Iloprost!

The Original Sin of preclinical research.

There is something rotten in the kingdom… No. I won’t write that.

Please avoid commonplaces! I have already mentioned Hamlet in another post and I kinda regret it. I made a resolution not to use commonplaces anymore. I see it could be used in self-irony, like comedians do. Maybe if I play the guy trying to display erudition, but is only capable of commonplaces… This irony is particularly dangerous because people could miss it… I don’t know. It’s better to avoid it. A poor stylistic choice, if nothing else.

Acacio! Councillor Acacio! Now I got you, my patient reader. Councillor Acacio is a character from Eça de Queiroz’s “Cousin Bazilio”. He is said to be an erudite man, but every time he opens his mouth comes a platitude. “O Primo Basílio” (the original Portuguese title) is a beautiful book. So many beautiful Portuguese words. Reciting its sentences aloud is a pleasure for my ears, delighted by the softness of our language. Our vowels make me feel at home, being the most beautiful those open, generous vowels from Northeastern Brazil.

Well, iloprost. If I close my eyes, I see maybe a middle-aged white man with a red face saying iloprost. I mean iloprost between the teeth of a closed mouth (try it), like in a Northern European language. Oppressed vowels. The cold weather, countless generations of harsh lives. Not even the heat of the mouth is lost to the atmosphere. I have been there. Copenhagen is something akin to the anti-Brazil. The anti-Rio, for sure. The functional and organized city (a high accomplishment of human civilization) compensates for the lack of an exuberant nature.

Brazil and Denmark are half a planet apart but tied together by a communal trait. Both countries have critical care researchers who are lost in causality, plausibility, marginal utility, etc. However, they are world-class at performing RCTs and data analyses.

Endothelial dysfunction is a long-known feature of sepsis pathophysiology. We are all aware of the capillary leak and transendothelial leukocyte migration, both local features of inflammation that may spread, bringing our minds around the idea of generalized inflammation. There is much more to it, of course. Every detail of these mechanisms is subject to exhaustive preclinical research. Of course, we will never forget vasodilation and its many competing mechanisms. Almost everything has been tested in the clinical scenario. Following the field long enough will show that preclinical hypotheses gradually become clinical trials.

The glycocalyx layer is more or less of a novelty. Most, including me, haven't learned about it in Med school. If you are not focused on sepsis and shock biology, as expected from a normal person, you probably avoid reading those daunting Shock Journal papers. I understand and accept it. But the glycocalyx is impressive.

Please don't run away while I talk about the glycocalyx layer. It's fascinating. This proteoglycan layer coats the endothelium and has many important roles. The glycocalyx is rich in heparinoids, so, under normal conditions, it prevents blood clot formation along the endothelium. Moreover, it mediates leukocyte, water, and nutrient traffic across the endothelium.

Glycalyx damage may result in the release of proteoglycan and glycosaminoglycan, which act as DAMPs, an inflammatory mediator. Moreover, and perhaps most importantly, heparinoid release induces coagulopathy. Preclinical and clinical studies show that many critical syndromes, such as shock, trauma, and sepsis, are associated with glycocalyx shedding.

So here is a new and shiny hypothesis: How about selecting patients with biomarkers of endothelial injury and striking inflammation and coagulopathy with a single intervention? It deserves testing. Well, there is no such drug (maybe apyrase could do it). How about targeting coagulopathy? Coagulopathy is associated with worse outcomes and we could try iloprost, a prostacyclin analog capable of platelet inhibition. It is worth trying.

But it didn't work. It would never work even in Danish hands.

The Land of Irrelevance #4: Iloprost

In this post:

• The failed causal chain

• Marginal utility and clinical irrelevance

• The “Original Sin” of preclinical research

• The dire consequences of misunderstanding translational research