Chloroquine effective in COVID-19: True or false?
Dr. Prashant R. Wankhade
Hypothesis:
It has been proposed that these viruses are internalized by receptor mediated endocytosis and delivered to lysosomes. At acidic pH, the membrane surrounding the virus fuses with the membrane of lysosome, allowing the nucleic acid of virus to cross lysosomal membrane and enter the cytoplasm where the virus replicates. Infection of tissue culture cells by these viruses can be prevented by chloroquine, an agent that blocks function of lysosome. Chloroquine is a weak base that diffuses in lysosome and raises the pH of lysosome causing impairment of function of lysosomal enzymes. Viruses that requires acidic pH to fuse with cell membrane can no longer do so in the presence of chloroquine and the cells are protected from infection.
Facts:
1. Aim of the virus is to reach the destination where it can replicate. This destination is cytoplasm for RNA viruses and nucleus for DNA viruses.
2. Normally viruses enter the cell by direct membrane fusion or endocytosis-based mechanism.
3. Exact mechanism of COVID-19 entry in cell isn’t clear (https://www.ncbi.nlm.nih.gov/books/NBK92477/). If its entry is via membrane fusion then there is no need for COVID-19 to cross Lysosome as the virus particles will get direct entry in cytoplasm. Even if the entry is endocytosis-based then also it is less likely to cross Lysosome.
4. Chloroquine and hydroxychloroquine are known to alter Lysosomal function. But there are discrepancies in the literature about whether or not chloroquine raises the lysosomal pH (Autophagy. 2018; 14(8): 1435–1455). Some studies do not support this fact whereas others state that the change in pH may not last longer than 1 to 4 hours. So, the fact that Chloroquine will cause alteration in viral cell cycle is not clear.
5. Viruses like polio virus and Hepatitis-C virus enters the cell via endocytosis; in that case Chloroquine would have helped in controlling these infections also, but no guidelines recommend its use.
6. This hypothesis related to Chloroquine and Viral infection is not new. One of the articles published in 2003 advocates its possible role in treatment of HIV infection but none of the guidelines has yet recommended (Lancet Infect Dis. 2003 Nov;3(11):722-7).
The same article advocates its possible role in clinical management of Corona related Middle East Respiratory syndrome (MERS) and Corona related severe acute respiratory syndrome (SARS) but no further data available on its definite role.
7. RNA viruses including COVID-19 can replicate in cytoplasm and need not require entry in the nucleus like DNA viruses. Chloroquine doesn’t have any effect on cytosolic pH to alter the replication of virus and in fact that will be hazardous for cell itself.
8. Thus, these facts put question mark on above hypothesis.
9. And finally, in this era of evidence-based medicine we need concrete evidence to support the hypothesis; as it’s not necessary for every hypothesis to reflect vis a vis in clinical applicability.
True upto some extent..(until and unless anyone is epi genetically mutated)...
Below mentioned article includes molecular epidemiology aspect too.
It elucidates pre entry, entry and post translational modifications of viral proteins at host’s cellular level by the drug.
Also states about changes in immune responses.
Reference: An article titled “ New insights on the antiviral effects of chloroquine against Corona Virus: What to expect for COVID-19.” Published online on 12th March 2020 in International Journal of Antimicrobial Agents.
True in part treatment, Trump did not say from his mind- he might have taken good advice from medical doctors. In India, some patients with this medicine along with other three/four medicine combination recovered earlier.
It is not true nor false. The fact is that it has not been proved.
The problem is that in the middle of this crisis it is not easy to make a well planned clinical trial prospective randomised and with control subjects. It would take to long and the problem is that every day 3,000 patients die.
As there is no other treatment available we are forced to use it.
However a more integral therapy would be required like:
1. Tocilizumab to antagonise the cytokine storm.
2. Nelfinavir to inhibit proteases required for cell entry and inhibition of SREBP 1c because the virus needs lipid synthesis for its reproduction.
3. Doxicyclin that reduces translation at ribosomal level.
4. Chloroquine for the reasons you very well explained in your question.
This four drug therapy may work on a theoretical basis.
Thanks for inputs.
Actually everyone has been intimidated by the virus impact. Most of the time we give placebos to patient but this time medical professionals themselves are consuming the placebo.
When we don't have any definite measures, we try everything hoping it will work but hard facts can't be denied.
Chloroquine is one form of hope, though it hasn't made any impact on clinical outcome, it might have caused some reduction in panick.
Try to add high doses of doxicyclin
I do not think it can do any harm and it will prevent bacterial over infection. At the same time you would be inhibiting translation of viral RNA. Good luck.
A very recent controlled clinical study conducted by French researchers on 80 Corona positive patients revealed a very successful outcome ( recovery just in 6 days) by giving Hydroxychloroquin +Azithromycin+Zinc sulphate regimen....
Now it is on the way of getting established as currently available therapeutic cure for COVID-19.
The only study I know made in France included ten patients.
Please can you include the references.
Thank you.
Dr. Didiair Raoult work on 80 patients and again one more study on 699 patients by Dr. Zelenko....
@ techstartups.com
Ruxolitinil has been mentioned as the miracle drug to treat interstitial pneumonitis produced by COVID 19. It was successful in 8 patients in ICU in Italy. However, this is only a newspaper article. It needs further testing.
I agree with Tomas Koltai that it is not a question of true or false. It is a matter of not having enough evidence to show whether it works or not. That notwithstanding, in this particular situation where we have no proven effective treatment, it might be worth administering chloroquine in COVID-19 especially for patients in very critical conditions, as the alternative to not giving the drug could be worse.
Doxycycline is known to be very potent even in atypical infections and hence could be useful in combination with chloroquine. However, it is also important to check for the effects of this combination to know if the combination is synergistic.
This review discusses the points I outline below.
Several medications that have been recommended for the treatment of Covid-19 are associated with prolongation of the QTc interval and therefore torsade de pointes and sudden cardiac death.
The evidence of the potential benefit of chloroquine and hydroxychloroquine in the treatment of Covid-19 is increasing.
Other medications which may be used in this cohort include the macrolide antibiotics (e.g. azithromycin). These can also prolong the QTc interval. Administering several medications that may prolong the QT interval is associated with a high risk of complications.
In medicine risks and benefits must be balanced. Safety netting is important whenever there is a great potential benefit but also a very significant risk. In that context QTc intervals, renal and liver function must be monitored closely in patients treated with chloroquine and or macrolides. They should probably not be started if the baseline QTc is more than 450 ms. It should probably be stopped if the QTc increases 25% above baseline. It should definitely be stopped if QTc is above 500 ms. This is an evolving situation and recommendations may change as the potential risks and benefits become clearer.
Beta-blockade is used in the treatment of congenital and acquired long QT syndrome, so may be beneficial in this setting.
Please see the link below.
https://www.thelancet.com/action/showPdf?pii=S2665-9913%2820%2930093-X
https://edition.cnn.com/2020/03/23/health/chloroquine-hydroxycholoroquine-drugs-explained/index.html
No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection
Jean Michel Molina et al.
PII: S0399-077X(20)30085-8
DOI: https://doi.org/doi:10.1016/j.medmal.2020.03.006
Reference: MEDMAL 4279
To appear in: Médecine et Maladies Infectieuses
Received Date: 28 March 2020
Yes because there is not another solution !
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v1
Chloroquine and Hydroxychloroquine share the same mechanism of action but hydroxychloroquine has more tolerable safety profile that makes it the preferred drug to treat malaria and autoimmune conditions.
The recent data, presented as the first results obtained from clinical studies ongoing in several Chinese Hospitals, show that the chloroquine treatment, compared to control group treatments, can reduce the length of hospital stay and decrease the evolution of COVID-19 pneumonia. This has led China to include Chloroquine in the recommendations regarding the prevention and treatment of COVID -19 Pneumonia (1). A recent paper, supported the in vitro antiviral activity of Hydroxychloroquine and its more potent effect to inhibit SARS-COV-2, if compared to chloroquine.(2) The drug can contrast the fusion of the virus with the cell membrane. It can also inhibit nucleic acid replication , glycosylation of viral proteins , viral assembly , new virus particle transport , virus release . (2,3). Furthermore, the immunomodulatory effects of hydroxychloroquine may be useful in preventing the cytokine storm that occurs in critically ill SARS-CoV-2 infected patients (4)
At the moment in Italy, especially in the nothern regions, political and health authorities are making incredible efforts to contain the spread of COVID -19 . In this setting, the Hydrossichloroquine results an ideal drug to fight the epidemia, for its antiviral and immunomodulatory effects combined with its tolerable safety profile and very low cost .
Hydrossichloroquine would appear to have a crucial role in the early treatment of covid 19 patients.5-6 .
References
1. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated
pneumonia in clinical studies. Biosci Trends. 2020;14(1):72–73. doi:10.5582/bst.2020.01047
2. Yao X, Ye F, Zhang M, Miao Z et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the
Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [published online ahead of print, 2020 Mar 9]. Clin Infect
Dis. 2020;ciaa237
3. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases?.
Lancet Infect Dis. 2003;3(11):722–727. doi:10.1016/s1473-3099(03)00806-5
4. Savarino A, Shytaj IL. Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS.
Retrovirology. 2015;12:51. Published 2015 Jun 18. doi:10.1186/s12977-015-0178-0
5. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19
[published online ahead of print, 2020 Mar 4]. Int J Antimicrob Agents. 2020;105932. doi:10.1016/j.ijantimicag.2020.105932
6.Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. doi:10.1016/j.ijantimicag.2020.105949
NIH clinical trial of hydroxychloroquine, a potential therapy for COVID-19, begins. NIH News. 2020 Apr 9.
https://www.nih.gov/news-events/news-releases/nih-clinical-trial-hydroxychloroquine-potential-therapy-covid-19-begins
No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv. 2020 Apr
May be it would be time to test Astemizol or itraconazol to accelerate viral clearance.
If chloroquine works, and I believe it does not and is also often deadly due to cardiotoxicity, why are we all looking for some different and effective therapies? On the contrary, EIDD-2801 seems a serious answer. Please look at:
T. P. Sheahan et al., Sci. Transl. Med.10.1126/scitranslmed.abb5883 (2020).
I trust on them.
No Hydroxychloroquine Benefit in Small, Randomized COVID-19 Trial
https://www.medscape.com/viewarticle/928798?src=wnl_edit_tpal&uac=72807PK&impID=2349039&faf=1
Here you are a preprint Paper that has not been peer reviewed.
the dosage is very high and gastroenteric intolerance was absolutely predictable for those who know the drug for clinical use in rheumatology.
Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
medRxiv 2020.03.22.20040758; doi:https://doi.org/10.1101/2020.03.22.20040758
Here you can read another preprint paper not peer reviewed that use low dosage without side effects with completely opposite results .
Because of confounding, the trials are unable to answer convincingly the question of whether HCQ can benefit COVID-19 patients"
I think it is better to wait The largest phase 3 placebo-controlled trial with anticipated enrollment of 1300 participants conducted by researchers at the University Hospital, Angers, France.
Article The Rise of New Coronavirus Infection (COVID-19): A Recent Update
It is far too early to know. The Recovery trial, which is a UK based RCT ,might have answers in the next few months.
https://www.recoverytrial.net/
There are no certinity that chloroquin is agood treatment for cornavirus
Until larger randomized controlled trials including WHO SOLIDARITY trial are available the role of Chloroquine or Hydroxychloroquine in the management of COVID-19 infection is still not definitely clear.
Article Use of product labels to investigate the treatment of Covid-...
It is important that chloroquine is not confused with chlorine. Chlorine is commonly found in disinfectants. Ingestion of chloroquine may be helpful.
It has also been suggested that ingestion of disinfectants may be beneficial to treat patients infected with SARS-CoV-2. DO NOT DO THIS. IT IS HARMFUL TO HUMAN HEALTH.
The above article may be of interest and provide some light relief.
Indian gift of 0.1 million HCQ tab is already received in Bangladesh today. It is also sending this (HCQ) to 55 COVID-19 hit countries. Ref: https://economictimes.indiatimes.com/news/politics-and-nation/india-sending-hydroxychloroquine-to-55-coronavirus-hit-countries/articleshow/75186938.cms?from=mdr
According to a study was done ,Yes may be used. This study accepted to be published soon.
No one knows the truth, nor will researchers know they are afraid of getting it, until they do serious autopsies and experiment with medications. It has been too long and all of the government and researchers are turning a blind eye.
Dear Dr. have a nice Sunday.
In my RG open question about the dramatic situation of Lombardia (N.Italy)
I propose the test of the natural compounds from Artemisia, according to previous extensive bibliographical reviews about toxic effect in potential biocontrol.
I hope this is useful.
RG open question and Artemisia review references: https://www.researchgate.net/post/The_novel_Coronavirus_in_N_Italy_Lombardia_COVID19_2019nCoV_SARSCoV2_shows_a_fatality_rate_compatible_with_SARS-MERS_Why#view=5eabf2ae32592944281a872b
______________________________________
https://www.researchgate.net/figure/ResGa-FxFac-post_fig102_339781431
|n.2|....The following 12 virus species have been recognized, both DNA-virus and RNAvirus, both phyto-virus and zoo-virus: BVDV bovine viral diarrhea virus; COPV, canine papilloma virus; DEN/2, dengue virus 1; FIV, feline immunodeficiency virus; HBV, human hepatitis B virus; HCMV, human cito-megalo virus; HFLUV, human influentia virus; HIV, human immunodeficiency virus; HSV/1, human herpes virus 1; HSV/2, human herpes virus 2; JUNV, junin virus; TMV, tobacco mosaic virus. ....
.. ... FROM Artemisia: absinthium, afra, annua, anomala, arborescens, capillaris, caruifolia, douglassiana, herbaalba,verlotorum, vulgaris.....
.. ... Natural compounds: aesculetina, arcapillina, artemisinina, artesunate, beta-arteannuina, beta-sitosterolo, deidro-artemisinina, deossi-artemisinina, isorhamnetina, N-N-N-3p-coumaroil-spermidina, stigmasterolo.
In fact, SARS-CoV2 (COViD19) and SARSCoV are one of the same kind. Low doses of chloroquine should be beneficial. In both viruses.
Article A SARS-like Coronavirus was Expected, but nothing was done t...
Dear researcher
You can download this article to know if chloroquine and hydroxychloroquine can be used or not in treatment of COVID19.
https://wjpr.net/dashboard/abstract_id/14381
The only people that will benefit from this hydroxychloroquine hoopla are malpractice lawyers that will go after doctors, elected officials and pundits that are pushing this snakeoil remedy.
Touting hydroxychloroquine as a virus cure is a fringe belief. It has no basis in reality. I have been on RG for a long time and this nonsense is horrifying.
This sort of pseudo-science has to be confronted especially now when so many lives are at stake.
People often ask me why I bother to confront and ridicule fake scientists on RG.
The answer is simple. I worked long and hard to gain the respect of my peers. I am not alone. There are thousands of us that strive to make a living using the scientific method to enrich the human experience.
Fake scientists spouting their nonsense on RG is not only a slap in my face, but also a slap in the face of all real scientists worldwide.
Let us wait for the results of sound clinical studies which are currently being done. A compilation can be seen at ClinicalTrials.gov. There are several modes of how CQ and HCQ might act, which I can explain.
Christian G Meyer . Please explain how disrupting the H+ gradient of all cell organelles including mitochondria can inhibit virus endocytosis and translocation of the viral genome.
Article Efficacy of chloroquine and hydroxychloroquine in the treatm...
Article Of chloroquine and COVID-19
Article Breakthrough: Chloroquine phosphate has shown apparent effic...
HCQ inhibits cellular metabolism.
Inhibiting cellular metabolism kills cells.
This is really simple cell biology.
Please stop promoting this HCQ nonsense "cure"
Christian G Meyer . Please tell me again how shutting down all cell metabolism using HCQ protects against viral endocytosis while maintaining normal cell functions.
I missed your first response.
Am not promoting HCQ at all, but I prefer to see the results of the clinical trials. By the way, CQ has been taken for decades as an antimalarial and a prophylactic drug and currently is applied in several other, mostly autoimmune, conditions. Maybe you wish to look at the safety profile of CQ and HCQ, e.g. at CDC websites.
Christian G Meyer .
Your words:
"There are several modes of how CQ and HCQ might act, which I can explain."
Please explain.
Again, I do not promote CQ/HCQ as as safe cure, but everything should be studied in detail in CTs, including Remdesivir, Tocilizumab and other (experimental) drugs, e.g. AT-100, APNO, TZLS-50, Leronlimab, OYA1, BPI-002, Brilacidin, NP-12, BST-25 and other substances.
Christian G Meyer . Lets try this again and please don't copy/paste nuggets that have nothing to do with the issue at hand.
You do know some cell biology, right?
Neither HCQ nor CQ have anything to do with receptor mediated endocytosis through clathrin coated pits, phagocytosis and pinocytosis through capping, lipid rafts, processes that are ATP/CTP dependent, proton pumps, ion channels, PS-modified membrane proteins, etc, etc
Again, your words:
"There are several modes of how CQ and HCQ might act, which I can explain."
You don't know jack.
I stop this discussion due to the obvious medical and pharmacological incompetence of the responder (SS).
I'm sorry that you can't publish in a peer-reviewed journal.
@Steingrimur Stefansson: Have published two papers on COVID-19 in peer reviewed journals. I don't want to be personal, but your rude, unpolite and unpleasant style urges me to state: If you think I can´t publish in a peer reviewed journal, please just compare our h-indexes and citations, if you wish so. Ok?
We know now that lockdown and other measures have severe effects on mental health.
Dear Steingrimur Stefansson,
I just read a few of your recent comments and the more I read the more I wondered about your rude wording.
I totally agree with you that not everything that is presented as "science" here and even in papers is good science in terms of study/experimental design, controls or interpretation of results.
From my point of view it's probably an outcome of the "publish-or-perish" principle and competing groups working against each other on the same field (being the first to publish becomes more important than having the better results) both leading to quantity over quality which is further pushed by the economical interest of some editors.
We all started on a low level once; critical reading of information is definitely not easy especially if something fits into your own theory. Unproven theories served as information tend to become fact-like in your head if they are just repeated often enough – the basic principle of (willingly) creating fake news.
Therefore it is absolutely okay to scrutinize statements made in a discussion and to show how "good science" should be done. This is what the purpose of research gate is to me: Fact-based discussion on the Pros and Cons helping others to improve their knowledge and their scientific skills. Unproven ideas may also be mentioned as long as they are not taken as facts but as a baseline for discussion. Research is done to gather new information and often by setting up a theory and trying to prove it by trial and error experiments. This can be even crude ideas. If your theory is that "somewhere in the arctic lives a green elephant" you are free in spending your live trying to find it and discuss the hypothetical existence with others as long as you don’t take a gray elephant from africa, paint it green, ship it into the arctic and present a picture of it as a proof for your publication titled “The existence of green elephants in the artic region”.
Pointing out missing/wrong facts in a discussion is a good thing generally and providing facts about elephants might show the nonsense of such a project before starting it.
But at least in my eyes your personally insulting comments against others and their ideas here mainly discredit you and not them. What I read between the lines is: “I’m loud, therefore I’m right”. Not a very scientific justification which makes me doubt that your posts on the topics are much better…
Vivica Grotelueschen . Full disclosure: I am old and mean tempered, but if you go through my answers to real scientific questions here on RG you will find most of my answers quite civil.
Pseudosciences like homeopathy, creationism and now miraculous COVID19 cures are questions that do not deserve to be discussed scientifically and rationally because their premise is rooted in superstitions, ignorance and disinformation gleaned from social media.
LATEST UPDATES ON THIS TOPIC:
Hydroxychloroquine alone or with Azithromycin for COVID-19: No benefit but increased risk
No significant benefit with Hydroxychloroquine and Azithromycin either alone or in combination on in-hospital mortality in COVID-19 patients in USA. However, increased risk of prolonged QT-interval with risk of ventricular arrhythmias.
References
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
https://jamanetwork.com/journals/jama/fullarticle/2766117
Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2012410
Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing
Positive for Coronavirus Disease 2019 (COVID-19).
https://www.ncbi.nlm.nih.gov/pubmed/32356863
I prefer to wait the results of the many randomized controlled clinical trials that are ongoing .
I don’t understand what is the rational for using very hight dosage of hydroxichororquine in the TRIAL RECOVERY
Hydroxychloroquineby mouth for a total of 10 days as follows
Initial dose 800 mg
6 hours after initial dose 800 mg
12 hours after initial dose 400 mg
24 hours after initial dose 400 mg
Every 12 hours thereafter for 9 days 400 mg
The same hight dosage is applied in SOLIDARITY (the WHO megatrial)
Toxic-pharmacological data and the clinical activity of chloroquine, given its worldwide use, are unquestionably acquired; chloroquine is reported on all official texts and is therefore to be considered a well-established drug.
Acute chloroquine intoxication (after high overdoses of 2-5 g) can cause death within 1-3 hours as a result of cardiocirculatory and respiratory arrest. ( the RECOVERY dosage of 1600 mg is very close to 2 grams)
Despite I use this drug every day and I'm sure that has a good safety profile and a good rational for using aganist SARS COV 2 , I would be afraid to recruit patients for these two studies.
Efficacy of Chloroquine in treatment of COVID-19 is still underway
By Abeen Shayiq
Dear Dr.Prashant Wankhade ,
Please go thru https://www.researchgate.net/post/Shall_we_beleive_that_the_Covid19_has_a_dual_characteristics_of_Maleria_and_Crown_virus
Studies to date on the role of Hydroxychloroquine alone or in combination with azithromycin in the management of COVID-19 are negative (1-2), but with increased risk of harm (3)
References
1.Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York Statehttps://jamanetwork.com/journals/jama/fullarticle/2766117
2. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2012410
3. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19).
https://www.ncbi.nlm.nih.gov/pubmed/32356863
Should we consider Hydroxychloroquine a dead horse for treatment of COVID-19?
Added to previous studies of lack of benefit, but increased risk as mentioned by
Muhammad Yousuf , a recent study on mortality of COVID-19 with hydroxychloroquiene with or without Azithromycin did not any benefit,
but increased mortality (2).
1. https://jamanetwork.com/journals/jama/fullarticle/2766117
2. https://www.nydailynews.com/coronavirus/ny-more-deaths-no-efficacy-of-malaria-drug-found-in-coronavirus-study-20200421-v4k45zwp5zc57dobqsa4xqexea-story.html
FALSE.
The Lancet just published results in over 96 000 patients: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext
It actually led to a decrease in survival rates.
Several limitations and too much confounding factors due to observational study design. I prefer to wait the results of many randomized clinical trials that are going on .
I have many doubts about high dosages that have been chosen in Recovery trial and Solidarity megatrial .
Can't speak to chloroquine, but hydroxychloroquine (hcq) has been used in much higher than 200mg/day in the treatment of Rheumatoid Arthritis and Lupus for many decades, under phyician care, without the side effects of concern, for a vast majority of patients. In addition, hcq has been used successfully by many clinicians in the US and Europe in Covid-19 treatment, especially as prophylaxis and early-stage treatment, again without side effects in the vast majority of patients under MD care. Most of the retrospective studies could not have been conducted in a way allowing partitioning of co-morbidities which influenced ultimate outcome. That, and the unfortunate politicization here in the US, has confounded any real attempts at discerning hcq efficacy. I am no expert in this field, but as a scientist, the variables discussed here make accessible a rational discussion. That said, the clinicians are the most reliable barometers.
I agree with you . HCQ is an ideal drug available for using in a large population , it has a rationale of efficacy, side effects already known because already employed for other indications in rheumatology, easy to do and low cost. Too much to put it all together ... The interesting role of hydroxychloroquine seems to be not the antiviral activity but the immunomodulation in a early stage of covid 19. On march 17th AIFA approved the off label use of hydroxychloroquine for covid 19 in italy and many general practitioners started to use this drug for treatment of not severe ill covid patients at home . The hospitalizations decreased and especially acute ill patients admitted in critical unit decreased. Now we are waiting for the results of currently randomized controlled large-scale trials.
WHAT'S THE PROBLEM?
I don’t understand what is the rational for using very hight dosage of hydroxichororquine in the TRIAL RECOVERY
Hydroxychloroquine by mouth for a total of 10 days as follows
Initial dose 800 mg
6 hours after initial dose 800 mg (1600 mg in 12 h ????)
12 hours after initial dose 400 mg
24 hours after initial dose 400 mg
Every 12 hours thereafter for 9 days 400 mg (800 mg for 9 days)
The same hight dosage is applied in SOLIDARITY the megatrial of WHO
Toxic-pharmacological data and the clinical activity of chloroquine, given its worldwide use, are unquestionably acquired; chloroquine is reported on all official texts and is therefore to be considered a well-established drug.
Acute chloroquine intoxication (after high overdoses of 2-5 g) can cause death within 1-3 hours as a result of cardiocirculatory and respiratory arrest. ( the RECOVERY dosage of 1600 mg is very close to 2 grams)
Despite I use this drug every day and I'm sure that has a good safety profile and a good ration for using aganist SARS COV 2 , I would be afraid to recruit patients for these two studies.
Moreover, this high dosage could not be used on a large population . So what is the goal of these trials ?
In the USA, use of this material has been politicized to the point of absurdity. As I understand, off-label use of many other prescribed medicines is pretty much a standard practice, and reserved to Doctor-Patient decision. Such a shame and a discredit to the effort.
Antonella Marcoccia
Umm...Do you know about how HCQ works on the cellular level?
Do you know that HCQ is a lysosomal and mitochondrial pH gradient disruptor?
Do you know what happens when all cellular metabolism is inhibited by pH disruptors such as chloroquine?
There is no magical cure-all for a pandemic viral infection.
In the course of pandemic, on my opinion it is unethical to wait the set up of clinical trial that started only in the last month. People died in a short time and intensive care units were full. Many doctors and nurses died too. In this setting a drug available for using in a large population with a rationale of efficacy, side effects already known because already employed for other indications in rheumatology, has been used as off label at the same dosage used in rheumatological clinical practice. In this setting the italian government approved the off label use of hydroxychloroquine for early stage of covid 19 . In the last month the hospitalizations decreased and especially acute ill patients admitted in critical unit decreased. Now we can wait for the results of currently randomized controlled large-scale studies of several drugs (including hydroxychloroquine) for fighting the outbreak all over the world and the next possible recurrence in autumn. The problem is that " the best" clinical trials have chosen toxic dosages of HCQ with a very difficult recruitment of patients and high risk of discontinuation for side effects and increased mortality .
Picot S, Marty A, Bienvenu AL, et al. Coalition: Advocacy for prospective clinical trials to test the post-exposure potential of hydroxychloroquine against COVID-19 [published online ahead of print, 2020 Apr 4]. One Health. 2020;100131. doi:10.1016/j.onehlt.2020.100131
Antonella Marcoccia
Yes ….Absolutely.....Everybody has to ingest ionophores and Zn++ to ward off the virus because somebody related to somebody who knows a person who lives next door to a quack in France who says that HCQ cures everything COVID19 related. /s
Don't bother with these pesky clinical trials that show whether a drug works or not. Pfffftttt. Clinical trials have only been able to prove whether a drug works in the general population or not for the last ~100 years.
Yes.... I know......boring facts...Who needs modern medicine when you can go by with your opinion /s.
No one is suggesting that clinical trials are irrelevant. However, compassionate use of off-label medicines during emergency treatments are, at this point, the ONLY solutions for beseiged clinicians working with what they have. So, modern medicine, with exception of off-the-shelf medicines in the tool box, has done little to help thus far, which is not a criticism of modern medicine, as this virus hit quickly. For hcq, clinicians have not suggested it was a cure, so much as a preventive of over-response by the immune system, which has kept patients from intubation, which for clinicians, is a success in "flattening the curve". And, by the way, clinical trials are not the be-all and end-all, as there are some highly advertised drugs on the market now, which are currently being litigated for longer-term side-effects not seen or anticipated in those same clinical trials. Unfortunately, nothing is certain. As an aside, we should consider ourselves fortunate that there are possible medical tools in the toolbox which allow for compassionate off-label use. Since when is it absolutely necessary that for every new medical challenge, we need new medicines? Having these tools at hand while a vaccine is attempted is a real gift. And, at this time, the only reliable markers for whether medical efficacy is seen for any drugs tried, come from clinicians actually faced with the day-to-day reality of Covid-19 in the ER.
I agree with you . HCQ is the only drug that can be used to treat covid-19 patients.
Hi there,
Obviously there is no clear beneficial effect of chloroquine derivatives on Covid-19... https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext
Dear Prof Steingrimur Stefansson ,
I perfectly agree with you about the importance of randomized controlled clinical trials . The gold standard ... but It could take months to correctly design a randomized controlled trial ...
During a outbreak clinicians could decide to use the previous evidence ... drugs in use with in vitro evidence of efficacy while people die day by day . In this setting I used the expression "on my opinion " and not against randomized clinical trials...
Nobody claims to use the results of off-label use and compassionate use of drugs as an evidence ... If the patient died, it's assumed he or she died of the disease, but if the patient survived, it's assumed he or she survived because of the given drug, but this is not true ...without a control group, we can never, ever safely find new medications for any disease.
For this reason people all over th world are waiting the results of clinical trials ...
As for your previous question about my knowledge of the mechanisms of cellular action of hydroxychlorokine, I know what I read in the scientific literature.
Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [published online ahead of print, 2020 Mar 9]. Clin Infect Dis. 2020;ciaa237.
If you have other evidence , any other evidence against the rational for the use of HCQ even in clinical trials it is very important to share it with us .
At the moment I believe that Everyone claims to improve knowledge in order to correctly interpret the results of ongoing clinical trials that will be completed in the coming months
Ms. Liger: Thanks for the Lancet article. It is clear from this study that BMI, independent of other factors, also contributed to poor Covid outcomes. Given that recorded clinical dosing was not controlled, is it possible that the "killing" dose of cq and hcq was, in fact, more responsible for increased deaths among the high BMI cohorts? I think Dr. Marcoccia mentioned that earlier in this discussion. Are there studies where dosing was included as a variable? I know that the Mayo Clinic in the USA is conducting such a study now.
Can the pro-HCQ crowd provide any mechanistic details on how an anti-lysosomal agent interferes with virus endoxcytosys/replication and assembly in an eukaryotic cell.?
I haven't seen any cell biologists on here offering a sliver of explanations of how HCQ specifically thwarts the virus lifecycle. checkpoints without screwing up all cell metabolism
Somebody can come here on RG and advocate drinking blue paint to ward off the virus and it would be taken as valid. if it came from a French quack.
Antonella Marcoccia
Some years ago I used chloroquine in a series of experiments to inhibit lysosomal mediated degration in tissue culture experiments of chlathrin coated pit endocytosis of receptor-bound ligands.
The experiment worked great for ~1hr at 37oC . All endosomal proteolytic activity was abrogated and endosomes were filled with unprocessed ligands and receptors.
I published those results, but I didn't publish that the cells eventually died because there was no way of washing out the chloroquine from the cells with media changes.
In short: Based on my experience of actually working with chloroquine in tissue culture, I would say that anybody who recommends it for human use should be held criminally liable.
Steinigrimr Stefansson
Wouldn't the rate at which the cell death occurred be correlated to the level of chloroquine left in the sample? Is there a threshold chloroquine concentration below which cell death rate would be minimal? Point is, one can make that argument for any treatment where efficacy is observed, but harm is caused if the material is in excess. I'm not an hcq advocate so much as an informed person who has heard (and not from your French Quack) that hcq (not cq) has worked clinically when administered prophylacticly to patients at doses familiar to those clinicians treating patients for other maladies, such as Lupus and RA. These clinicians claim that hcq mitigates Covid-19 immune response such that intubations become unnecessary during treatment. I'm no expert by any means, but rather than belittle those who can't explain mechanistically why hcq might work, someone with your background should take on the challenge for why it might work for the reasons those clinicians actually observe. TEACH US.