[Sciences/Junk Sciences] Remember the deadly turmeric IV infusion done in a holistic clinic? Lessons from the FDA report

You have remember this story of this young woman that died shortly after recieving an IV infusion of turmeric acid (aka curcumin, a bioactive compound found in Curcuma) in a holistic clinic in California few months ago (http://www.10news.com/news/team-10/encinitas-woman-dead-after-i-v-infusion-of-turmeric).
This story baffled me for many reasons. First, it was really puzzling me on how quack medicine (rebranding itself as “holistic” and “integrative” to appear more sciencey) have been moving slowly but surely into medical procedures normally held by medical staff, with some dubious claims of “IV therapy” in which the onset of an IV line and pumping up vitamins straight into your systemic circulation will help you “detox” or “rejunevate”.
Second, how turmeric acid that have been bounced by some “health/food gurus” as superfood (move on kale and quinoa, you are so 2015!) quickly moved on as therapeutics without even having the right science to back it up (until now only preclinical studies done in cells grown on Petri dishes and in rodents), with the glittery “cures-it-all” sticker all over it.
You see, turmeric acid is way far from being the next wonder drug as sold by woo peddlers. Why? Lets see some of its features (https://pubchem.ncbi.nlm.nih.gov/compound/curcumin#section=Top).
First thing, turmeric acid has a problem. A huge problem. This problem is solubility. It has a calculated xLogP of 3.2, this is already telling us this compounds is lipophilic (likes fat). It will dissolve well in oil, but not well in water (less than 0.1mg/mL according to Santa Cruz Biotechnology data sheet). If you try to go beyond that value, you will have a saturated solution with turmeric acid precipitates. These precipitates can have serious effect if injected into an IV line, if these particles are big enough to clog some capillaries.
You can circumvent things around by tweaking nanoparticles carriers. Still, even from food intake, turmeric has a very low bioavailability. From 100g of pure turmeric acid swallowed, only 1g will effectively reach the circulation and circulate through your body.
The second problem with turmeric is its pharmacokinetic profile. According to the reference cited by the FDA report, turmeric is highly unstable at physiological pH (7.4). According to this review, the elimination half-life (t1/2) for turmeric is very low (1.7+/-0.5h). By 6 hours, most of the turmeric injected via IV route will be gone. Therefore, if turmeric was considering for therapeutic, it would require multiple dosing that are either ridiculous (Dosing interval of about ~2 hours, therefore swallowing a pill every two hours) or being on a constant IV infusion (that is not realistic for everyday life).
Third problem with turmeric? Its pharmacological activity. Two important parameters have to be accounted for a drug candidate: its selectivity (does the drug targets one or several proteins?) and IC50 (what is the concentration needed to achieve 50% inhibition).
The problem with turmeric is that it is considered as a “dirty” molecule because it hits a bit of everything, with many signaling pathways affected by it. The second problem is its very high IC50. Anti-cancerous activity of turmeric swings around 10microM in various cancer cell lines in a Petri dish and have other targets at higher doses. This is not a horrible value, not a good value either. Usually we want to reach an IC50 in the nanoM range (10’000 less concentration than 10µM). Thats not the case for turmeric. Maybe by tweaking the chemical structure we may improve its IC50, but since the compound itself has so many targets trying to optimize it for therapeutic purposes maybe simply a waste of time.
If we stick to the 10µM concentration and an average molecular weight of 328g.mol-1 for turmeric, we need a concentration of 3mg/L or (0.003mg/mL) to expect some biological activity. Now the problems come in with the FDA report. There are two reported cases of adverse events, including the fatal cases. In both cases, patient had an IV line of turmeric acid. In both cases, both patients were mentioned an IV infusion of turmeric acid at 10mg/mL. First, this concentration would have made no sense. It is 300 times higher than the hypothetical dose needed to achieve a biological activity in vivo. Second, the final concentration in the IV bag was much less than this concentration, as the FDA reported only 1% of the prescribed concentration was found in the IV bag (0.00235mg/mL).
Someone has been not only been deceiving their customers by selling you less product than advertised (1% net content is honestly a huge rip-off) but also had absolutely no clues on what they were injecting. So we can blame two actors: either the compounding company that prepared the turmeric or the holistic clinic (I guess you can point who is the crook in the story).
Both cases involved ImprimisRX, a compounding pharmacy. These are laboratories under the responsibility of a pharmacist holding a specialization in compounding. He or she has to follow established rules and protocols, adhere to good manufacturing procedures in compliance with the FDA. It seems there is no wrongdoing from the compounding. The compounding produced an emulsified form of turmeric (to increase its solubility). Yet, the final concentration in the vial was about 0.205mg/mL or about 2% of the amount put on the label. Since turmeric is highly unstable under aqueous solution (even in its emulsified form) we cannot exclude a degradation of the product from the time it got compounded to the time it was administered. In aqueous protein-free solution, 90% of turmeric acid is degraded within 30 minutes (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM466380.pdf).
Now comes an another problem: was there any deception between ImprimisRX and the holistic clinic? One of the reason is the use of polyethylene glycol 40 (PEG40) castor oil in the compounding process. PEG40 may contain traces of diethylene glycol (DEG), a very well known toxic compound if ingested, with a toxicity of about 1mg/kg. DEG is a byproduct of PEG production, therefore the FDA has different quality grades of PEG whether it is destined for non-medical usage or for human consumption. DEG was found at a concentration of 0.21% (0.21g pure DEG in 100g of PEG40). The PEG40 used for the compounding was 1.25% with the clear label “CAUTION: For manufacturing or laboratory use only.” Why the compounding pharmacy used that ungraded PEG40? We don’t know yet.
PEG40 oils are used for cosmetics and considered safe for cosmetics usage  because the bioavailability of this compound is small and suited for topical application (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505343/). But you have to remember that a product that is considered safe in an administration mode is not in another administration route. This is probably explaining the adverse effect observed.
The second possible issues is a possible allergic reaction to PEG40, as the FDA cited previous reports of allergic reactions of patients exposed to PEG formulations following IV infusion of anti-cancerous agents.
By now, your enthusiasm for cur turmeric should (rightly) wind down. Turmeric is certainly great for spicing your food, not much for your health. But most of all, don’t let a “holistic clinic” perform any type of IV infusion.
IV infusion is a very delicate procedure, used for restricted applications (chemotherapy, anesthesia, infectious disease……) by a trained personnel in a medical environment (hospital or medical clinic).


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