Saturday, March 21, 2020

COVID-19: vitamina C; hyperinsulinemia; others.

Simply for collecting interesting things, in my opinion, about COVID-19, for those who don't mind wasting their time reading unreliable misinformation.

Of course chloroquine seems to be a good hospital treatment at least, but I am not going to deal with any xenobiotic substance here.


Vitamin C



I have already commented on the work of Dr. Fowler's group on its effect in the case of sepsis:
  • Main mechanism of action identified with in vitro and mice study in 2013: high dose of vitamin C prevents the last desperate kamikaze broadside of neutrophils, the formation of the extracellular trap, causing the lung damage that led to the death of all mice in the control group (0 survivors out of 7) by 3 deaths of those treated with vitamin C (4 survivors out of 7); the probability of obtaining this result or more extreme (more survivors in the treated group, that is, one-sided test) by pure chance is 0.17%. This extracellular neutrophil trap is observed in the lungs of patients with acute respiratory distress syndrome.
    Figure 7 from Fowler et alter (2013) showing in vitro inhibition by vitamin C (C and F) of the extracellular neutrophil trap (B and E)
  • Phase I randomized trial in severe sepsis patients, with a placebo group of 8 patients and two intervention groups for 4 days, one with 8 patients and a dose of 50 mg/kg/24 h, and another with 8 patients and a dose of 200 mg/kg/24 h. Mortality at 28 days (yes, 24 days after finishing the treatment), was 62.5% in the placebo group and 44.4% in the treatment groups: the probability of giving the same or more favourable result for the randomised treatment groups is 14.6%.
There I commented on the phase II multicenter trial that had been initiated... for which we already have results:
  • A dose of 50mg/kg/6 h (about 3.5g every 6 hours for a 70kg patient) of vitamin C for 4 days.
  • The main measures of the trial (the truly important ones) did not improve with respect to the placebo: neither at 4 days the evaluation score of organ failure related to sepsis (improvement of 3 points in the group under vitamin C, 3.5 in the group under placebo, p=0.9 (all of the p-values from two-sided tests if not stated otherwise), on the one hand, nor at 7 days the levels of C-reactive protein (54.1 vs 46.1 μg/mL, p=0.33) and thrombomodulin (14.5 vs 13.8 ng/mL, p=0.7), on the other.
There was a slight improvement when measured in terms of total fillers, such as mortality after 24 days of treatment, of 29.8% in the group with vitamin C compared to 46.3% in the group with placebo (p=0.03).
Figure 3 from Fowler et alter (2019)

The incredible p-value drop. Source: Jiajia et alter0 (2020) (via George Henderson)

What about mortality after 4 days (duration of treatment)?: although some innocent minds might think that the initial benefit of vitamin C —dropping to a mortality of about 4% (4?/84) from about 27% (22? /83) from the placebo (p=0'0001)— should persist if the treatment would be continued beyond 4 days, the high toxicity of vitamin C (🙄) makes it totally unadvisable to prolong it, so it is a spurious result that is totally ignorable and dispensable. That the main measures have not improved (because fewer severe patients died on the treatment group) clearly supports such a result.

[BEGIN added section on 4/22/2020]

Dr. Fowler's presentation on his CITRIS-ALI trial (on sepsis patients who have developed acute respiratory failure) commenting upon mortality results:
 

CITRIS-ALI mortality and ICU graduadion at treatment end point
Dr. Fowler reports on some out-of-protocol measures:
  • Deaths at 4 days (treatment end point): 19/83 in those under placebo, 4/84 in those under treatment, p=0.00068=0.068%.
  • ICU graduates at 4 days (treatment end point): 1/83 in those under placebo, 9/84 in those under treatment, p=0.0096.

Bonferroni multiple comparison correction with these two measures added to the 49 measures stated at the paper (3 main outcome measures and 46 secondary ones): 5%/51=0.05/51=0.00098=0.098%. Even disregarding mortality at treatment end point as an objective main measure by itself, it is still statistically significant* (0.068%<0.098% —it still would have been statistically significant with 73 total measures) except when you think that selecting mortality at treatment end point is fishing within an unlimited set of irrelevant outcomes (without reporting doing it) to get a "statistically significant" one by pure chance alone.

It is important to point out that p-hacking consists of checking as much measures as needed to get a "statistically significant" one with p<0.05: you don't make any multiple comparison correction or even further if you don't report that all those measures have been checked at all. Adding a given number of measures and checking for statistically significant ones with p<0.05/n is NOT p-hacking at all: the family-wise error rate is still 0.05 at most*. Moreover, it must be my medical ignorance but I cannot think of any other important measure to a potential patient than mortality at treatment end point. I think disregarding this result is simple cult of methodolatry. My opinion.

Taking a look at Table 2 of Fowler et alter  (2019), it boggles the mind why mortality at 96 hours wasn't included too. Perhaps the reason is related to Dr. Farkas perception:
This is pure speculation, but my guess is that the CRP and thrombomodulin endpoints were added primarily to obtain the NIH grant (they’re unusual primary endpoints to choose in a multi-center clinical trial).

[END added section]

[Added on 4/24/2020 and edited on 4/25/2020] *Actually, adding them after Bonferroni correction of 49 previous on-protocol measures it still would be statistically significant at the 5'2% level at most —5%•(1+1/50+1/51)—, that is, adding two measures more would imply a slightly larger family-wise error rate.

Some will not wait for the results (expected date 9/30/2020), including medical staff who follow the Shanghai protocol. Moreover, three days ago Dr. Cheng summarized for us (video) the preliminary results of Dr. Mao treating at Ruijing Hospital in Shanghai approximately 50 moderate (10g per day) to severe (20g) cases for 7–10 days: all recovered. In one severe case the patient was injected 50g in 4 hours, with clear improvement in that time.

However, it is interesting to look at some of the previous (inconclusive) evidence that was available before Fowler's group's multicenter phase II randomized trial to appreciate the speed with which unpatentable substances are studied (other technical factors were presumably at play too):
  • First anecdotal case of respiratory complication in pneumonia (cyanotic) treated by Dr. Klenner with intramuscular vitamin C, at home, with improvement at half an hour: 1943 (a simple count, from the year of publication of Klenner's and Fowler's results: 2019-1953=66 years).
  • Dr. Cathcart's clinical experience with oral vitamin C, published in 1981.
  • In 2009 Allan Smith was going to be disconnected from life support after his swine flu complications: a doctor, at the insistence of the relatives and for leaving them at ease before disconnecting him, agreed to give him intravenous vitamin C, 50g twice. He got better (actually because a bus passed by). They lowered the dose. The relatives ended up giving him vitamin C encapsulated in liposomes as soon as he was able to swallow.

If you are considering joining the group of those of us who saturate in vitamin C in the face of colds, flus and other suspected viruses, as in the case of COVID-19, remember that the serious complication of ingesting vitamin C in high doses (apart from genetic deficiency of the enzyme G6PD, where even at the Riordan clinic they have put intravenous treatment with 25g of vitamin C), oxalate nephropathy, is only documented to occur in situations such as dehydration, previous kidney transplant, fat malabsorption (by medication or after bariatric surgery, among others) or kidney failure (Spanish blog with all the links).


If you are encouraged to try, how do you proceed with sodium ascorbate powder?
  • At least let 2 hours pass from last food intake, in order to take advantage of it.
  • Mix one level tea spoon (something like 4000mg of vitamin C) in a glass of water.
  • After 1/2 hour to 1 hour, if you have not saturated go to point 2.
  • Space out doses when you return to take vitamin C after a few hours.

Don't forget drinking plenty of liquids.

If you proceed with vitamin C tablets, and if the symptoms are acute, take 1 every 5 minutes with plenty of water.

How will we know that we have saturated: sodium ascorbate no longer absorbed → retains water in the intestines → roar of guts or mild diarrhea (no cramps). The necessary dose will depend on the disease, as already checked by Dr. Cathcart.


Where can you buy vitamin C? Here are some of the shops on the Internet selling sodium ascorbate:
I would ask at your bakery too if the need arises.

If you get better, when will you know if vitamin C is likely to have contributed to it and not simply because you were going to get better anyway?: hopefully in October this year. Why bother then and take it now: just in case it is going to be effective as the injectable one is in the case of sepsis. Yes, you have to make a decision in the face of incomplete information: there is no certainty that you will make the right one. Personally, the risk-benefit analysis supports saturating yourself with vitamin C at the first signs of a suspected viral infection. By now it's a question of credibility (no, I'm not talking about Linus Pauling), and for the moment the late doctors Klenner and Cathcart have it for me as long as their hypotheses are not falsified: the effectiveness of high-dose intravenous vitamin C on the one hand and oral vitamin C to saturation on the other, in keeping you alive and speeding up your healing from a viral infection. Dr Levy (a cardiologist) also has it with respect to vitamin C encapsulated in liposomes for the above-mentioned viral infections.


In case someone goes the route of vitamin C encapsulated in liposomes, it could be that taking 4–6g two or three times a day (half an hour before meals) is enough. Stores and brands, e.g. Altrient, California Gold Nutrition or Aurora.


Hyperinsulinemia



In the Chinese report published a few days ago on COVID-19 (via Henry Lahore), the higher than average mortality (2.6%) was noted in those patients with some previous diseases, all associated with insulin resistance and its hyperinsulinemia (high blood insulin):

However, it could also be that the comparison with the average mortality rate does not take into account age (higher mortality in older people who are more likely to have one of these chronic diseases): we will have to wait for a future paper.


If it is ultimately true that COVID-19 is more severe in hyperinsulinaemia (according to Petro's hypothesis because the virus would take advantage of the higher amount of insulin to replicate more quickly) then it would have made sense to try to reduce this state of excess insulin:

Risk/benefit analysis of the three: no risk, possible benefit.



Others



Any further action to consider, even if it is more speculative (or not) than the previous ones.



Fever



Dr. Chan Kan Ping's hypothesis is that the 2002 coronavirus, SARS-CoV, may be sensitive to high body temperature. It simply doesn't make sense to reduce fever with antipyretics, and more so if it does not even rise above 40°C. As George Henderson points out, it is not wise to take paracetamol for viral infection when the available data, in animals infected with flu, indicate higher mortality. The widespread use of antipyretics, shielded by the stupid "treat the discomfort", is only understundable in mild disease, by inertia and by giving satisfaction to the impulse to act and do something... if it leads you to the use of antipyretics during COVID-19 be aware that you will be making an even potentially worse decision than the use of homeopathy.


Vitamin D


I personally see vitamin D more as a background treatment, not as an acute measure. Even so, if you haven't worried about maintaining good levels during the fall/winter, you can supplement, perhaps first days with higher dose.

As a matter of fact, good levels of vitamin D could reduce the likelihood of the serious complication (via Ana), acute respiratory distress syndrome.



Selenium



This connection, pointed out by George Henderson, is not really workable, but I put it in here for completeness. It seems that, like the flu virus, SARS-CoV-2 would mutate more rapidly in the face of selenium deficiency. Unworkable because we would have to guarantee selenium sufficiency for everyone.


I have used www.DeepL.com/Translator but edited it afterwards. So, anything wrong is my fault.