Why does amphotericin B lead to rigors and fever?

I learned about his side effect by the moniker "shake and bake" (thank you First Aid).

Let's have a brief look at this commonly tested side-effect.
Amphotericin B was introduced in the 1950s.

It was clear early on that fevers and chills were common side effects.

More contemporary data show lower - though still relevant - rates of both side effects.

pubmed.ncbi.nlm.nih.gov/13749466/ - 1960
pubmed.ncbi.nlm.nih.gov/10072411/ - 1999
When thinking back to the mechanism of fever, recall that PGE₂ is a key mediator.

Amphotericin B leads to an increase in PGE₂. This is likely the mechanism of chills and fever.

As this study shows, amphotericin B acts in a similar way to LPS!

Given these effects, amphotericin has been examined as an "immunostimulant" in combination with antineoplastic chemotherapy.

I am unaware of its use in any current regimen.

This is my first follow-up to a tweetorial on fevers, chills, and rigors.

Next up: meperidine (Demerol)

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More from @tony_breu

14 Sep
Why do we feel cold (i.e., experience "chills") when we have a fever? Shouldn't we feel hot?

And what are rigors?

Answers to these questions will help us better understand when we should obtain blood cultures.

When do you think is the best time to draw them?
Bacteremia exposes us to exogenous pyrogens. For example, the cell wall of gram-negative rods contains lipopolysaccharide (LPS; endotoxin).

When injected into humans LPS induces fever. But, there is a 3-5 hour delay between exposure and peak fever.

The delay between clinical bacteremia and fever was demonstrated in 1932 by Weiss and Ottenberg.

Their conclusion: Obtain blood cultures BEFORE fever. If only it were easy to predict future fevers!

[Maybe we can as you'll see in tweet 10 below.]

Read 14 tweets
1 Sep
Does hemochromatosis (HH) protect against Mycobacterium tuberculosis (MTB) infection?

If so, how could that be?

◾️MTB needs iron and HH is associated with overload
◾️MTB resides within macrophages, a site of iron storage

It seems that MTB should thrive in HH. Does it?
It turns out that the distribution of iron overload in HH is not uniform. It preferentially accumulates within parenchymal (e.g., heart, liver, pancreas) cells.

One place it remarkably spares?

Macrophages of the reticuloendothelial system!

How is this discrepancy explained?

Monocytes from patients with HH release twice as much iron as normal human monocytes after RBC phagocytosis.

Read 7 tweets
29 Aug
Why is ferritin elevated in anemia of chronic inflammation?

If the evolutionary point was/is to keep iron away from bacteria, why is our main maker of iron stores elevated?
Let's start by reviewing a few key features of iron. First, recall that it has high redox potential. As a result, it is:

🔳Beneficial: Utilized for myriad cellular functions


🔳Potentially harmful: Creates damaging reactive hydroxide radicals

Based on its role in cellular functions and its ability to cause cell and tissue damage, it is unsurprising that >99% of iron is intracellular.

And the iron that's extracellular is bound to proteins (e.g., transferrin).

Read 14 tweets
15 Aug
Why is our thirst immediately quenched after the ingestion of water?

As we'll note, it takes ~10 minutes for serum osmolarity to change. And yet thirst drops far more rapidly.

Something must be bypassing the blood...
Though I suspect we all agree that thirst is quenched rapidly after a sip of water, some of you will demand data.

If you infusion 5% saline, thereby increasing osmolarity, thirst shoots up. But, as soon as drinking is allowed, thirst drops.

pubmed.ncbi.nlm.nih.gov/19523569/ Image
Notice that in the experiment in tweet 2, the serum osmolarity had NOT dropped when thirst plummeted.

This is because it takes 10+ minutes for ingested water to be fully absorbed into the bloodstream, decreasing osmolarity.

link.springer.com/article/10.375… Image
Read 8 tweets
15 Aug
Why do patients with primary polydipsia continue to drink, sometimes to the point of severe hyponatremia?

To answer this question, we'll have to explore what makes us thirsty.

Grab a beverage and read on! Image
Cases of primary polydipsia in patients with psychiatric illnesses have been reported for decades.

While thirst isn't always mentioned as the primary driver, it is present often enough to suspect it has a role.

pubmed.ncbi.nlm.nih.gov/1551044/ Image
One driver of thirst is osmolarity.

As osmolarity increases, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) sense these changes and send projections to other brain structures.

The result: thirst

pubmed.ncbi.nlm.nih.gov/30699320/ Image
Read 16 tweets
15 Jul
Why does uremia cause platelet dysfunction (i.e., what are "uremic platelets")?

The association between kidney disease and bleeding has been observed for centuries and remains incompletely understood.

Let's have a look at platelets, bleeding, and a few of those humours.
Just about every aspect of primary hemostasis is affected in uremia. For this thread, I'll focus on how toxins disrupt:

▪️Adhesion (attachment of platelets to exposed subendothelial collagen)
▪️Aggregation (attachment of platelets to each other)

One study took blood from patients with ESRD just before dialysis and found reductions in platelet adhesion and aggregation.

When normal platelets were placed in uremic plasma, the results were similar.

🔑Something in the plasma causes the problem!

Read 23 tweets

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