Ivermectin proponents point to in vitro studies as proof of efficacy
One problem: the dose required in vitro (IC50) to inhibit #COVID is 30-90x higher than the plasma or tissue levels (Cmax) achieved with a standard 12mg IVM dose
A 🧵 explaining & debunking this myth
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First some definitions:
- Cmax is the maximum concentration achieved after a medication is given; it is usually measured in healthy people
- IC50 is the concentration of a drug necessary to inhibit a particular enzyme or process by 50%; it is measured in vitro.
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Since the pandemic began, many studies looked at repurposing FDA approved drugs to treat COVID
Literally dozens of candidate drugs have been found that inhibit viral replication in vitro
One of these candidates is ivermectin
But as we will see the devil is in the details... 3/
The key study by Caly et al found that at a concentration of 5 μM ivermectin inhibited SARS-CoV-2 replication (IC50) in Vero cells (African Green Monkey Kidney cells)
🐒 kidney cells aren’t exactly proof of efficacy in humans but this is promising
Except there’s a problem... 4/
...the dose that inhibits SARS-CoV2’s replication (IC50) in vitro is MUCH higher than the concentration of ivermectin (Cmax) that’s actually achieved in humans taking the highest dose of the drug:
IC50 5 μM
vs
Cmax 0.05 μM (on 200 mcg/kg)
That’s 100x less drug than needed!
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Ivermectin proponents argue that the drug accumulates in lungs & therefore reaches an effective level.
This too has been debunked in this excellent paper by Schmith et al👇
Using measurements from cow lungs & serum, they calculate the tissue distribution of ivermectin.
Even though Cmax was higher for lung (0.08 μM vs 0.05 μM) it was still much less than the IC50 needed to inhibit SARS-CoV2 (5 μM).
That’s still 62x too low to be effective! 7/
What if we just use a 10x higher dose of Ivermectin (e.g. 120 mg instead of the standard 12 mg)?
We still come up well short!
Even at this dangerously high 10x usual dose, our lung specific Cmax is only 0.8 μM compared to an IC50 of 5 μM (still 6x too low to be effective). 8/
This brings us to another key point: toxicity.
Ivermectin proponents argue that the drug is safe & widely used. This is true, in healthy outpatients treated with a low *weekly* dose.
Critically ill inpatients on a high *daily* dose are much more likely to develop toxicity.
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Dr Carlos Chaccour wrote an excellent thread on Ivermectin a year ago👇
He points out that if ivermectin crosses the blood brain barrier it can interact with GABA receptors causing serious 🧠 side effects. This is more likely in inflamed patients on high dose ivermectin: 10/
The next time you hear that ivermectin is “perfectly safe” & “effective in COVID” remember:
- plasma or lung levels of ivermectin in vivo (Cmax) don’t get anywhere close to the IC50 required in vitro
- there ARE risks of potentially fatal neurological toxicity with ivermectin
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Every year, there is a predictable spike in fatal car accidents, medical errors, & heart attacks.
It’s estimated that there are thousands of excess deaths, a 1% increase in energy consumption, & billions of dollars in lost GDP.
The cause? Daylight savings transitions.
🧵
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Earth's axis of rotation and orbital axis are not precisely aligned. The 23.5 degree difference - 'axis tilt' - gives us our seasons and a noticeable difference in day length over the course of the year.
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For millennia this seasonal variation was an accepted fact of life.
In 1895, George Hudson, a New Zealand entomologist, was annoyed that less afternoon light meant less time for bug collecting.
He realized that clocks could be adjusted seasonally to align with daylight.
Unlike other Trump moves, this is arguably GOOD news for researchers!
If the NIH budget is unchanged (a big if), this allocates more money to researchers; if you go from an indirect of 75% to 15% it means you can fund 3 grants instead of 2.
Between 1947 and 1965, indirect rates ranged from 8% to 25% of total direct costs. In 1965, Congress removed most caps. Since then indirects have steadily risen.
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A lot of indirects go to thing like depreciation of facilities not paying salaries of support staff.
This accounting can be a little misleading.
If donors build a new $400m building, the institution can depreciate it & “lose” $20m/year over 20 years. Indirects pay this.
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🚨Apparently all NIH Study Sections have been suspended indefinitely.
For those who don’t know, this means there won’t be any review of grants submitted to NIH
Depending on how long this goes on for, this could lead to an interruption in billions in research funding.
With a budget of ~$47.4B, the NIH is by far the biggest supporter of biomedical research worldwide.
Grants are reviewed periodically by committees of experts outside of the NIH.
When these study sections are cancelled, it prevents grants from being reviewed & funded.
Hopefully this interruption will be brief (days)
A longer interruption in study sections (months) will inevitably cause an interruption in grant funding. This means labs shutdown, researchers furloughed/fired, & clinical trials suspended. This will harm progress & patients!
#HurricaneHelene damaged the factory responsible for manufacturing over 60% of all IV fluids used in the US, leading to a major national shortage.
As clinicians what can we do to about the #IVFluidShortage and how can we prevent this crisis from happening again?
A thread 🧵 1/
There are many things we can do as clinicians to improve ICU care & reduce IVF use.
1️⃣Don't order Maintenance IV Fluid!
Almost no patient actually needs continuous IV fluids.
Most either need resuscitation (e.g. boluses) or can take fluid other ways (PO, feeding tube, TPN).
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Frequently if someone is NPO overnight for a procedure, MIVF are ordered.
This is wrong for two reasons.
We are all NPO while asleep & don't need salt water infusions!
We should be letting people drink clears up to TWO HOURS before surgery, per ASA.
New favorite physiology paper: Central Venous Pressure in Space.
So much space & cardio physiology to unpack here including:
- effects of posture, 3g shuttle launch, & microgravity on CVP
- change in the relationship between filling pressure (CVP) & LV size
- Guyton curves! 1/
To measure CVP in space they needed two things:
📼 an instrument/recorder that could accurately measure pressure despite g-force, vibration, & changes in pressure. They built & tested one!
🧑🚀👩🚀👨🚀 an astronaut willing to fly into space with a central line! 3 volunteered! 2/
The night before launch they placed a 4Fr central line in the median cubital vein & advanced under fluoro.
🚀The astronauts wore the data recorder under their flight suit during launch.
🌍The collected data from launch up to 48 hrs in orbit. 3/