176

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

Genesis of Islatravir: 1- Race for Efficiency

By Charles-Edouard!

Islatravir and Soy Sauce

To understand Islatravir and what I'm going to talk about today, you have to be sure you've read this first post, because Islatravir is a novel that starts a thousand miles away from 1/15...

At the beginning was a group of Japanese university researchers who were looking for ways to add value to food products, by breaking molecules to make 'valuable' molecules at lower cost... In a word, cutting a big molecule, existing and cheap, rather than synthesizing, ex-nihilo. Vast program where the Ministry married them with a local Kronenbourg, a brewer of beer (agrobusiness, we say...).

The idea is to cut 'natural' molecules into elementary bricks. This allows to manufacture animated acids for which the market (pharmacy, biology,...) is emerging. The beer brewer doesn't care about this, but a manufacturer of Soy sauce, the one that decorates your Sushis (yes, yes...) has a division of specialized products. Yamasa (Soy Sauce) takes the place of Asahi (Beer) in this academic project. Surprising, isn't it? Neither Merck nor the usual parrots will tell you this. Because Merck will defend itself from the shameless price it will get for its research efforts, which were insignificant, as we shall see...

Islatravir and Efficacy Gain

The project is the manufacturing by (enzymatic?) cutting of molecules in bricks, with very high added value, at lower cost... At the turn of the century, the most expensive molecules, facing huge challenges of industrialization, are the ARVs, which the (third) world needs so much. So here are our brilliant university chemists(paid by the penny) who undertake to make a derivative ARV, which costs less! Thus saving the world from a certain AIDS death.

A major track is the increase of efficiency. Indeed, if we use less drugs for the same effect, it costs less per patient. Leibowitch develops a method(largely ignored by the medical-pharmaceutical mafia) which divides the cost by 10. The Japanese chemists will reduce the cost by ... One thousand!(and we will combine the two, hi, hi, hi... ). Efavirenz is 600 mg, Islatravir is 0,75 mg, which makes a ratio of 1 to 1000, by a ladleful!

So here are our chemists who start with an expensive molecule and try to improve it. Well... The scheme is hyperclassic, we start from a molecule with a known but moderate efficiency and we try to adapt the molecule to its target. A vast program!

Step 1: better resistance profile but high toxicity...

NRTIs are 2', 3'-dideoxynunucleoside (ddN) derivatives whose efficacy is due to the fact that nucleosides are RT chain terminators (CT). However, all these drugs have a low barrier to resistance. Since the structural difference between dN and ddN is whether or not they have 3'-OH, they surmised that the presence or absence of 3'-OH changes the resistance profile. A 4'-substituted 2-desoxynucleoside (4'SdN) substituent at the 4'-position was designed to achieve this goal (Fig. below).

In their hypothesis, the new compound can be recognized by Reverse Transcriptase (of HIV), and mess with it... That would be cool! The problem is that it is also recognized by the human DNA polymerase, which would be highly toxic.

Step 2: solve the toxicity problem...

Well yes... We might be able to treat better, of course, but increasing toxicity is not great, especially in the context of the 2000s. We will see next time how they solved this problem

Obligation of treatment / Judiciarization

The idea of making screening compulsory, regular, for all, from 15 to 75 years old, for transmissible diseases (HIV, HCV, Syphillis, etc) seems to me to be quite acceptable: screening is without danger, by itself it allows to reduce the epidemic, it does not imply a compulsory treatment. Voluntary screening with community pressure on risk groups has had its day: it is useful but we have reached a plateau. While we have spent crazy amounts of money(yours) for a virus that probably escaped from a research center(not from our country), we could finally put in place a total strategy of multiple screening. Of course, the associations, who gain from the 'targeting' and the martyrdom of the afficinados of natural contraceptive penetration, are against it. What the hell!

They are against you as patients and participate in the expansion of the epidemic, under the guise of fighting against it. They are the objective ally of BigPharma, which would not be at all happy with the extinction of the epidemic. Have we ever seen these associations of frightened seronegs come to your rescue for the intermittence? Never... Total radio silence.

Protocol medicine is becoming totalitarian medicine... It is inevitable!

In the news

- The front line in the global war on Benevolent Medicine is currently in the state of Goa, India. Maudrux, bothered by the Council to the Orders, is following up on it, here. This state has taken it upon itself to deal with the Indian resurgence of the epidemic by distributing Ivermectin widely. The crisis is being contained, which no one is talking about. After Chiapas, all of Mexico is getting in on the act. Opposite Goa, Tamir Nadul (180 million inhabitants) is a comparison for having followed the negative advice of the WHO and thus backed off. Two regions, in the same area, epidemic at the same time, 2 opposite strategies, this makes a credible judge of peace. Concerned' but not destitute doctors have taken the case against the State of Goa to the Supreme Court, citing the negative warning of the WHO. The Government of Goa, defends its initiative, with arguments in support. The Supreme Court lets it go ahead: see here...(one will remember the role of an Indian Supreme Court in the resolution of the Gordian knot where the ARV industry had taken the HIV world hostage)

- Remarkable interview with Prof. Montagnier: we will come back to it, one day, because his argument on the thermodynamic stability of DNA deserves our attention. The argument has its part in my strategy of reducing the reservoir.

- The IHU (Pr Raoult) publishes its series of 10,000 patients treated in day hospitals: no deaths in patients under 60 years of age, if HCQ/AT. If we exclude very old patients with low life expectancy (heavy comorbidities), they have only 3 deaths out of 10,000, if HCQ/AT. This is the largest single-center series in the world! Greetings to the Pharisees!

The French genius... seen from America...

Did you know that? The late Anthony Perkins (Hitchcock's Psycho), sadly deceased from AIDS, had tried his hand at French song. There is no more after in Saint-Germain... It's nice, and touching. You Tube offers it to you. Let's enjoy it !

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The real insider tip is to know which doctor to go to...

175

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



Bithérapies en Cycle Court

By Charles-Edouard!

Dovato in x/7: first favorable results!

The DUETTO trial (ANRS) is announced... Well... Why not: Relief AND Intermittence combined. CoronaFolie obliges, it drags on... To the point of arriving after the battle, a bit like Recovery. Too late, it's too late... Well, we know since August 2008, in the NCT00708110 trial (Phase IIa Dose-ranging Study of GSK1349572 in HIV-1 Infected Adults), that the action of DTG lasts 3-4 days at least after the last dose. So trying DTG/3TC in 4/7 makes sense. By the way, it's JeSuisDuTreize (Mono-DTG in 4/7) who hooked me up.

So, here is our ANRS, although not very valiant, which extends the success of Quatuor(not her idea...) towards a consensual thing, which allows at least to clear the ground where the stipendiated Pharmacolâtres had with impunity amalgamated Lightening and Intermittence.

Dr. Lanzafame submits a letter to the Editor of the International Journal of Antimicrobial Agents, by M to Phillipe Colson (IHU, again!) , which is published in March 2021. The original is here. I propose a translation here: Short-cycle therapy (5 days on/2 days off) with a Lamivudine + Dolutegravir regimen in a cohort of virologically suppressed HIV-infected patients

Dovato in 5 of 7: no failure in a cohort of 27 patients

As usual, nobody talks about it, but it is interesting (and that is why the omerta is total...), and here, it is not only the result that counts. One will be sensitive to the way of presenting... Well... 27 patients, various profiles, go from Dovato 7/7 to Dovato 5/7. Nobody goes above 50, so it's all good!

A tribute to Leibowitch and the Eclipse

This is encouraging... Can do better...

Why not 6/7 ? or 6,5/7, while we are at it ??? That works too! A fortiori! Staying miles behind the front line does not allow to flush out the enemy. What will these pussilanimities be worth the day when Merck will excite, at the cost of propagandist contributions, the cage to the crazy parrots? A short shot is better than a crooked shot(Katlama, Raffi and so on), but it is still too short!

7/7 End of game, thanks to Islatravir and ... Merck

I anticipated a simple marketing problem: how can Merck regain market share with Islatravir without taking advantage of its extended pharmacodynamics (more than 10 days)? First approach: divide the dose by 10... That way you have to take it every day, and it's the JackPot. Except that now with Biktarvy practiced for a long time in 4/7, or even 2/7 or better, there is not much room for a 7/7... And ViiV which proposes an injectable...

Merck is also considering an injectable, with Doravirine. Bad luck: it doesn't work! Well... It probably does work, but the worshippers of the Pharmacokinetic Goddess lose their minds and give up the game.

Anyway, Merck (cf MK-8507) has understood what makes Islatravir strong: a 'trick' invented... almost 20 years ago! and, unwillingly, we say, launches a bi-therapy in weekly doses. You read that right! Phew!!! Saved!

At least they think so... The Phase II clinical trial is here. We'll see if it's a success: it's about time! Because Merck is accumulating failure after failure(Dutrebis and Issentress HD, which nobody is taking... ). Did you see how fast they developed a new ARV with extended duration of effect? Funny ... No ??

What will Gilead do? What are we going to do? We'll see that another time...

Weekly intake and 1/15

The mystery of the missing tank is slowly becoming clearer... Is it its disappearance that allows the 1/15 or is it the 1/15 that caused its disappearance. Well... On this one we are rather on the right side of the handle. Better to be cured without really knowing why than to think about doing nothing (Rouxioux, Hoqueloux, etc.)

Obligation of treatment / Judiciarization

It may have gone unnoticed, but YouTube has explicitly listed, and named (please!), H*Q and I*T as cause for banning. They didn't mind Foley's decapitation, but Kory's, Perronne's, etc. explanations were not. Ah well, no! Let's go to the trash! Long live cancel culture! Well... The history of the Disappeared Reservoir will also pass perhaps under the yoke of censors, who made literary studies, precisely because Sciences put them off... Conjuration of the fools...

In the news

- Garches will be a difficult label to wear... Davido, trained at a good school, therefore, safeguards his professional future. He comments, positively, on an essay that leaves however perplexing: In serious pneumonia, in hospitals, an antibacterial profilaxis is given. Isn't this futile? A double-blind trial with a non-inferiority threshold. Well... The (small) group without prophylaxis does statistically no worse than the (small) group with. So it's all good! Except that in the group without, he has a death by... bacterial sepsis. But well... It doesn't bother anyone...

- The "Journal of Experimental Pathology" publishes the study of Claude Escarguel, on the interest of azithromycin in the prevention of long Covid! But well... Nobody is interested, especially not the ANSM, whose transparency commission seems to be invisible(read Maudrux here)... Well... We are not done with I*T since it is an inhibitor of entry into the reservoir... Funny, isn't it ?

We still haven't found the pangolin... Raoult, in 2 times 3 movements, he found you an intermediary for the M.1 (green monkey of Senegal) for the M.4 (mink of Mayenne, whose genome was withdrawn from the public attention). The Chinese, they are desperately looking for the Missing Pangolin. They are looking for, they are looking for... Just like the enlightened man of Nazareth, he probably never existed except in a hysterical delirium...

The State of Goa (India) is doing a deworming campaign by providing I*T kits to the population for therapeutic and/or preventive use, all at the same time, hoping to curb the epidemic surge that India is undergoing. The WHO has rightly denounced the uselessness of the gesture. We will see! As a result, no more pharmaceutical I*T is available, including in India... One can still find veterinary I*T, but it is difficult to find a factual difference (other than the presentation, as it is generally a paste), such as a difference in purity, in molecule, etc. Nada

The French genius taken over by a Russian

Ravel's bolero accompanied the Russian Pluchenko in his sporting and artistic feat: the quadruple-triple-double jump in skating. He is the first (the first Quad is by Browning, it seems). You can find this video on YouTube, which has not aged. It is sublime. It took more than 15 years for a small Asian jig (Uno) to make the first Quadruple Flip. Since then, there is not a single champion who does not combine several Quad.

Between the first and the second, there is a lapse of time, then everything accelerates to the point of banality.

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