Why Chloroquine Isn’t The Panacea For This Pandemic.
On March 19th, 2020, it had been roughly three months since the first reports of novel coronavirus-2019, COVID-19, began to appear out of Wuhan, China. According to some reports the White House had intelligence of an outbreak in Wuhan as far back as November. In those early days of the outbreak, Donald Trump dismissed any notion that a national and global crisis on a scale never seen before was about to unfold. Then, six days after that Friday the 13th when everything in the world changed, Trump made an announcement that caught everyone by surprise. The antimalarial drug chloroquine would be a “game changer” in the fight against COVID-19 according to the American President.
There has been a great deal made about the fact that there is still not enough data available to state whether or not chloroquine is effective, but I haven’t heard much about the potential adverse events that can and have occurred as a result of chloroquine. This is not a benign substance, it is toxic and potentially dangerous or even deadly in some instances. Therefore a great deal of care must be exercised and all available information about it must be made before anyone can or should make a decision about taking this or any other drug.
Disclaimer
I want to make it clear that the reasons for my position on this are by no means political in nature and that they come from scientific and anecdotal information that I have acquired over the course of the last several months.
Hydroxychloroquine sulphate
Available in the United States under the brand name Plaquenil, chloroquine is used as an antimalarial and is also widely used off-label in the treatment of Rheumatoid Arthritis (RA). Not long after Trump’s endorsement, a number of statements about chloroquine began to circulate online with two of the more common being:
- The safety profile of chloroquine is well understood from its use in over a billion people for malaria. As you would be aware, despite the similar sounding name, chloroquine is not mefloquine and does not share the same adverse events, and;
- A range of national and international organisations such as the World Health Organisation and the Gates Foundation are coordinating worldwide efforts to test these compounds to determine their efficacy.
Unfortunately, both of those statements are false or misleading. Chloroquine is used at similar malaria treatment and prophylaxis dosages as mefloquine. This drug can, in fact, cause severe acute and chronic neuropsychiatric reactions similar to mefloquine, at similar frequency. The military developmental history of this drug in Germany and the United States during the pre and post-WWII era also has a close parallel with the development of mefloquine in the post-Vietnam War era. In addition, exposing medical personnel to chloroquine in high-stress environments during the Covid-19 pandemic would likely exacerbate those stresses and/or confound prompt recognition of the prodromal symptoms of toxic encephalopathy.
History
Quinoline antimalarials
In the 1820’s two German scientists were the first to isolate quinine from the bark of the cinchona tree, as the compound that gave the bark its anti-malarial properties.
Quinine is an alkyloid, which are naturally occurring compounds usually found in plants and mostly contain basic nitrogen atoms. Many alkyloids have medicinal purposes and are used to treat a variety of diseases, however they can also be highly toxic to humans. Morphine, strychnine, atropine, colchicine, ephedrine, and nicotine are also alkyloids.
There are also synthetically developed derivatives of quinine such as mefloquine and tafenoquine which were made with the hope that they would be less toxic. However evidence clearly shows that this is simply not the case.
Chloroquine
Eventually malaria became resistant to quinine and a replacement would need to be found. This replacement was first synthesized in 1934 by Hans Andersag, a scientist at the Elberfeld laboratories of the Bayer I.G. Farbenindustrie A.G. in Germany, and given the brand name Resochin. In subsequent trials later however it was deemed to be “too toxic for practical use in humans.”
W. Kikuth, of the Elberfeld laboratories, tested Resochin against bird malaria (1935) and found it to be as effective as Atabrine but slightly more toxic. On the basis of the Kikuth tests, the compound was given to F. Sioli who tested it (1935 or 1936) against blood-induced vivax malaria in four paretics at the psychiatric clinic in Dusseldorf. There are no actual records of these tests but he is credited with reporting it, 1) as equally effective as Atabrine, and 2) as saying that it was “too toxic for practical use in humans.” Whatever his conclusions might have been, the report of its slightly greater toxicity over Atabrine in lower animals seems to have been the factor which brought the decision to abandon it.
PITFALLS IN A DISCOVERY: THE CHRONICLE OF CHLOROQUINE*
This decision by Bayer. . . may have had merit in terms of the times although later it became
known by the Germans as the “Resochin error.”
G. ROBERT COATNEY
https://www.astmh.org/ASTMH/media/Documents/Presidential%20Addresses/1962-G-Robert-Coatney.pdf
Auschwitz: IG Farben and the History of the “Business with Disease”
https://www.globalresearch.ca/ig-farben-history-business-disease/5701804
A less toxic compound, methylated Resochin, was formulated in 1936 under the brand name Sontochin and was given to the Afrikakorps during the war. The drug would find it’s way into Allied hands in Africa after a supply was found by French troops in Tunisia who turned it over to the Americans, which would ultimately lead to the release of chloroquine in 1945.
Potential Adverse Effects
Significant risk of permanent neurological damage
The simple fact is that chloroquine, as with the related drugs tafenoquine and mefloquine, is able to cause severe, chronic toxicity including (but not only) lasting or permanent brain damage. I know this because over the last fourteen or so months I have had the opportunity to talk to a number of veterans whose lives were torn apart after they took one of these drugs, some have had the misfortune of having taken all three of them. The adverse effects that many now suffer include:
- psychiatric disorders including depression, anxiety, bipolar disorder and schizophrenia.
- cognitive impairments including memory and concentration difficulties.
- hearing problems including tinnitus, hearing loss and hyperacuity.
- vestibular disorders including dizziness, vertigo and spatial disorientation.
- neurological disorders including neuropathies, seizures, Parkinson’s disease
- and motor neurone disease (MND)
Although exact numbers are not known, a very significant number of individuals who have taken these drugs have died as a result of either suicide or a motor neuron disorder.
It should be noted that while these incidents may only occur in a minority of people, it is nevertheless a rather significant minority and although these and other adverse events are typically seen with long term use and higher dosages, it is possible and has been known for them to occur after a SINGLE dose.
We present a case of a Mr A, who is 32 years old gentleman with no significant past medical or Psychiatric history. He was admitted in general surgery ward of our tertiary care teaching hospital where he was diagnosed with amoebic liver abscess and underwent management in the form of percutaneous aspiration of pus and received intravenous antibiotics during his stay in the ward. He was discharged on chloroquine phosphate 600 mg in divided doses. After discharge the initial 4 days were uneventful. Since the fifth day Mr A started feeling that there is some supernatural power in his room and became extremely fearful and pleaded for constant company of family members. Following day started having irrelevant talk, muttering, aggression and suspiciousness and had a firm belief that some supernatural force is going to harm him. He was brought to our Psychiatry OPD by parents and was admitted as there was a risk of harm to others or self. In the ward patient became extremely aggressive and ran out and smashed random bikes.
Chloroquine Induced Psychosis in an adult patient with
Amoebic Liver Abscess: a case report
http://www.indianmentalhealth.com/pdf/2019/vol6-issue1/CR1%20CHOLORQUINE%20CASE%20REPORT.pdf
Other potentially serious adverse effects
Apart from the neurological damage it can cause, chloroquine can also prove toxic to other organs in your body such as your heart, eyes, and ears.
Cardiotoxicity
Chloroquine by itself is cardiotoxic and can potentially lead to life threatening cardiac arrhythmia causing death. The proposed treatment regimen for COVID-19 calls for chloroquine to be used in conjunction with azithromycin, which also carries with it the very same risk making it more dangerous.
A small study in France enrolling 26 treated patients and 16 non-randomized controls showed that hydroxychloroquine alone or in combination with azithromycin shortened the time to resolution of viral shedding of COVID-19.1
Based on this study, clinicians in many countries have begun using these medications in clinical practice, and multiple randomized trials are being initiated. However, chloroquine, hydroxychloroquine and azithromycin all prolong QT interval, raising concerns about the risk of arrhythmic death from individual or concurrent use of these medications.
Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19
https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19
There would seem to be a consensus amongst the scientific community that a great deal more research remains to be needed.
Balanced against the clear life-saving benefits of giving effective antimalarials promptly in malaria, with the exception of halofantrine, concerns over cardiotoxicity have not limited the current use of the quinoline and structurally related antimalarial drugs.
The importance of robust detection and evaluation of extremely rare and serious adverse events such as sudden unexplained death in real-world populations and the implications of such findings for population-based drug administration strategies underscore the need for ongoing synthesis of all available clinical evidence.
The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review.
Ilsa L. Haeusler,
Xin Hui S. Chan,
Philippe J. Guérin &
Nicholas J. White
BMC Medicine volume 16, Article number: 200 (2018)
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1188-2
Ocular Toxicity
According to some, the risk of eye damage is perhaps on of the biggest risks. Chloroquine can cause retinopathy, permanent damage to the retina, as well as damage to the cornea and/or lens which would have a detrimental effect on vision. “Even when the clinician and patient adhere to screening guidelines and retinopathy is detected in a sub-clinical stage, discontinuation of chloroquine or hydroxychloroquine therapy may not stop the progression of retinopathy to a stage where the patient loses vision.”
Chloroquine (CQ) is used to prevent and treat malaria and amebiasis,[1] while hydroxychloroquine (HCQ), a less toxic metabolite of chloroquine, is used to treat rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and Sjogren’s syndrome.[2] Both medications can cause corneal deposits, posterior subcapsular lens opacity, ciliary body dysfunction, and most important, irregularity in the macular pigmentation in the early phase, a ring of macular pigment dropout in the advanced stage, and peripheral bone spicule formation, vascular attenuation, and optic disc pallor in the end-stage. Ocular symptoms of retinopathy include blurred and partial loss of central vision, side vision and in the later stage, night vision. Symptoms of corneal deposits include haloes and glare.
Chloroquine And Hydroxychloroquine Toxicity
Thomas J. Stokkermans; Georgios Trichonas.
https://www.ncbi.nlm.nih.gov/books/NBK537086/
Ototoxicity
Although there isn’t as much risk of hearing damage as there is vision damage, it is still a distinct possibilty.
Hydroxychloroquine (Plaquenil®) is an antimalarial agent which is approved for rheumatoid arthritis, systemic lupus erythematosis, discoid lupus erythematosis, prophylaxis and treatment of acute malaria, and photodermatosis [1]. In the Netherlands it has been approved since 1966.
Hydroxychloroquine is chemically closely related to chloroquine (Nivaquine®). Hearing loss or ototoxicity are not mentioned in the SPC of hydroxychloroquine [2]. The SPC of chloroquine states both hearing loss and deafness as possible ADRs.
Until May 31, 2005 Lareb received three reports of hearing loss associated with the use of hydroxychloroquine. No cases have been reported in association with the use of chloroquine. Report A concerns a female aged 69, who experienced hearing loss (especially low tones) and tinnitus several months after starting hydroxychloroquine for indication lupus erythematosis. The hearing loss was confirmed with an audiologic examination. Five years after discontinuation of the hydroxychloroquine, functioning of her right ear is still impaired.
Case B was reported by the MAH and concerns a female aged 57, who experienced deafness and tinnitus 4 years after starting hydroxychloroquine. Hydroxychloroquine was withdrawn and one year later the patient had not recovered.
Recently we received a third report of hearing loss (C). It concerns a female aged 51, who experienced hearing loss 7 months after starting hydroxychloroquine for the indication scleroderma. An audiogram showed a bilateral perception hearing reduction of 30 to 50 dB for high frequencies. The hydroxychloroquine has been withdrawn, 2.5 months later patient has not recovered.
Hydroxychloroquine and hearing loss
Netherlands Pharmacovigilance Centre
https://databankws.lareb.nl/Downloads/kwb_2005_3_hydro.pdf
The Johns Hopkins Guide
Experts from Johns Hopkins Medicine have published a number of guides online including their antibiotics guide, Johns Hopkins ABX. These experts, from the one of the most respected medical institutions in the US, routinely update the guides to provide the most up to date information.
Regarding the proposed use of chloroquine in the treatment of COVID-19, the guide stated that there was “minimal, low quality evidence” to support it. In addition to this it states:
Retinopathy is one of the most serious adverse events associated with hydroxychloroquine and it is NOT reversible. The American Academy of Ophthalmology recommends screening for hydroxychloroquine-related retinopathy: examination prior to therapy initiation to rule out preexisting maculopathy and annual screening after 5 years for patients on acceptable doses and without major risk factors
Hydroxychloroquine has been used in a recent COVID-19 outbreak. Limited available data are largely based on in vitro studies and clinical series and one small RCT showing no effect.
In a small, observational, non-randomized study of (n=36) patients with SARS-CoV-2 infection, administration of hydroxychloroquine 200 mg q8h for 10 days (n=20) resulted in higher clearance of virus (70%) on day 6 compared to controls (12.5%). Six patients also received azithromycin, and authors argued in a post-hoc analysis that addition of azithromycin resulted in even higher, but statistically nonsignificant clearance[1]. This study, however, has many limitations including small sample size, exclusions from analysis of patients who were lost to follow-up (e.g. escalation of care, death), no clinical outcomes were reported or colation of viral clearance and clinical outcomes has been made.
A pilot RCT of 30 patients comparing HCQ v. placebo found that on day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). There was no significant clinical difference between the groups. The study suggests that if HCQ has an effect it is at most modest, so larger studies need to be performed.
Larger and properly designed studies are needed to determine the benefits of hydroxychloroquine in the treatment of COVID-19-positive patients and the role of combination therapy (e.g. with azithromycin).
Johns Hopkins ABX Guide
https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540748/all/Hydroxychloroquine#5.0
Johns Hopkins University also has an excellent online corona virus resource centre available at:
https://coronavirus.jhu.edu/map.html
Response from The Quinism Foundation
Dr. Remington Nevin is an epidemiologist and an expert on anti-malarial drugs. He is also the founder and a director of the Quinism Foundation, a nonprofit organization dedicated to promoting and supporting education and research on quinism, the family of medical disorders caused by poisoning by mefloquine, tafenoquine, chloroquine, and related quinoline drugs. They have been quite vocal in their opposition to the notion of using chloroquine as a treatment for COVID-19.
For more information you can visit the Quinism Foundation website at:
Not the only choice
There are a number of other possible treatments, much less toxic treatments, that are also being looked at. For example studies have shown ivermectin, an antiparasitic, might also be effective at treating COVID-19 so it is important to remember that hydroxychloroquine isn’t the only drug that could work. Under no circumstances should you take medication that has not been prescribed for you by your doctor.
Listen to what the medical community says
I formed my opinions after doing a great deal of research and all I would suggest to you is that you do some of your own before you come to any conclusions. This should be the case any time you are considering a matter that might have life or death consequences. Where you get your information is equally important when it comes to decision making, so I am more likely to rely on academic research and journal articles as primary sources rather than public figures like the President of the United States.
Google Scholar
Right now most of the major scientific and medical journals are offering free access to any articles relating to COVID-19, and Google Scholar has links to all of them. It is a good way to keep up to date with the latest research as it becomes available.
The Advocate-Equalizer 
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