REFERENCE: Moriarty LF, Plucinski MM, Marston BJ, et al. (ePub: 23 March 2020). Public Health Responses to COVID-19 Outbreaks on Cruise Ships — Worldwide, February–March 2020. MMWR Morbidity and Mortality Weekly Report. DOI: http://dx.doi.org/10.15585/mmwr.mm6912e3external icon. ARTICLE| FREE FULLTEXT PDF
By Neuronicus, 24 March 2020
In the past few days, a new hot subject has gripped the attention of various media and concerned the medical doctors, as if they don’t have enough to deal with: chloroquine. That is because the President of the U.S.A., Donald Trump, endorsed chloroquine as treatment of COVID-19, a “game changer”, despite his very own director of the National Institute of Allergy and Infectious Diseases (NIAID), Dr. Anthony Fauci, very emphatically and vehemently denying that the promise of (hydroxy)chloroquine is beyond anecdotal (see the White House briefing transcript here).
Many medical doctors spoke out urging caution against the drug, particularly against the combination the President endorses: hydroxychloroquine + azithromycin. As I understand it, this combo can be lethal as it can lead to fatal arrhythmia.
As for the (hydroxy)cloroquine’s possibility to help treat COVID-19, the jury is still out. Far out. Meaning that there have been a few interesting observations of the drugs working in a Petri dish (Liu et al. 2020, Wang et al., 2020), but as any pharma company knows, there is a long and perilous way from Petri dishes to pharmacies. To be precise, only 1 in 5000 drugs get from pre-clinical trials to approval and it takes about 12 years for this process to be completed (Kaljevic et al., 2004). The time is so long not because red tape, as some would deplore, but because it takes time to see what it does in humans (Phase 0), what doses are safe and don’t kill you (Phase 1), does it work at all for the intended disease (Phase 2), compare it with other drugs and evaluate the long-term side effects (Phase 3) and, finally, to see the risks and benefits of this drug (Phase 4). While we could probably get rid of Phase 0 and 4 when there is such a pandemic, there is no way I would submit my family to anything that hasn’t passed phases 1, 2, and 3. And those take years. With all the money that a nation-state has, it would still take 18 months to do it semi-properly.
Luckily for all of us, chloroquine is a very old and established anti-malarial medicine, and as such we can safely dispense of Phases 0, 1, and 4, which is fine. So we can start Phase 2 with (hydroxy)chloroquine. And that is exactly what WHO and several others are doing right now. But we don’t have enough data. We haven’t done it yet. So one can hope as much as they want, but that doesn’t make it faster.
Unfortunately – and here we go to the crux of the post -, following the President’s endorsement, many started to hoard chloroquine. Particularly the rich who can afford to “convince” an MD to write them a script for it. In countries where chloroquine is sold without prescription, like Nigeria, where it is used for arthritis, people rushed to clear the pharmacies and some didn’t just stockpiled it, but they took it without reason and without knowing the dosage. And they died. [EDIT, 23 March 2020. If you think that wouldn’t ever happen in the land of the brave, think again, as the first death to irresponsible taking chloroquine just happened in the USA]. In addition, the chloroquine hoarding in US by those who can afford it (is about $200 for 50 pills) lead to lack of supply for those who really need it, like lupus or rheumatology patients.
For those who blindly hoard or take chloroquine without prescription, I have a little morsel of knowledge to impart. Remember I am not an MD; I hold a PhD in neuroscience. So I’ll tell you what my field knows about chloroquine.
Both chloroquine and hydroxychloroquine can cause severe psychosis.
That’s right. More than 7.1 % of people who took chloroquine as prophylaxis or for treatment of malaria developed “mental and neurological manifestations” (Bitta et al., 2017). “Hydroxychloroquine was associated with the highest prevalence of mental neurological manifestations” (p. 12). The phenomenon is well-reported, actually having its own syndrome name: “chloroquine-induced psychosis”. It was observed more than 50 years ago, in 1962 (Mustakallio et al., 1962). The mechanisms are unclear, with several hypotheses being put forward, like the drugs disrupting the NMDA transmission, calcium homeostasis, vacuole exocytosis or some other mysterious immune or transport-related mechanism. Because the symptoms are so acute, so persistent and so diverse than more than one brain neurotransmitter system must be affected.
Chloroquine-induced psychosis has sudden onset, within 1-2 days of ingestion. The syndrome presents with paranoid ideation, persecutory delusions, hallucinations, fear, confusion, delirium, altered mood, personality changes, irritability, insomnia, suicidal ideation, and violence (Biswas et al., 2014, Mascolo et al., 2018). All these at moderately low or therapeutically recommended doses (Good et al., 1982). One or two pills can be lethal in toddlers (Smith & Klein-Schwartz, 2005). The symptoms persist long after the drug ingestion has stopped (Maxwell et al., 2015).
Still want to take it “just in case”?
P.S. A clarification: the chemical difference between hydroxychloroquine and chloroquine is only one hydroxyl group (OH). Both are antimalarial and both have been tested in vitro for COVID-19. There are slight differences between them in terms of toxicity, safety and even mechanisms, but for the intents of this post I have treated them as one drug, since both produce psychosis.
REFERENCES:
1) Biswas PS, Sen D, & Majumdar R. (2014, Epub 28 Nov 2013). Psychosis following chloroquine ingestion: a 10-year comparative study from a malaria-hyperendemic district of India. General Hospital Psychiatry, 36(2): 181–186. doi: 10.1016/j.genhosppsych.2013.07.012, PMID: 24290896 ARTICLE
2) Bitta MA, Kariuki SM, Mwita C, Gwer S, Mwai L, & Newton CRJC (2 Jun 2017). Antimalarial drugs and the prevalence of mental and neurological manifestations: A systematic review and meta-analysis. Version 2. Wellcome Open Research, 2(13): 1-20. PMCID: PMC5473418, PMID: 28630942, doi: 10.12688/wellcomeopenres.10658.2 ARTICLE|FREE FULLTEXT PDF
4) Good MI & Shader RI. Lethality and behavioral side effects of chloroquine (1982). Journal of Clinical Psychopharmacology, 2(1): 40–47. doi: 10.1097/00004714-198202000-00005, PMID: 7040501. ARTICLE
3) Kraljevic S, Stambrook PJ, & Pavelic K (Sep 2004). Accelerating drug discovery. EMBO Reports, 5(9): 837–842. doi: 10.1038/sj.embor.7400236, PMID: 15470377, PMCID: PMC1299137. ARTICLE| FREE FULLTEXT PDF
4) Mascolo A, Berrino PM, Gareri P, Castagna A, Capuano A, Manzo C, & Berrino L. (Oct 2018, Epub 9 Jun 2018). Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article. Inflammopharmacology, 26(5): 1141-1149. doi: 10.1007/s10787-018-0498-5, PMID: 29948492. ARTICLE
5) Maxwell NM, Nevin RL, Stahl S, Block J, Shugarts S, Wu AH, Dominy S, Solano-Blanco MA, Kappelman-Culver S, Lee-Messer C, Maldonado J, & Maxwell AJ (Jun 2015, Epub 9 Apr 2015). Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy. Clinical Case Reports, 3(6): 379-87. doi: 10.1002/ccr3.238, PMID: 26185633. ARTICLE | FREE FULLTEXT PDF
6) Mustakallio KK, Putkonen T, & Pihkanen TA (1962 Dec 29). Chloroquine psychosis? Lancet, 2(7270): 1387-1388. doi: 10.1016/s0140-6736(62)91067-x, PMID: 13936884. ARTICLE
7) Smith ER & Klein-Schwartz WJ (May 2005). Are 1-2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers. The Journal of Emergency Medicine, 28(4): 437-443. doi: 10.1016/j.jemermed.2004.12.011, PMID: 15837026. ARTICLE
Studies about chloroquine and hydoxychloroquine on SARS-Cov2 in vitro:
First study about chloroquine and hydoxychloroquine on SARS-Cov2 in vivo below. Unfortunately, it has some methodological flaws, see here and here, which hopefully will be corrected once the peer-reviewers will take a closer look at it. UPDATE [31-3-2020]: It seems the article is flawed in more than one way, with serious ethical issues (timeline of treatment doesn’t match the methods reported, patients appear and disappear from data points, graphs different depending on the venue, published in the same journal where the author is editor, no peer-review, no blind, no placebo, controls barely tested, plus, no reputable researcher should announce that they are the genius that cured COVID-19 on a YouTube video, particularly when they get to publish in 24 hours anyway).
Anyway, here it is:
These studies are also not peer reviewed or at the very least not properly peer reviewed. I say that so as to take them with a grain of salt. Not to criticize in the slightest. Because I do commend the speed with which these were done and published given the pandemic. Bravo to all the authors involved (except maybe the last one f it proves to be fraudulent). And also a thumbs up to the journals which made the data freely available in record time. Unfortunately, from these papers to a treatment we still have a long way to go.
By Neuronicus, 22 March 2020
I was looking for what kills coronaviruses and I found this little gem in a paper by Walker & Ko (2007):
“MHV coronavirus was easily inactivated in PBS with 0.01% Tween but was relatively stable when suspended in MEM with 10% FBS”.
Tween is a relatively inexpensive standard molecular biology reagent for cell culture. Is otherwise known as POE (20) sorbitan monooleate, Polyethylene glycol sorbitan monooleate, Polyoxyethylenesorbitan monooleate, Polysorbate 80, Sigma says. It costs about $30 for 100 ml, but you could probably get it cheaper if bought in bulk, like I did a few months ago.
The paper in itself is on a different subject: comparing survival rate of the infectious agents after exposure to UV light. The one sentence about Tween was put in to emphasize differences between the infectious agents. The actual point of the paper is that while the bacteriophage MS2 and the respiratory adenovirus serotype 2 were not affected too much by UV, the murine hepatitis coronavirus was. Namely, after exposure to a dose of 599 microW s/cm2 of 254 nm UV, the coronavirus survival was only 12.2 % +/- 7.2, but to reduce the MS2 and adenovirus survival rate to around 32%, a much higher dose of UV of 2608 microW s/cm2 was needed (see Table).
The infectious agents were aerosolized. This is important because the “UV susceptibility is higher in viral aerosols than in viral liquid suspensions” (p. 5464).
Of extreme importance: DO NOT SHINE UV ON SKIN! It will harm you more than it will harm the virus:
The only thing I’m a bit unclear is the duration of UV exposure. In the Methods it says: “16.2 s at 12.5 L/min airflow […] was considered the UV exposure time” (p. 5461), but elsewhere in the paper we find: “The duration of sample collection was 15 min, with the UV on (UV dose = 2608 or 599 microWs/cm2) or off” (p. 5462). So weren’t the aerosols exposed for 15 minutes then? Or they passed away since there was an airflow in the experimental chamber and then they were only exposed for 16 sec? I dunno, it’s not my field.
Nor is cell culture my field, so I’m definitely not an expert though I have learned how to do it as a matter of principle because it keeps happening around me and in the papers I read. So perhaps the fact that Tween kills coronaviruses might be common knowledge for a good portion of the molecular biologists and immunologists, but maybe not for everybody. So here you go:
P.S. As soon as I published, I have been thoroughly (and repeatedly!) informed that every scientist that works with viruses knows that Tween kills coronaviruses. Because… drum roll… Tween is a soap. Duh! And we know how soap kills viruses, by dissolving their protective cover. Oh well :). I’d rather be chided for repeating well-known facts than for spreading disinformation.
REFERENCE: Walker, C. M., & Ko, G. (1 Aug 2007). Effect of Ultraviolet Germicidal Irradiation on Viral Aerosols. Environmental Science & Technology, 41(15), 5460–5465. PMID: 17822117, DOI: 10.1021/es070056u ARTICLE
By Neuronicus, 3 March 2020
The Science Portal 