to a bus in China.
Sublingual temperature is lowered by being in a cold environment and slowly rises to a stable reading in a warm environment. (1)
During the SARS epidemic, the temperature screening site was the aural canal. It has been shown that aural temperature is lowered by being in a cold environment, an effect that can be eliminated by keeping the outer ear at the same temperature as the aural canal using a servo-controlled heat pad (2). I warned at that time that care should be taken when screening for SARS so that cases are not missed (3).
Using and infrared thermometer, Erenberk et al. (4) demonstrated cooling of the forehead took place when children were exposed to cold outdoor temperatures before entering a paediatric emergency department. It took up to 10 minutes for that temperature to increase to a steady reading. They recommended that children should be acclimatized in a warm environment for at least 10 minutes before taking body temperature readings.
I recently bought Fairywill infrared thermometer model JPD-FR401 (made in China). It can measure either forehead (contact) or eardrum temperature. The accompanying instruction manual is comprehensive. “Make sure both user and thermometer have stayed in a steady state room condition for at least 30 minutes. Recent exposure to hot or cold temperatures will impact your reading”. I measured my forehead temperature in a warm (21.2C) room before and after being outside(5.3C) for 5 minutes. Repeated measurements showed it took 9 minutes for the forehead temperature to return to a steady state of 37.3C from 36.4C. The operating temperature of that thermometer is stated as between 10C and 40C.
The environmental temperature in Beijing (population over 20 million) is forecast to be between -1C and 10C from 24th February to 7th March.
Measuring temperature from the forehead in a coronavirus screening procedure undertaken in cold environments is likely to result in many cases being missed thus causing spread of the infection.
1. Depression of sublingual temperature by cold saliva. R E G Sloan, W R Keatinge. British Medical Journal, 1975, 1, 715 – 720.
2. Keatinge WR, Sloan REG. Deep body temperature from aural canal with servo- controlled heating to outer ear. J Appl Physiol 1975; 38: 919–21.
3. SARS: screening, disease associations and response. Lancet. 31 May 2003. DOI: https://doi.org/10.1016/S0140-6736(03)13507-6
4. Skin temperature measurement using an infrared thermometer on patients who have been exposed to the cold. Erenberk, U et al. Pediatrics international August 2013. http://doi.org/10.1111/ped.12188
Competing interests: No competing interests
Dear Editor,
The authors seem to have made an obvious mistake. They misinterpreted ACE2 with angiotensin II receptor which are totally different molecular entities. The putative receptor for the new coronavirus (Covid-19) is ACE2, but NOT angiotensin II receptor. Therefore, it is unlikely that ARBs such as telmisaltan and losartan will be effective in inhibiting the binding of Covid-19 to ACE2. Instead, however, ACE inhibitors such as perindopril erbumine may be effective as a preventive measure, while we must be aware that ACE inhibitors in class may cause dry cough as an adverse side effect that may make it difficult to distinguish the cough caused by the lung infection.
Competing interests: No competing interests
Dear Editor
The authors say,” .....inequalities are emerging....” Surely they know that there always were inequalities and always will be.
Our government is doing some things. It needs to do more.
The spread is largely aerial. The government could mandate NO OVERCROWDING in buses, trains, underground.
It could mandate NO MATCHES
It could order CLOSURE of UNIVERSITIES, POSTPONEMENT OF EXAMINATIONS, CLOSURE OF CINEMAS, THEATRES
It could RECRUIT competent doctors and nurses, keep them in employment, or pay them a retainer.
It could ask as many of its office staff as possible to work from home. Computers are there.
Am I over-egging the pudding?
Please tell me if I am.
Competing interests: No competing interests
Dear Editor
Our public health is ahead of the game in many ways. I just want to share two important points that concern me.
The first is that the Department of Health information to the public recommended that adults/ parents stay at home for 14 days after arriving from Wuhan or Hubei Province (or elsewhere in China if they have symptoms), and avoid public places. Where possible, contact a friend or family member to take your children to school. In this recommendation it is not clear whether children with the same travel history should avoid public places including schools. The recommendation should be clearer for the public. Additionally it will be necessary to keep children at home if their parents or family members with risk factors become symptomatic.
The other concern I have is about assessment pods to make a 111 call. It is an excellent way to reduce staff and visitors exposure to this virus. The pods should be used meticulously. Are they supervised by staff? Are we cleaning the phones with disinfectant after each use or are the visitors using disposable gloves and masks?
I hope all trusts will take the necessary measures to prevent cross infection.
Competing interests: No competing interests
Against the backdrop of the rapid spread of novel corona virus infection from Wuhan, China, to large areas globally and that besides supportive management, no novel modalities of treatment have been offered, we suggest the use of angiotensin II receptor blockers as a treatment for this infection.
Yushun Wan, Jian Shang et al [1] have analysed the potential receptor usage by 2019- nCoV based on the knowledge on sequencing of SARS- CoV. They have found that the sequence of 2019 nCoV receptor binding motif that directly contacts ACE2 (receptor Angiotensin converting enzyme 2) is similar to that of SARS–CoV & suggest that 2019-nCoV (Wuhan) uses ACE2 as its receptor. Their structural analysis predicted that the Wuhan Corona Virus uses ACE2 as its host receptor. They have further stated that a single mutation significantly enhances the ability of nCoV (Wuhan) to bind with human ACE2.
Based on this, we hypothesize the use of angiotensin II receptor blockers (ARB) available for clinical use can be potential drugs to be given for control of viral spread of novel corona virus (Wuhan) infection. An unpublished observation by one of us (MP) is that people using Losartan or Telmisartan tablets as antihypertensives get lesser attacks of cold & flu like illnesses. Both these drugs also do not produce cough as the side effect so commonly seen with ACE inhibitors.
Losartan and Telmisartan strongly bind to the AT1 receptors more than Valsartan [2]. Therefore, use of the former could be suitable in treatment of novel corona virus (Wuhan, China) infections. Mode of administration in addition to being given orally, could be in the form of a nasal spray. Published literature is scant on this information. Clinicians and scientists may consider use of Losartan or Telmisartan in therapeutic doses for preventing the nCov virus entering the host cell and spread of infection. Rapid clinical trials are the need of the hour.
M Phadke [1], S Saunik [2]
[1] Sr. Advisor, N.H.M., Govt. of Mah. & UNICEF, Ex-Vice Chancellor, Maharashtra Uni. Health Sciences, Mah., India
[2] Addl. Chief Secretary, Govt. Maharashtra, Mumbai, India, Takemi fellow, T.H.C. School of Pub. Health, Harvard University, USA
We declare no conflict of interest.
References:
1. Yushun Wan, Jian Shang, Rachel Graham, Ralph S Baric, Fang Li. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. Journal of Virology, 2020; DOI: 10.1128/JVI.00127-20.
2. Hardman Lee Limbard, Goodman Gilman’s. The pharmacological basis of therapeutics 2001; 829-832.
Competing interests: No competing interests
The spread of novel coronavirus (nCoV) has raised quarantine alarms worldwide. As of today, it has been reported to spread to 25 countries.[1] The latest figures estimate a total of 14,300 infected and 305 deceased.[1] Finding new treatments can take a long time. However, trying existing drugs that could affect the virus is an alternative and faster strategy. On the 2nd of February, Thai doctors were successful in treating coronavirus patients with a combination of flu and anti-HIV medications.[2] A total of 19 cases were administered a mixture of lopinavir, ritonavir, and oseltamivir in large doses.[2] This resulted in clinical improvement in at least 8 cases.[2] Results indicate that the improvement in condition occurs 48 hours after drug administration.[2] It was also noted that diagnostic tests yielded negative growth after 48 hours.[2]. Chinese health officials have also started to administer HIV and flu drugs to eradicate this virus. It is also important to note that one patient undergoing treatment displayed signs and symptoms of severe allergic reactions. As of now, this approach is only limited to severe cases. These updated events are exciting but further studies need to be conducted to target optimal eradication.
REFERENCES
1. Coronavirus news and live updates: First death confirmed outside mainland China - CNN [Internet]. CNN. 2020 [cited 2 February 2020]. Available from: https://edition.cnn.com/asia/live-news/coronavirus-outbreak-02-02-20-int...
2. Wongcha-um P. Cocktail of flu, HIV drugs appears to help fight coronavirus: Thai doctors [Internet]. U.S. 2020 [cited 2 February 2020]. Available from: https://www.reuters.com/article/us-china-health-thailand/cocktail-of-flu...
Competing interests: No competing interests
Re: Use of AT1 receptors antagonists in corona virus disease
Dear Editor,
I think that the idea of the possible usefulness of angiotensin II receptor blockers (like Irbesartan, losartan, etc.) in the treatment of COV-19 virus disease may derive from a paper publshed in 2005 (NATURE MEDICINE VOLUME 11 | NUMBER 8 | AUGUST 2005).
In that paper it was demonstrated that SARS-CoV, binding on ACE2 enzyme, induces the formation of an excess of ATII, thus leading to severe lung injury.
The use of "sartans" can't be presumed as antiviral therapy, nonetheless it could ameliorate the pulmonary deleterious effects of the virus infection.
Regards,
Massimo Pinori
Competing interests: No competing interests