5 ms·

Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry attenuated by TMPRSS2

16 points by drocer88 6y ago

AndrewBissell 6y ago
> We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein. That's interesting, it's a furin cleavage site that the New York "Lab leak hypothesis" article pointed to as suspicious and possibly man-made, though I'm not sure if it's exactly the same.
11thEarlOfMar 6y ago
"human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19." But no mention of whether any of the trials included both Zinc and Azithromyzin, which are frequently cited as necessary co-medications.
- rualca 6y ago
  > But no mention of whether any of the trials included both Zinc and Azithromyzin Meanwhile, there is still no evidence that hydroxychloroquine has any usefulness as treatment for COVID19.
  - barbacoa 6y ago
    https://www.wsj.com/articles/hydroxychloroquine-given-early-helped-coronavirus-patients-study-finds-11593729664 https://www.wsj.com/articles/hydroxychloroquine-given-early-... Not a doctor or well read on the subject but I have seen some studies claiming it does. Have also seen many studies saying there is no benefit too. Seeing such wild contradiction from respectable medical sources makes me wonder if anyone really knows what does what.
    - lazyeye 6y ago
      Its become political. If you are prepared to consider the possibility that hydrochloroquine could be beneficial, it means you are a Trump supporter.
      - rualca 6y ago
        > Its become political. Hydroxychloroquine was never anything other than pure political propaganda. It was the promise of a magical politically endorsed silver bullet designed to mitigate the political fallout of having to manage a pandemic with little to no success. Pure believers were not only kept in line because of the empty promises of a solution to their personal problem but also mobilized to persecute any contrasting opinion.
        lazyeye 6y ago
        As I said...
        dTal 6y ago
        This is not correct. Chloroquine was first suggested as a possible treatment by Chinese researchers in early February - well before there was even any attempt to manage a pandemic in the west. Those of us who were paying attention at the time were watching it carefully (and in some cases even buying supplies of it in case it proved effective). When Trump jumped on it (trailing a social media storm by several days) we all collectively groaned at the inevitable politicization. You surely didn't think that Trump picked a drug at random? https://thediplomat.com/2020/04/how-wuhan-virologists-pegged-chloroquine-as-a-potential-covid-19-cure/ https://thediplomat.com/2020/04/how-wuhan-virologists-pegged...
      - zug_zug 6y ago
        I would upvote you for rightly pointing out that it seems political, which is worth calling out, but I disagree with your sarcastic tone. But largely, yes, somehow, in some people's heads I think people have made an emotion association that endorsement of a drug is somehow a validation of an ex-political-figure. Hopefully that can all be put behind us now. I looked on wikipedia and found "Hydroxychloroquine is being studied to prevent and treat coronavirus disease 2019 (COVID‑19), but all clinical trials conducted during 2020 found it is ineffective and may cause dangerous side effects.[3][4][5][6]" But interestingly, the systematic review it referenced concluded "There is sufficient pre-clinical rationale and evidence regarding the effectiveness of chloroquine for treatment of COVID-19 as well as evidence of safety from long-time use in clinical practice for other indications [3] to justify clinical research on the topic." The rest of the citations were prior to June. I'm not specifically saying it does or doesn't work, I couldn't care less. I do care about citations matching.
  - e9 6y ago
    That’s not true. In a number of countries they extensively use Hydroxychloroquine which is anti malaria drug and super important especially in Africa. Indian government is very open in using it for covid-19: https://www.newsweek.com/india-promotes-hydroxychloroquine-d https://www.newsweek.com/india-promotes-hydroxychloroquine-d... As well as many African countries: https://www.voanews.com/covid-19-pandemic/djibouti-treating- https://www.voanews.com/covid-19-pandemic/djibouti-treating-... https://www.theafricareport.com/26726/coronavirus-recovery-r https://www.theafricareport.com/26726/coronavirus-recovery-r... can provide more sources if requested (or just google it)...
  - AndrewBissell 6y ago
    Did you read the article? It specifically discusses a mechanism by which hydroxychloroquine might be effective in combination with other medication. So if you want to just insist that HCQ by itself is not very useful, I'd say that's true but largely irrelevant. Meanwhile ivermectin is being shown to be effective as both prophylaxis and treatment in numerous studies but it's become anathema to consider the possibility of generics, it's "vaccines or bust."
    - manwe150 6y ago
      Did you read the article? It is literally investigating a possible mitigation using a generic drug that is not a vaccine. I strongly suspect doctors are even treating sick patients currently, and not just telling them to wait for a vaccine. Although, if you're instead trying to compare their effectiveness, yeah, vaccines kinda do appear to be that much starkly better. I'm blown away by how much the actual data curve looks like the dramatic XKCD cartoon version: https://m.xkcd.com/2400/ https://m.xkcd.com/2400/ https://www.idsociety.org/covid-19-real-time-learning-network/vaccines/ https://www.idsociety.org/covid-19-real-time-learning-networ...
      - AndrewBissell 6y ago
        "Vaccines or bust" was in reference to the parent comment, which seems to reflect a broader and widely held perception that any generic drugs must be a bad idea, and the only legitimate course of intervention is vaccines. It was not a (flatly absurd) claim that there are zero studies going on into various generic treatments. Some doctors are refusing to use ivermectin to treat seriously ill patients because the FDA will not issue any recommendations regarding its use: https://buffalonews.com/news/local/after-judge-orders-hospital-to-use-experimental-covid-19-treatment-woman-recovers/article_a9eb315c-5694-11eb-aac5-53b541448755.html https://buffalonews.com/news/local/after-judge-orders-hospit... If you include suspected COVID cases (which dwarfed confirmed PCR results) in the Pfizer trials, vaccine effectiveness falls to between 19% and 29%: https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-modernas-95-effective-vaccines-we-need-more-details-and-the-raw-data/ https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-...
- manwe150 6y ago
  I'm not a doctor or medical training, but have attempted to do limited meta-research of my own (generally just building on what others have already written for months now about it). I think there's good reason people are still skeptical that this is a useful treatment, and this is after many attempted trials. The latest "study" of that I saw (from https://www.sciencedirect.com/science/article/pii/S0924857920304258 https://www.sciencedirect.com/science/article/pii/S092485792...) seems to have compared patients who were very sick (high fever) and received normal treatment against patients who weren't very sick (no fever) and received zinc+hydroxychloroquine. When viewed in that way, it should be unsurprising then that the not-very-sick patient cohort fared better then the very sick. Additionally, the report notes that the not-treated people in that not-very-sick group also did much better than the treated people in that group. So, all told, that seems like too little evidence and too late, with the real conclusion being that if you want to avoid being sick, don't go get sick.
gnusty_gnurc 6y ago
corroborated by this paper "Azithromycin Downregulates Gene Expression of IL-1β and Pathways Involving TMPRSS2 and TMPRSS11D Required by SARS-CoV-2": https://www.atsjournals.org/doi/full/10.1165/rcmb.2020-0285LE https://www.atsjournals.org/doi/full/10.1165/rcmb.2020-0285L... So for the Hydroxychloroquine/Azithromycin combo recommended by Dr Raoult - seems like there's growing scientific support that there's something sensible and definitely not loony there. Notice all the quick dismissals of HCQ, etc. because of the Trump association, without caring to look for any RCT of HCQ in combination with the other drugs claimed to be required for it to be effective. I'm honestly done with all the people over the past 4 years that outsourced their thinking to Trump by taking the exact opposite opinion of him on every issue. Add this paper to the mix too, recently published: "Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection" https://www.sciencedirect.com/science/article/pii/S0002934320306732 https://www.sciencedirect.com/science/article/pii/S000293432...
8bitsrule 6y ago
Paper's DOI: https://doi.org/10.1371/journal.ppat.1009212 https://doi.org/10.1371/journal.ppat.1009212 Wayback URL: https://web.archive.org/web/20210122215919/https://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1009212 https://web.archive.org/web/20210122215919/https://journals.... Summary conclusion: "Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack of in vivo efficacy... "

16 points by drocer88 6y ago

> We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein. That's interesting, it's a furin cleavage site that the New York "Lab leak hypothesis" article pointed to as suspicious and possibly man-made, though I'm not sure if it's exactly the same.

11thEarlOfMar 6y ago

"human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19." But no mention of whether any of the trials included both Zinc and Azithromyzin, which are frequently cited as necessary co-medications.

rualca 6y ago
> But no mention of whether any of the trials included both Zinc and Azithromyzin Meanwhile, there is still no evidence that hydroxychloroquine has any usefulness as treatment for COVID19.
- barbacoa 6y ago
  https://www.wsj.com/articles/hydroxychloroquine-given-early-helped-coronavirus-patients-study-finds-11593729664 https://www.wsj.com/articles/hydroxychloroquine-given-early-... Not a doctor or well read on the subject but I have seen some studies claiming it does. Have also seen many studies saying there is no benefit too. Seeing such wild contradiction from respectable medical sources makes me wonder if anyone really knows what does what.
  - lazyeye 6y ago
    Its become political. If you are prepared to consider the possibility that hydrochloroquine could be beneficial, it means you are a Trump supporter.
    - rualca 6y ago
      > Its become political. Hydroxychloroquine was never anything other than pure political propaganda. It was the promise of a magical politically endorsed silver bullet designed to mitigate the political fallout of having to manage a pandemic with little to no success. Pure believers were not only kept in line because of the empty promises of a solution to their personal problem but also mobilized to persecute any contrasting opinion.
      - lazyeye 6y ago
        As I said...
      - dTal 6y ago
        This is not correct. Chloroquine was first suggested as a possible treatment by Chinese researchers in early February - well before there was even any attempt to manage a pandemic in the west. Those of us who were paying attention at the time were watching it carefully (and in some cases even buying supplies of it in case it proved effective). When Trump jumped on it (trailing a social media storm by several days) we all collectively groaned at the inevitable politicization. You surely didn't think that Trump picked a drug at random? https://thediplomat.com/2020/04/how-wuhan-virologists-pegged-chloroquine-as-a-potential-covid-19-cure/ https://thediplomat.com/2020/04/how-wuhan-virologists-pegged...
    - zug_zug 6y ago
      I would upvote you for rightly pointing out that it seems political, which is worth calling out, but I disagree with your sarcastic tone. But largely, yes, somehow, in some people's heads I think people have made an emotion association that endorsement of a drug is somehow a validation of an ex-political-figure. Hopefully that can all be put behind us now. I looked on wikipedia and found "Hydroxychloroquine is being studied to prevent and treat coronavirus disease 2019 (COVID‑19), but all clinical trials conducted during 2020 found it is ineffective and may cause dangerous side effects.[3][4][5][6]" But interestingly, the systematic review it referenced concluded "There is sufficient pre-clinical rationale and evidence regarding the effectiveness of chloroquine for treatment of COVID-19 as well as evidence of safety from long-time use in clinical practice for other indications [3] to justify clinical research on the topic." The rest of the citations were prior to June. I'm not specifically saying it does or doesn't work, I couldn't care less. I do care about citations matching.
- e9 6y ago
  That’s not true. In a number of countries they extensively use Hydroxychloroquine which is anti malaria drug and super important especially in Africa. Indian government is very open in using it for covid-19: https://www.newsweek.com/india-promotes-hydroxychloroquine-d https://www.newsweek.com/india-promotes-hydroxychloroquine-d... As well as many African countries: https://www.voanews.com/covid-19-pandemic/djibouti-treating- https://www.voanews.com/covid-19-pandemic/djibouti-treating-... https://www.theafricareport.com/26726/coronavirus-recovery-r https://www.theafricareport.com/26726/coronavirus-recovery-r... can provide more sources if requested (or just google it)...
- AndrewBissell 6y ago
  Did you read the article? It specifically discusses a mechanism by which hydroxychloroquine might be effective in combination with other medication. So if you want to just insist that HCQ by itself is not very useful, I'd say that's true but largely irrelevant. Meanwhile ivermectin is being shown to be effective as both prophylaxis and treatment in numerous studies but it's become anathema to consider the possibility of generics, it's "vaccines or bust."
  - manwe150 6y ago
    Did you read the article? It is literally investigating a possible mitigation using a generic drug that is not a vaccine. I strongly suspect doctors are even treating sick patients currently, and not just telling them to wait for a vaccine. Although, if you're instead trying to compare their effectiveness, yeah, vaccines kinda do appear to be that much starkly better. I'm blown away by how much the actual data curve looks like the dramatic XKCD cartoon version: https://m.xkcd.com/2400/ https://m.xkcd.com/2400/ https://www.idsociety.org/covid-19-real-time-learning-network/vaccines/ https://www.idsociety.org/covid-19-real-time-learning-networ...
    - AndrewBissell 6y ago
      "Vaccines or bust" was in reference to the parent comment, which seems to reflect a broader and widely held perception that any generic drugs must be a bad idea, and the only legitimate course of intervention is vaccines. It was not a (flatly absurd) claim that there are zero studies going on into various generic treatments. Some doctors are refusing to use ivermectin to treat seriously ill patients because the FDA will not issue any recommendations regarding its use: https://buffalonews.com/news/local/after-judge-orders-hospital-to-use-experimental-covid-19-treatment-woman-recovers/article_a9eb315c-5694-11eb-aac5-53b541448755.html https://buffalonews.com/news/local/after-judge-orders-hospit... If you include suspected COVID cases (which dwarfed confirmed PCR results) in the Pfizer trials, vaccine effectiveness falls to between 19% and 29%: https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-modernas-95-effective-vaccines-we-need-more-details-and-the-raw-data/ https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-...
manwe150 6y ago
I'm not a doctor or medical training, but have attempted to do limited meta-research of my own (generally just building on what others have already written for months now about it). I think there's good reason people are still skeptical that this is a useful treatment, and this is after many attempted trials. The latest "study" of that I saw (from https://www.sciencedirect.com/science/article/pii/S0924857920304258 https://www.sciencedirect.com/science/article/pii/S092485792...) seems to have compared patients who were very sick (high fever) and received normal treatment against patients who weren't very sick (no fever) and received zinc+hydroxychloroquine. When viewed in that way, it should be unsurprising then that the not-very-sick patient cohort fared better then the very sick. Additionally, the report notes that the not-treated people in that not-very-sick group also did much better than the treated people in that group. So, all told, that seems like too little evidence and too late, with the real conclusion being that if you want to avoid being sick, don't go get sick.

gnusty_gnurc 6y ago

corroborated by this paper "Azithromycin Downregulates Gene Expression of IL-1β and Pathways Involving TMPRSS2 and TMPRSS11D Required by SARS-CoV-2": https://www.atsjournals.org/doi/full/10.1165/rcmb.2020-0285LE https://www.atsjournals.org/doi/full/10.1165/rcmb.2020-0285L... So for the Hydroxychloroquine/Azithromycin combo recommended by Dr Raoult - seems like there's growing scientific support that there's something sensible and definitely not loony there. Notice all the quick dismissals of HCQ, etc. because of the Trump association, without caring to look for any RCT of HCQ in combination with the other drugs claimed to be required for it to be effective. I'm honestly done with all the people over the past 4 years that outsourced their thinking to Trump by taking the exact opposite opinion of him on every issue. Add this paper to the mix too, recently published: "Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection" https://www.sciencedirect.com/science/article/pii/S0002934320306732 https://www.sciencedirect.com/science/article/pii/S000293432...

8bitsrule 6y ago

Paper's DOI: https://doi.org/10.1371/journal.ppat.1009212 https://doi.org/10.1371/journal.ppat.1009212 Wayback URL: https://web.archive.org/web/20210122215919/https://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1009212 https://web.archive.org/web/20210122215919/https://journals.... Summary conclusion: "Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack of in vivo efficacy... "