This cheap drug used by Trump may treat the COVID-19?

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This cheap drug used by Trump may treat the COVID-19?

The new coronavirus has ravaged the world for 2 years, causing more than 400 million infections and nearly 6 million deaths [1]!

After the new coronavirus enters the human body, it infects cells by binding to the surface receptor ACE2 of human cells by means of the spike protein. Subsequently, in the cell, TLR3 recognizes and binds to the double-stranded RNA of the virus, which in turn activates the production of type I interferons and cytokines, and initiates immunity to eliminate infected cells [2].

When the immune system responds too strongly, cytokines are released in large quantities, setting off a “cytokine storm” in the body, which will seriously damage normal cells and tissues. “Cytokine storm” is one of the main causes of disease progression and death in COVID-19 patients [3].

This cheap drug used by Trump may treat the COVID-19? Coronavirus causes ‘Cytokine storm’

Famotidine, a histamine H2 receptor antagonist, can inhibit gastric acid secretion and is a commonly used gastric drug for the treatment of acid reflux, heartburn and gastric ulcers. As an over-the-counter drug, famotidine is readily available in pharmacies and is cheap, often less than 20 dollar per box.

Recently, studies have found that famotidine can regulate immunity, completely eliminate histamine receptor-mediated cytokine production [4], and also has a broad-spectrum antiviral effect [5].

In the early days of the Covid-19 pandemic, computer-screening experiments on drugs suggested that famotidine could play a role in fighting Covid-19.

Subsequently, a retrospective analysis of 6,212 COVID-19 patients found that the fatality rate of COVID-19 hospitalized patients who used famotidine was about 14%, while the fatality rate of patients who did not use famotidine was as high as 27% [6] ].

In 2020, after former US President Trump was infected with the COVID-19, he was treated with a regimen including famotidine and cured three days later.

Then-President Trump’s COVID-19 treatment plan contains famotidine (shown in red box)

In vitro experiments [7] showed that famotidine treatment of 2019-nCoV infected cells can inhibit the expression of TLR3 induced by histamine, reduce the transduction of TLR3-dependent inflammatory signals, and control the level of inflammation.

The good performance of famotidine in the treatment of COVID-19 pneumonia has attracted the attention of Professor Janowitz of the Cold Spring Harbor Laboratory in New York. Prof. Janowitz conducted a small case study [8], including 10 patients with COVID-19, treated with high-dose oral famotidine. All patients reported significant improvement in disease-related symptoms within 48 hours of starting famotidine.

Subsequently, Prof. Janowitz conducted a Phase II clinical trial of famotidine in conjunction with several hospitals in New York. Recently, in the latest issue of the international top medical journal Gut, Professor Janowitz announced the results of the trial [9]: famotidine can relieve the symptoms and inflammation of non-hospitalized patients with mild to moderate COVID-19s more quickly, and improve the relief of COVID-19 infections. rate, and was safe and well tolerated.

This cheap drug used by Trump may treat the COVID-19?
Screenshot of the homepage of the official website paper

In this randomized, double-blind, placebo-controlled clinical trial, Professor Janowitz recruited 55 mild to moderate COVID-19 outpatients as subjects and divided them into a famotidine group and a placebo group.

All subjects received 80 mg of famotidine or placebo three times a day for 14 consecutive days, followed by 14 additional days of monitoring, with final follow-up and symptom assessment on day 60; Measure the COVID-19 symptoms such as fatigue, shortness of breath, cough, headache and loss of smell and taste, and continuously monitor until the symptoms are relieved or for 28 days; Swab and venous blood were used to detect the new coronavirus, biochemical indicators, famotidine blood concentration and interferon alpha level.

This cheap drug used by Trump may treat the COVID-19? Experimental Design and Procedure

Baseline characteristics of the two groups of subjects were well matched .

The famotidine group and the placebo group had the same average COVID-19 total symptom score and average symptom duration, and similar indicators such as age, gender and ethnic composition ratio, body mass index, blood oxygen, body temperature and heart rate.

The subjects were highly diverse, with almost twice as many female patients as males, and were racially diverse.

Baseline characteristics of subjects in the famotidine and placebo groups

The most common symptoms of COVID-19 outpatients were fatigue, muscle pain, cough, runny nose and shortness of breath, the trial found .

By day 14 of treatment, the proportion of symptomatic subjects in the famotidine group dropped to half of that in the placebo group , and by day 28, symptom remission rates were the same in both groups.

Panel A: Symptoms related to COVID-19 in subjects; Panel B: Changes in symptom remission rates in the two groups over time
(black: placebo group; red: famotidine group)

Comparing the linear rate of change over time in the total symptom score between the two groups, the researchers found that the linear rate of change in the famotidine group was −0.085 (95% confidence interval: −0.099 to −0.071), and the time to 50% symptom relief was 8.2 days (95% confidence interval: 7 to 9.8 days), while the linear rate of change in the placebo group was −0.061 (95% confidence interval: −0.067 to −0.055), and the 50% time to symptom relief was 11.4 days (95% confidence). interval: 10.3 to 12.6 days), the difference was significant (p<0.0001). This suggests that famotidine can relieve the symptoms of the COVID-19 earlier .

In terms of various symptoms of the COVID-19, of the 16 related symptoms, 14 of the famotidine group experienced early remission (87.5%), while only 2 (12.5%) of the placebo group. Among them, famotidine can provide early relief of energy deficit, loss of smell or taste, dyspnea, chest tightness and muscle pain .

This cheap drug used by Trump may treat the COVID-19? Figure C: The linear change rate of the total score of COVID-19-related symptoms in the two groups over time; Figure D: The relief of each symptom in the two groups

By analyzing the blood biochemical indicators of the subjects, the researchers found that compared with the placebo group, the patients in the famotidine group had significantly lower plasma interferon alpha levels on the 7th day of the trial (p=0.039).

RNA sequencing confirmed that the type I interferon gene score of the patients in the famotidine group was significantly decreased (p=0.032). Among them, the genes OAS1–3 are antiviral proteins induced by type I interferon, which have antiviral activity and have antiviral activity in cells.

It plays a key role in the innate immune response, and its expression was also significantly down-regulated in the famotidine group.

In addition, the researchers also found that the type I interferon score was correlated with the total COVID-19 symptom score, indicating that the severity of COVID-19 symptoms was related to the degree of interferon-mediated inflammation.

Famotidine can reduce the level of type I interferon in patients with COVID-19s, thereby relieving symptoms of COVID-19s.

After taking the famotidine group for 7 days, the plasma interferon alpha level (Panel B) was significantly decreased, the type I interferon gene score decreased (Panel C), and the type I interferon gene score was significantly correlated with the symptom score (Panel D). , the expression of type I interferon-related genes OSA1-3 (Figure EG) was down-regulated

In summary, through a small-scale prospective clinical trial, Prof. Janowitz’s team observed the efficacy of oral famotidine on mild to moderate non-hospitalized patients with COVID-19, and found that famotidine can reduce type I interferon in patients with COVID-19. level, improve most mild to moderate clinical symptoms of the COVID-19, and promote the remission of the COVID-19.

In the current absence of powerful and cheap COVID-19 drugs, famotidine, as a cheap “old drug” that has been tested for safety, may play a “new use” for the treatment of patients with COVID-19 outpatients or home isolation.

In this trial, due to the contagious nature of the new coronavirus, the researchers did not visit the patient’s bedside in person, but adopted a complete remote control, which reduced the burden on the patient and protected the medical staff.

However, Due to the early trial, the subjects included in this study were not vaccinated against the COVID-19, nor were they infected with the Delta and Omicron variants that currently cause most cases in the world; in addition, due to the inclusion of There are fewer subjects, and the conclusions of the study still need to be verified by larger-scale clinical trials.

References

[1] covid19.who.int
[2] Sallenave JM, Guillot L. Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets?. Front Immunol. 2020;11:1229. Published 2020 May 28. doi:10.3389/fimmu.2020.01229
[3] Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: “When You Come Out of the Storm, You Won’t Be the Same Person Who Walked in”. Front Immunol. 2020;11:2132. Published 2020 Sep 2. doi:10.3389/fimmu.2020.02132
[4] Takagaki K, Osawa S, Horio Y, et al. Cytokine responses of intraepithelial lymphocytes are regulated by histamine H(2) receptor. J Gastroenterol. 2009;44(4):285-296. doi:10.1007/s00535-009-0019-9
[5] Bourinbaiar AS, Fruhstorfer EC. The effect of histamine type 2 receptor antagonists on human immunodeficiency virus (HIV) replication: identification of a new class of antiviral agents. Life Sci. 1996;59(23):. doi:10.1016/s0024-3205(96)00553-x
[6] Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Gastroenterology. 2020;159(3):1129-1131.e3. doi:10.1053/j.gastro.2020.05.053
[7] Mukherjee R, Bhattacharya A, Bojkova D, et al. Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection. J Biol Chem. 2021;297(2):100925. doi:10.1016/j.jbc.2021.100925
[8] Janowitz T, Gablenz E, Pattinson D, et al. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series. Gut. 2020;69(9):1592-1597. doi:10.1136/gutjnl-2020-321852
[9] Brennan CM, Nadella S, Zhao X, et al. Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial [published online ahead of print, 2022 Feb 10]. Gut. 2022;gutjnl-2022-326952. doi:10.1136/gutjnl-2022-326952