Molnupiravir is a pro-drug that is converted to the ribonucleoside analog N4-hydroxycytidine (NHC).
Phosphorylated NHC is incorporated into SARS-CoV-2 RNA by the viral RNA polymerase. This causes many mutations in the virus (“viral error catastrophe”), preventing replication. 2/
But wait aren’t mutations bad? Isn’t Omicron a bunch of mutations that make it more infectious?
The distinction is the *number* of mutations.
RNA viruses are error prone - accumulating on average 1-5 mutations with every copy.
MOLN induces many DOZENS of mutations at once. 3/
Most mutations decrease fitness; they damage vital proteins & make the virus uninfectious
Rarely, a mutation increases fitness. These helpful mutations are selected for
If the mutation rate is too high, harmful mutations outnumber helpful ones. This is “error catastrophe” 4/
Omicron has accumulated about 50 mutations over 2 years, carefully selecting one by one for those that increase its infectivity
On the other hand, MOLN treatment (at the right dose) induces more mutations all at once. This causes every virus copy to be damaged/nonfunctional. 5/
Thus, despite a mechanism that literally causes viral mutations, MOLN isn’t likely to “make a worse strain of COVID”
Also worth noting that people taking an antiviral for 5 days are hopefully in isolation! Even if there was magically a worse variant - how would it spread?
6/
This is a great segue into another aspect of MOLN: who can take it?
Unlike Paxlovid which is approved in people >12 yo, molnupiravir is only approved in people over 18.
This is because of potential toxicity to cartilage in developing bones 🦴 7/
MOLN is also contraindicated in pregnancy🤰🏻due to potential toxicity in embryogenesis.
For comparison, PAX isn’t contraindicated in pregnancy but there is no human data demonstrating safety. 8/
More comparisons:
Unlike PAX, which has many drug drug interactions involving CYP3A4, MOLN doesn’t appear to have any significant ones.
Also unlike PAX, which requires a dose adjustment for GFR <60, there is apparently no renal dosing for MOLN. 9/
One important concern to mention is underdosing & compliance:
- it’s important that patients understand that they should take MOLN as prescribed (eg twice daily for 5 days).
Theoretically if they were to stop early or underdose it *could* lead to harmful viral mutations.
10/
Last, the all important question: how well does MOLN work? To answer, we need to look at the trial data…this is where it gets less compelling btw
They enrolled outpatients with a positive COVID test within 5 days. Participants had to have a risk factor for severe COVID, though they were pretty common ones:
obesity (40% of Americans)
age >60 (22% of US)
CKD (15%)
DM (10%)
CHF,CAD,CM (~7%)
COPD (6%)
active cancer
12/
Outpatients from 107 sites in 20 countries were randomized to molnupiravir 800 mg BID x5 days vs placebo.
The primary outcome was hospitalization/death or incidence of adverse events (AEs).
Secondary outcomes include time to resolution of symptoms: 13/
The patients were fairly representative of a COVID population.
Roughly event split of men and women
About 2/3 were under 50yo
About 1/3 had Delta, the rest a mixture of other clades
About 1/2 were randomized within 3 days of symptoms 14/
There were fewer hospitalizations/deaths with MOLN:
6.8% (48/709 participants) vs 9.7% (68/699); an ARR of 3% or a NNT of 33 to prevent 1 hospitalization/death
Mortality was (just barely) significant
0.1% (1 death) MOLN vs 1.3% (9 deaths) placebo
NNT 83 to prevent a death 15/
The rate of AEs and SAEs was similar in both groups:
Diarrhea, nausea, and dizziness were more frequent with MOLN (occurred in 1-2% of patients)
The single death in the MOLN group was reportedly related to bacterial pneumonia
(side note: this is a super weird figure legend) 16/
MOVe-OUT was stopped early for efficacy after interim analysis.
After stopping enrollment, the numbers got a bit worse as they followed patients out to 29 days
This isn't shocking - regression to the mean & late worsening - but it was bad optics after their big press release 17/
A 2nd study, done by Hetero pharma in 🇮🇳 also looked at MOLN in outpatients.
This open label trial enrolled n=741 patients.
They found a less impressive (but still significant) reduction in hospitalization: 1.9% vs 6.2%, ARR 4.3%.There were no deaths or SAEs 18/
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If you intubate you need to read the #PREOXI trial!
-n=1301 people requiring intubation in ED/ ICU were randomized to preoxygenation with oxygen mask vs non-invasive ventilation (NIV)
-NIV HALVED the risk of hypoxemia: 9 vs 18%
-NIV reduced mortality: 0.2% vs 1.1%
#CCR24
🧵 1/
Hypoxemia (SpO2 <85%) occurs in 10-20% of ED & ICU intubations.
1-2% of intubations performed in ED/ICU result in cardiac arrest!
This is an exceptionally dangerous procedure and preoxygenation is essential to keep patients safe.
But what’s the *BEST* way to preoxygenate? 2/
Most people use a non-rebreather oxygen mask, but because of its loose fit it often delivers much less than 100% FiO2.
NIV (“BiPAP”) delivers a higher FiO2 because of its tight fit. It also delivers PEEP & achieves a higher mean airway pressure which is theoretically helpful! 3/
Results from #PROTECTION presented #CCR24 & published @NEJM.
- DB RCT of amino acid infusion vs placebo in n=3511 people undergoing cardiac surgery w/ bypass.
- Reduced incidence of AKI (26.9% vs 31.7% NNT=20) & need for RRT (1.4% vs 1.9% NNT=200)
Potential game changer!
🧵 1/
I work in a busy CVICU & I often see AKI following cardiac surgery.
Despite risk stratification & hemodynamic optimization, AKI remains one of the most common complications after cardiac surgery with bypass.
Even a modest reduction in AKI/CRRT would be great for my patients. 2/
During cardiac surgery w/ bypass, renal blood flow (RBF) is reduced dramatically. This causes injury, especially in susceptible individuals.
But what if we could use physiology to protect the kidneys?
Renal blood vessels dilate after a high protein meal increasing RBF & GFR! 3/
77 yo with respiratory distress, RR 30, SpO2 80% on non-rebreather at 15 lpm
CXR & TTE are unrevealing
pH 7.58 / PaCO2 24 / PaO2 >500 / HCO3 22
MetHb 0% CarboxyHb 0%
The ABG looks like this:
The answer is sulfhemoglobinemia.
Sulfhemoglobinemia is a *permanently* modified hemoglobin associated with exposure to TMP/SMX, dapsone, phenazopyridine, & other amino & nitro compounds.
It has an altered oxy-hemoglobin dissociation curve.
2/
Sulfhemoglobinemia is easily confused with methemoglobinemia. Both have very dark colored blood & present with cyanosis. Diagnosis typically requires a specialized lab.
Spoiler: you may have heard that SulfHb is green. It isn’t really. You’re thinking of Vulcans’ blood.
Damn. Under Trump the White House Medical Unit was a pill-mill. Thousands of ambien & provigil per month.
Worse, for a clinic that doesn’t typically do procedures w/ moderate sedation they sure are they ordering prodigious quantities of morphine, fentanyl, versed, & ketamine…?
Honestly, this reminds me of Norman Ohler’s Blitzed.
The AG report was largely concerned with the enormous cost of prescribing these non-genetic meds.
It’s worth pointing out that dispensing prescription meds without documentation is malpractice. In the case of controlled substances it’s also likely a crime.