179

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Islatravir and safety

By Charles-Edouard!

As the HAS is struggling to rule, we sometimes read a lot of nonsense (anonymously, on the net):

Where on earth did this come from? The conditions for inclusion in ANRS-4D and QUATUOR are 1 year of certain virological success. The treatment starts with a horse dose (induction) followed, in case of success and stability, by a reduction. We do not start with a reduction of the dosage on the first day or the day before our own death! The undetectability must be reached and confirmed by a test at more than 6 months (cf rare cases, seen in the Gilead trial, for example, the load can be undetectable a first time, then rise again, it is Raffi who spoke about it, that is to say!), one leaves oneself a little margin, thus that leads to approximately 12 months after the first undetectability... It's simple: too early you lose the benefit of the induction, too late you lose years of unnecessary overmedication!

Islatravir, a development not very XXI century

In previous posts, we have seen how Dolutegravir marks a fundamental evolution in pharmaceutical chemistry and inhibitors in particular. We find this same modernity in the development of anti-SARS antivirals. The idea is simple and the most modern technology is beginning to make it possible. Inhibition is a key-lock system: the better a key fits the lock, the more efficient it is: it sticks as close as possible to the function and therefore prevents any other molecule from accessing the enzyme, i.e. the protein that catalyzes the reaction. No catalyst, no reaction. [As a reminder, in classical chemistry, an inhibitor is called a poison, of which the best-known example is... lead (as it screwed up the function of the catalytic pot, it was removed...)]

The modern method benefits from the latest advances in protein (including enzyme) imaging/mapping. It's long, it's complicated, but more or less we manage to make a 3D map, with a very high definition of the coastal profile, thus of the harbor which shelters the catalyst. It remains to design a Sardine that will block the port of Marseille. A lot of tools are needed, the map and docking software that calculates affinity, steric hindrance, etc.

There is a method and tools. So much so that it raises the question of 'discovery'. Indeed, the lock controls the key and there are not 2 perfect keys for the same lock! The one who presents an optimal key for the lock will obtain the patent, thus the exclusivity. However, he has only made the 'negative' of the card. The question then arises as to the fair remuneration of the person who has made... the card! Because the real discovery is the map, and the invention is its symbol(in the etymological sense of counterpart). And for a given map there is only one optimal pharmacore. This forbids any further invention! Dolutegravir marks a new generation of INI and also its end. The possible improvements, relative to this catalytic site, are marginal. It is therefore not surprising that Bictegravir(Gilead, actually Japan Tobacco, Tokyo) is the look-alike of Dolutegravir(GSK, actually Shionogi, Osaka): all this is drunk from the same glass of sake!

Well, Islatravir is just the opposite! It's a fin-de-siècle molecule, developed in the old way, and kept in a closet(yes, yes, this part is a bit painful to the heart, when you think about it), it's due to intuition, to experimentation, to expertise.

Islatravir: episode 2, safety

As we saw in a previous episode (read it absolutely), the starting point is a shitty ARV(we'll come back to that) which has been worked on to optimize the recognition. Great except that other enzymes recognize it too! It messes up the reverse transcriptase (what a bitch!) but also natural and useful polymerases. Shit!

Islatravir and... antibiotics

Many naturally isolated nucleoside antibiotics are available. Most of them have been modified with a physiological nucleoside, and although they have high antibacterial and antitumor activity, they were also very toxic and could not be used clinically (e.g. Tubercidin, Aristeromycin, Nucleocidin...). They were unusable... Therefore, in the 1960's and 1970's, nucleoside chemists chemically modified these antibiotics again on a single site in order to obtain nucleosides with a better biological activity.

However, once modified, the activity was lost in all cases. Dang!!! So, you're ticking your thing off at one point (or more), you eliminate the toxicity, but goodbye the efficacy��! Needless to say, by the turn of the 80's, no one was doing this anymore...

Thus, many researchers at that time left nucleoside chemistry, claiming that "nucleoside chemistry has no future" (especially in the United States, it became difficult to get research funding and the move was rapid). However, the Japanese researchers surmised that "loss of activity means loss of toxicity."

Loss of efficiency on the polymerase

The idea is the following. The problem is twofold: the selected molecule is efficient against Reverse Transcriptase(good) and Polymerase(not good). If we try to reduce the toxicity of the molecule/polymerase couple by the classical way (now abandoned) we will reduce the toxicity (towards Polymerase) and the efficiency (towards Polymerase), which is a good thing because it will reduce the toxicity due to the efficiency on Polymerase !

Therefore, if the toxicity of 4'SdN in which one of the physiological nucleosides is modified is high, it is considered that the toxicity can be reduced by modifying it further. This is because human nucleic acid polymerase recognizes our modified nucleoside (the candidate molecule) at one site (it attracts it as a docking port) and integrates it into the DNA or RNA, but it is expected that a nucleoside modified at two or more sites will not be recognized and will not attract it anymore!

That's it! Islatravir's ancestor has just lost his toxic virginity!

... Without losing its efficiency towards the reverse transcriptase. An efficient aegis, whose first descendants are non-toxic... And it is not finished! Researchers are going to work on the metabolism (the life span), because it is the objective: to make a cheaper ARV!

Well... We'll see this next time

The French genius: Sonigo and Raoult, always...

You have to read the best! The best modern and accessible microbiologist is Raoult, unless you have someone else to suggest, if you wish. Even if he is not involved in the problem of the moment, we must read and reread Sonigo. He predicted, on the basis of general considerations, that the virus would become less dangerous as it would inevitably mutate. Let's go for the general rule, and we'll see if the massive Spikisation comes or not to disturb the context. We will see... Remains that Raoult, he comes with marbles, genomes: the virus/variant cannot not mutate and its effect d��croit at the grè of successive mutations. There you have it... The usual future of a variant is to disappear, within about 2 months of its emergence. A whole new understanding of RNA virus epidemics is emerging to the public eye.

For the record, THE video of Raoult which dedicates this erosion is here. Erosion considered by Sonigo and quoted in my post here. Because it is necessary to read and re-read Sonigo! And we applaud the prescience in this issue of JDS, remarkable! The interview dates from ... 1996! it reads:

One will also read with interest the interview with Leibowitch, and in particular this
Why is this important? because it is the culmination of a series of posts to come on the responsibility of all (including patients) in overdosing. To be continued...

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Turn off the TV and don't be fooled by Pharisaical veracity

178

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Lorgeril and his filly: a little science in a hysterical world

By Charles-Edouard!

Lorgeril and his filly: an already old observation

In the trial that paved the way for the marketing authorization of Genvoya(Gilead, again and again...) there is an annomaly, which, very appropriately, is resolved (by itself?) in the last stretch. I'm curious about this, but at the time I would never have questioned the solid science of double-blind trials. However, it was strange...

Is it possible to cheat a clinical trial? Normally not, but what about it? Once you open Pandora's box you find so many and more. The first one that made some noise was the Jupiter trial. The controversy continues (see BMJ article). And the valiant de Lorgeril, who put forward the cheating, will have been consigned to conspiracy, despite an impressive career (remember, the Lyon Study and the Mediterranean diet is him, among others). The denunciation of the Jupiter essay is here

So he has often discussed a bias in trials that seems to be on its way to being found in THE vaccination-that-is-not-a-vaccination...

Lorgeril and horse racing

His demonstration was brilliantly illustrated in a TV program that I did not find again. Too bad... It's still easy to visualize...

At the Grand Prix du Président de la République (yes, it would not be for sale, but it has a price...), the competitors are at the start. The favorite, Astra de Zeneca, makes a great start. She dominates! At the halfway point, her lead is clear: she wins, she wins! And it is the fall of her followers. The owner calls out to the judges: what's the point in continuing the massacre: for the sake of everyone, we might as well stop here and declare Astrée de Zeneca the winner, hands down. The public is all for the filly, favorite of the media.

The time to consult the Wise Men, which is, as we know, only a formality, Delta du Bengale comes from the end of the race and makes an unprecedented comeback. The outsider is relentlessly climbing back up and it is urgent to declare Astrée de Zeneca the winner.

It goes very fast and Delta du Bengale is neck and neck... Here she overtakes Astrée de Zeneca, beaten at the finish, to the great displeasure of Sir Zeizer, the owner

One must beware of a temporary superiority

The effect of statins is deceptive. They seem to be beneficial for a while, then the cardiovascular risk takes over. This is normal... In the end, everyone dies!

Obviously, the industrialist-sponsor of the trial has every interest in winning the decision at the most favorable moment! And to erase the traces of his misdeed. Out of compassion, the trial will be stopped in view of the obvious benefit (provisional, it is true) and we will even treat the control group in emergency. Oh the unfortunate ones who otherwise would have been victims of their abnegation: no more control group, no more remontada!!! And the trick is done!

Relative decline in the performance of genetic therapies

The hypothetical theater is being built in front of us: let the show begin! Israel, once shown as an unmistakable example, is turning into a fiasco... It's not yet sure, but it's taking the shape of a big increase of positive PCRs, for some or the others. Of course the pro-vaxx people look the other way. Yet Pfizer had negotiated with the Israeli government to have (and publish) the data, which they hoped would be unassailable.

Will Laurent Alexandre eat his hat?

A promise is a promise...

Obligation of treatment / Judiciarization

I had opened a section "Obligation of treatment / Judiciarization" concerning HIV... I kind of gave up because it's so hopeless! But well... Here we go straight to it!

The 1/15 / My tank

Well... Almost 2 years in 1/15 and an undetectable CV... I'm looking for my "missing tank" ... Well, not quite disappeared but it is confirmed that it went under the radar. That's good, it's confirmed! How much is it? We don't know more for the moment! I hear that people argue that as long as it hasn't disappeared entirely, there would be no benefit in reducing it to mini-mini... Really??? How many people do you know who measure their tank every year, make new arrangements and see it drop below the radar in less than 12 months? Leibo would have been thrilled as hell: It is nevertheless the strategy that he went to expose to Pasteur...

The French genius: Luc Montagnier

Me, I gladly listen to Montagnier... 4 pillars support Eclipsotherapy and 2 are perfectly predicted by Montagnier!(I will do a paper on this... )
A very good view of things in this Letter from Montagnier

1/ Coronaviruses in general are not dangerous.
2/ The SARS-COV2 Coronavirus has a natural origin which has been modified in a laboratory from which it came out. It is a pathogenic chimera.
3/ Both DNA and RNA viruses are made up of nitrogenous bases that belong to nucleotides.
4/ Variants are all the more frequent as vaccines become more widespread.
5/ The messenger RNA vaccines aim at producing a toxic antigen: the Spike protein.
6/ The fate of the virus
7/ Vaccinating during an epidemic period is a nonsense, increasing the undesirable effects: epidemiologists know it.
8/ Nature is stronger than scientists: collective immunity is a delusion.
9/ The health pass imposes quasi-mandatory vaccination to too many people, to avoid the responsibility of the government or the manufacturers.


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