Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Results of the first interim analysis

by | Oct 7, 2021 | Commentary, Integrative Therapies, Integrative Treatments

By Giuseppe Fiorentino published in The Lancet September 9, 2021 below with analysis of the article & research by Chris Masterjohn, PhD below and commentary by Mark Bricca, ND

“Based on an interim analysis recently published in a journal affiliated with the Lancet from an Italian randomized double-blind placebo-controlled trial, it looks probable that ordinary arginine may have an important role to play in treating Covid-19.” 

Arginine is safe (except for the possibility of inciting a herpes outbreak, although most people would prefer temporary herpes discomfort to death… ), inexpensive, and readily available.
Here is an excerpt from the trial interpretation (italics are mine):

“We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25th,75th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups.”
Will this potentially exciting information be widely reported in the media?  Sadly, I doubt that it will be.  Merck has just made a big splash regarding it’s new antiviral pill, which, at $700/course of treatment, is being rushed along based on data that’s a few small steps ahead of this Italian arginine trial.  The Merck trial, as I recall, enrolled just shy of 800 people, and showed relative risk reduction for mortality of ~50%.  Meanwhile, if the Italian trial results hold with maturation, it looks as though, for about $10, we might be able to cut the duration of hospital stays for many severely ill Covid-19 patients roughly in half (i.e. possibly a similar relative risk reduction).
Certainly, this is an interesting possibility.  And what might happen if we made sure that the same patients (and all people) were replete with vitamin D via nationwide public health recommendations–since data indicates that people replete in vitamin D, when they get sick with Covid-19, are less likely to become severely ill compared to people who are vitamin D deficient?  There is good data showing reduced rates of severe Covid-19 when people engage nasopharyngeal sanitation rinses with povidone iodine early in illness (personally, I prefer xylitol nasal spray and zinc acetate lozenges, but povidone iodine is well known and widely available).  What if we educated people on these basic practices–how might these three simple, low-cost strategies be additive, while being broadly accessible?  Sadly, I won’t expect to hear this discussed on tomorrow morning’s news, although I am sure I will hear lots this week about Merck’s new pill (nothing at all against Merck’s pill, which I hope is effective and safe–I just wish we had a level playing field where all information could be equal regardless of potential for profits, and where we could appreciate such low tech, widely available therapeutic strategies just as much as the new, high tech, and costly ones).
With care and blessings, Mark”

Mark Bricca, ND, MAcBodhicitta Healing Arts

Abstract

Background

We and others have previously demonstrated that the endothelium is a primary target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and L-arginine has been shown to improve endothelial dysfunction. However, the effects of L-arginine have never been evaluated in coronavirus disease 2019 (COVID-19).

Methods

This is a parallel-group, double-blind, randomized, placebo-controlled trial conducted on patients hospitalized for severe COVID-19. Patients received 1.66 g L-arginine twice a day or placebo, administered orally. The primary efficacy endpoint was a reduction in respiratory support assessed 10 and 20 days after randomization. Secondary outcomes were the length of in-hospital stay, the time to normalization of lymphocyte number, and the time to obtain a negative real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. This clinical trial had been registered at ClinicalTrials.gov, identifier: NCT04637906.

Findings

We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25th,75th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups.

Interpretation

In this interim analysis, adding oral L-arginine to standard therapy in patients with severe COVID-19 significantly decreases the length of hospitalization and reduces the respiratory support at 10 but not at 20 days after starting the treatment.

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Analysis of Article & Research by Chris Masterjohn PhD from chrismasterjohnphd.com on October 2, 2021

The One Amino Acid That Could Cure COVID

Disclaimer: I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and this information is educational in nature.

An Italian clinical trial peer-reviewed and published this past month in EClinical Medicine, one of the journals published by The Lancet, is nothing short of incredible.

It provides rigorous evidence that 3.2 grams per day of the amino acid L-arginine dramatically hastens the improvement in respiratory function in patients thaty already have confirmed pneumonia and are already suffering from hypoxemic respiratory distress. It may turn out to be lifesaving.

One of the things that is so remarkable about this study is that usually nutritional treatments have to be started early in the course of illness to work. For example, as I covered in my comprehensive review of the vitamin D literature, maintaining high vitamin D status is the single best thing you can do for prevention, and if administered early in the course of illness it is extremely powerful in preventing the illness from getting bad enough to put someone in the ICU. By contrast, if vitamin D is given to people who already have severe respiratory distress — at least in the standard form of vitamin D you would buy in the store — it does nothing at all.

In this case, however, the L-arginine works when things have already gotten very bad.

Background

The protein in the food we eat — especially rich in meats, fish, shellfish, dairy products, and legumes such as lentils, peas, and beans — is made of building blocks called amino acids. One of those building blocks is L-arginine, or just “arginine.”

Arginine is the raw material from which we make nitric oxide.

Nitric oxide plays three critical roles that are likely to be extremely important for COVID protection:

  • Since nitric oxide is antimicrobial, the immune system always makes massive amounts of nitric oxide to kill pathogens.
  • Nitric oxide is the main vasodilator. This means it dilates your blood vessels, making them wider, and allowing blood to flow more freely. This would protect against clotting.
  • In the lungs, nitric oxide combines with another molecule we make from the protein we eat, glutathione, to make nitrosoglutathione. Nitrosoglutathione is our own natural bronchodilator. This means it opens up the airways, just like nitric oxide opens up the blood vessels. This allows us to breathe more freely.

In addition, arginine itself is needed for lymphocytes to proliferate. Lymphocytes are a type of white blood cell, and a key player in our immune system. If your doctor orders a complete blood count (CBC), a panel of tests that is also used to diagnose anemia, it will have the number of lymphocytes found in your blood on it. If lymphocytes can’t reproduce, or “proliferate,” their numbers will be low. Low lymphocyte counts are a major predictor of whether a COVID patient will die.

Adults and children hospitalized with COVID-19 have low blood levels of arginine. Arginine levels are even lower in those with severe cases than in those hospitalized for more moderate cases. This appears to be at least partly driven by a type of cell that suppresses the immune response, commonly found in obesity and cancer. These immunosuppressive cells make an enzyme known as arginase that destroys arginine. This depletes the arginine available for lymphocyte proliferation, causing low lymphocytes. The low lymphocytes become the major predictor of death.

Lymphocytes taken from severe patients have trouble reproducing. Dumping a little arginine on top of them helps them start multiplying again.

The short of it is this: patients hospitalized with COVID have increased levels of immunosuppressive cells that make the enzyme arginase. This depletes arginine. Arginine depletion causes low lymphocytes and low nitric oxide. Low lymphocytes are known to drive the risk of death, and low nitric oxide probably plays a role as well by making blood vessels and airways more constricted. This makes blood vessels more vulnerable to clotting risk and airways less able to oxygenate the blood.

Read More Here

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