Back in April 2020, after evaluating plenty of numerous knowledge sources together with bench research, scientific trials, and epidemiologic investigations pertaining to the results of nitric oxide (NO) upon coronaviruses, I appealed to the medical literature and analysis neighborhood to analyze the potential utility of arginine (ARG) supplementation within the prevention of extreme COVID-19. At that time, the out there proof, whereas convergent, was pretty restricted to the unique SARS virus in fact — even then although, the clues appeared overwhelmingly constructive.
There’s not some huge cash to be made in finding out dietary dietary supplements, and my hat is off to the physicians and scientists who performed the primary randomized, double-blinded potential trial of ARG in hospitalized COVID-19 sufferers in Italy (with collaboration from the Albert Einstein College of Medicine). Near as I can collect, they acquired no funding for his or her efforts, that are groundbreaking and deserving of worldwide recognition and gratitude.
Let’s begin with the thrilling stuff: the trial confirmed a statistically vital distinction in secondary endpoint comprising hospital size of keep (LOS). Median LOS was 25 days within the ARG group in comparison with 46 days within the placebo group (PP=0.01), however misplaced significance at day 20. Having stated that, the authors notice that this obvious attrition of profit may very well reveal attrition of sickness: a really giant variety of the ARG group had already healed/been discharged, enriching the proportion of the sickest in that arm.
Now let’s analyze the research a little bit extra. In all equity, the remedy group confirmed considerably decrease age — 7.5 years decrease. Multivariate modeling nonetheless nonetheless confirmed great attributable affect of ARG, and moreover, distribution of comorbidities didn’t fluctuate. Interestingly, what did fluctuate considerably was preliminary severity quotient of respiratory assist between the 2 teams. Far extra individuals within the ARG arm began out on non-invasive air flow and CPAP. In different phrases, the remedy arm began with extra extreme respiratory illness. One might argue that the deck was stacked in favor of the ARG group by way of major endpoint (extra room for enchancment!), however there is not any method to nay-say the gorgeous distinction seen by way of hospital discharge.
The different refined discovering (too small by the numbers to make it into any type of evaluation) was that three sufferers within the placebo arm died after day 20…in comparison with zero within the ARG arm.
The most essential level of fastidiously managed trials (and regulatory businesses) echoes the introduction to the doctor’s oath: primum non nocere (first, do no hurt). Let’s guarantee security. The large theoretical concern from ARG supplementation is the potential for elevated systemic inflammatory response and cytokine storm. What if rising NO is akin to throwing gasoline on the coals?
To tackle that hypothetical, let us take a look at the research outcomes: no harms have been seen within the remedy group.
Well, we have all been fooled by the outcomes of 1 research earlier than. Let’s take into account plausibility primarily based upon different strains of proof. What have we discovered currently concerning the extremely complicated biology of NO?
The “NO” Technical Manual
It’s definitely extra sophisticated than we have grasped thus far, however mainly, there are two useful variations of nitric oxide synthase (NOS), the enzyme that makes NO from ARG: constitutive NOS or cNOS (at all times working) and inducible NOS or iNOS (works when referred to as upon). cNOS moreover has two sorts, for the hardcore amongst you: a neuronal model and an endothelial model referred to as eNOS.
We’ll begin with iNOS. This “PRN” isoform appears to perform primarily throughout the immune system, rendering potent NO-mediated antimicrobial actions by numerous leukocytes. We will not go into all these mechanisms (a lot of that are extra directed towards micro organism), however slightly concentrate on proposed anti-SARS-CoV-2 mechanisms. In vitro research have proven that elevated NO exercise inhibits the flexibility of the virus to each bind the ACE2 receptor with its spike protein and to duplicate. Conversely, a couple of research has now proven that ARG ranges are poor in individuals with extreme COVID-19 and leukocyte depletion/dysfunction (significantly CD8 T-cells), and one other fascinating research demonstrated in vitro rescue of stated T-cell perform with an ARG-enriched atmosphere.
Excess (iNOS-generated) NO nonetheless has been implicated within the growth of pulmonary vascular toxicity, possible contributory to the ARDS state, and presumably the “cytokine storm” of systemic inflammatory response syndrome seen in extreme an infection.
Well what about eNOS? This constitutive model is (below regular circumstances) at all times at work producing NO for the endothelium of blood vessels, dilating them, defending them from platelet and leukocyte aggregation, and atherogenesis. In pathologic states nonetheless (particularly these related to tetrahydrobiopterin deficiency, corresponding to diabetes or just outdated age) eNOS can generate reactive oxygen species slightly than NO, resulting in vascular injury. Interestingly, this so-called eNOS “uncoupling” has additionally been proven to happen in ARG-deficiency.
It’s troublesome to piece collectively for positive, however what we predict we’re seeing right here is that ARG deficiency results in a double whammy of enhanced vulnerability to viral entry and replication, and vasculopathy.
One last factor to think about right here is the potential function for citrulline (CIT), an amino acid that’s generated from ARG but additionally serves as a reservoir for reverse synthesis of ARG. It seems the cNOS household primarily generates its NO from a particular compartment of ARG that’s generated from this reverse CIT metabolism. iNOS however would not appear to make use of that stash, however slightly, an intake-dependent pool of ARG. In this case, supplementation with CIT may very well make as a lot or extra sense.
Toward Future Research
I am unable to consider a greater method to each honor the work of those researchers and spotlight the necessity for additional trials (ideally evaluating ARG and CIT to placebo) than to cite their conclusion:
“…our outcomes could have essential scientific implications for COVID-19 remedy particularly in low-resource environments [where] vaccination is just not broadly out there given the security and the affordability of oral L-arginine.”
This doesn’t represent medical recommendation. What it does represent, as communicated final yr, is an attraction for pressing analysis right into a dirt-cheap doubtlessly life-saving measure with no demonstrated danger.
Heath McAnally, MD, MSPH, is a board-certified anesthesiologist, ache doctor, and addictionologist practising in Alaska (the army despatched him there and he determined to remain). If he wasn’t attempting to information individuals in enhancing their very own lives, educating medical college students to do the identical, or writing about it, he’d most likely be outside proper now slogging up a mountain with a superb buddy or two.
Last Updated October 08, 2021