Blissful Life

Category: facts

  • What to Make of Itolizumab?

    It is the worst of times. Science is suffering an identity crisis. The world is in dire need of science. Science isn’t used to being rushed. “It is a giant and slow churn”, said a friend once, “and spews a breakthrough once in a while”. Is it possible to make the process faster? That’s what everyone is wondering. And praying. And waiting, eagerly. Science isn’t used to getting this attention.
    “Coronil is 100% effective”, said Patanjali folks. “Favipiravir is 88% effective”, said Glenmark folks. How to know the truth? Seeking truth has never been easy. Never has it been easy for journalists, scientists, or the common person. In some sciences there are multiple truths. Is medicine one of those sciences? Can there be a single truth in medicine?
    I won’t use words like epistemology and ontology in this post. (Because I still can’t remember which is which). But the question is essentially two:
    1. Is there a single truth?
    2. Is there a way to know the truth?
    I believe medicine is a dangerous subject because of these two questions. Biology is extremely contextual. A drug’s effect on a person with any particular infection can be influenced by a thousand factors including – that person’s biology, the day, where that person is, what that person is eating, what other medicines that person is taking, the virus that infected them, all the infections they’ve had in past, other diseases they currently have, the health of their body organs, and so on.
    When there are so many things that keep changing, how do we know whether a drug is going to be useful for a person or not? Most of medicine today is an approximation. Many drugs are used because when given to n random people it worked better than it not being given. A gross measurement, if you allow me to call it. Put something in a balance and see which side is hanging lower.
    Not that medicine is all guess work. He he. There are some theories. There are some “well-known” pathways. There are some molecules which we understand. There are some we don’t. There are some drugs we know act on some molecules in some of these pathways. Sometimes we don’t understand some parts of how a drug acts, but we fill in those gaps with the “random” trials as described above.
    For example, let us take Paracetamol which is a drug commonly prescribed for fever. And the only drug that many people need during COVID (and Dengue, and many other viral fevers). We don’t know how exactly it works. But we have a rough idea on the pathways that it affects. We also have very rich clinical experience in using the drug successfully for fever.
    The reason why we don’t rely a lot on theory in medicine is that we don’t have a lot of theoretical understanding about the biology of our body. We do know a lot. But there are still so many known unknowns. And who knows how much unknown unknowns.
    We know a bit about molecules called “interleukins”. We seem to know about a molecule we call Interleukin 6. It seems to have a role in acute immune responses. It may very well make sense to somehow block IL-6 to decrease the damage that could be caused by what is called a cytokine storm (which, as it sounds, is a storm that wrecks havoc inside the body) in sick COVID patients.
    We seem to know about a class of drugs called monoclonal antibodies. These are molecules (which can be natural or artificial) that target specific kind of molecules. There are some mAbs which seem to be able to target a type of cell called CD6 cells, including Itolizumab.
    Now, here is the deal. If Itolizumab can act on CD6 and decrease IL-6 and if IL-6 has a role to play in cytokine storm in COVID, then the inference could be drawn that Itolizumab can help sick COVID patients not die. That’s the theory.
    But the problem with medicine is that theory doesn’t always work. And sometimes what presents as reasonable with our current understanding of the body sometimes becomes dangerous when we actually try it.
    As for Itolizumab, Biocon seems to have given it to 20 patients with COVID and moderate to severe respiratory difficulty. And they all seem to have survived. Of the 10 they didn’t give it to, three people apparently died. I’m sure they’re doing this study on more people at the moment.
    According to them this is “statistically significant”. I don’t have a very deep understanding of statistics. Here, let me do the math.
    The way I read it is that based on that data we can be 95% sure that if someone with moderate to severe COVID-19 ARDS takes the drug their chance odds of survival is somewhere between 0.8802 fold to 415.9060 fold the chance odds of their survival without taking the drug.
    Didn’t I tell you this is the worst of times?
    Update: Don’t look at my math. That was not the point of this post. Also, my math sucks. Here is why:
    At a sample size of 30, the power of this study is like 30% which means it is completely unreliable. I think. I don’t know.
    Update 2: As per this article, and as per my understanding of beta, if p-value is already acceptable, then it doesn’t matter whether beta is high as all that power makes sure is that we don’t miss the effect when there is an effect.
    But then, am I confusing myself because in this study the effect of the drug is protective? I am 70% sure that the power of this study is not to be worried about.
    Update 3: Maybe the contradiction is resolved if we consider this as a type S error.

  • Glenmark Lies About Favipiravir

    I received from a friend a PDF which happened to be Glenmark’s press release about Favipiravir. The release is full of claims that make it sound like Favipiravir is a wonder drug that is going to solve COVID problems. It becomes my responsibility to refute some of these claims, considering how majority media outlets are doing what they’re best at – exaggerating an already exaggerated PR claim.
    Firstly, we have to verify the claim whether India’s drug controller did approve the drug. The way to do that is visit CDSCO’s website and navigate to approvals -> new drugs. And as per that, “Favipiravir bulk and Favipiravir film coated tablet 200mg” did in fact receive approval on 19th of June for “the treatment of patients with mild to moderate Covid-19 disease” as the 18th entry.
    I do not think CDSCO publishes details of the approval process, about what evidence they considered for approval, etc. Making these processes transparent would be useful for avoiding putting people in great danger.
    The deceptions start from the title itself. “Glenmark becomes the first pharmaceutical company in India [..] blah blah blah [..] COVID” – what does it mean to say “first pharmaceutical company in India in this context? They just want it to sound like this is the first drug for COVID.
    They then start with a bullet point about accelerated approval process which makes it sound like it was CDSCO who wanted the approval to be accelerated so that the “benefit” of Favipiravir can reach everyone. I doubt that’s what really happened.
    They then talk about “responsible medication use” and informed consent. The reality is that this informed consent is necessary because there is no way to know if Favipiravir is really useful in COVID. According to the Telegraph article, the approval was based on a trial on 150 patients. (The CDSCO website does list approval for a Favipiravir trial in May, although this was given to Cipla. Interestingly, the CDSCO website seems to be missing details of any approvals given in April (and Glenmark received approval in late April, as per them))
    In that last pdf they do share the details of the clinical trial. They say they would enroll exactly 150 patients and give Favipiravir to half of them. 75 people!
    Now, next in their bullet point they come up with the ridiculous and unsupported claim that Favipiravir shows clinical improvements of 88% and rapid reduction in viral load. In the text, they do add a citation which points to this PDF report of an observational study done in Japan. This was an observational study with no control arm or anything to compare with. The report itself states this:
      It  should  be  noted,  however,  that  this  study    only    captures    patients    who    received    favipiravir,  which  precludes  direct  comparison  of  the  clinical  course  with  those  who  did  not  receive  the   agent.   Given   that   over   80%   of   COVID-19 patients have mild disease which often improves by supportive   therapy6),   caution   is   required   in   interpreting  efficacy  of  favipiravir  based  on  the  data presented here
    And this is what is cited to support the ridiculous claim in the PR.
    I’m not going to go ahead and waste my time talking about each point made in the PDF.
    But the fact is that saying Favipiravir is useful for treating COVID is as correct as this claim by Patanjali:

    #WATCH We appointed a team of scientists after #COVID19 outbreak. Firstly, simulation was done&compounds were identified which can fight the virus. Then, we conducted clinical case study on many positive patients&we've got 100% favourable results: Acharya Balkrishna,CEO Patanjali pic.twitter.com/3kiZB6Nk2o

    — ANI (@ANI) June 13, 2020

    —
    Conflict of interest disclosure: I have 2 shares in Natco pharma worth about 1000 rupees the last time I checked.

  • Why is Benzylpenicillin called Penicillin G and Phenoxymethylpenicillin Penicillin V?

    This one took a lot of searching. My initial hunch was that the G and the V stood for amino acids. G for Glycine and V for Valine. I thought, maybe, if these amino acids were not substituents, at least they would be the precursors involved in synthesis of Penicillins. I had also heard the word “Penicillin Gold” somewhere suggesting that they could be acronyms as well.

    After some searching around, there was a chance discovery of this page on some encyclopedia that said “The different forms of penicillin are
    distinguished from each other by adding a single capital letter to their
    names. Thus: penicillin F, penicillin G, penicillin K, penicillin N,
    penicillin O, penicillin S, penicillin V, and penicillin X”

    Now I knew there are more letters and these are chosen just because they are in the alphabet and not because of anything special. So the question became, why these letters? Did they start with Penicillin A and go down all the way till Penicillin V and even X? Is there a list of all Penicillins? Who maintains this list?

    After figuring out what Penicillin A and B was, I remembered Alexander Fleming. If Fleming discovered Pencillin, then we should start with him.

    So, here’s Fleming’s 1929 paper where he describes the discovery of “mould broth filtrate” which for convenience he decided to call “penicillin” : On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ.

    He wrote the fungus closely resembles P. rubrum. Some people “corrected” him later. Some then corrected the corrections.

    Okay, so in 1929, there was only one Penicillin and it was Fleming’s Penicillin.

    Then, for almost 10 years nothing happened. That’s when Ernest Chain and Howard Florey came into the picture. They figured out a way to get good Penicillin. As early as 1940, they discovered Pencillin resistance. An Enzyme from Bacteria able to Destroy Penicillin. If you want to read more about the interesting history of the discovery of penicillin, read this review.

    What Chain and Florey synthesised apparently was different from what Fleming discovered and therefore they initially named it Penicillin A and filed a patent. Later, they renamed it to “notatin” to avoid confusion. They also wrote this brilliant article on how they used it on some patients.

    Van Bruggen and others in 1943 described another compound from Penicillium which had bactericidal activity and was different from any of the Penicillins till then and named it Penicillin B.

    It was soon clear that Penicillin A and Penicillin B were identical. This compound is now called Glucose Oxidase.

    From then on, it was mostly about improving on the techniques and therefore most literature is on patent articles. Here is one where Penicillin F and Penicillin G is described. I have no clue why they skipped over C, D, and E.

    Around this time, people started producing all kinds of Pencillins.

    As I could not find the list anywhere, I decided I will make that list. Here it goes.

    Penicillin A – Glucose Oxidase
    Penicillin B – Glucose Oxidase
    Penicillin C –
    Penicillin D –
    Penicillin E –
    Penicillin F – C14H20N2O4S
    Penicillin G – Benzylpenicillin
    Penicillin H –
    Penicillin I –
    Penicillin J –
    Penicillin K – Natural penicillin
    Penicillin L –
    Penicillin M –
    Penicillin N – Natural penicillin
    Penicillin O – Almecillin
    Penicillin P –
    Penicillin Q –
    Penicillin R –
    Penicillin S –
    Penicillin T –
    Penicillin U –
    Penicillin V – Natural penicillin
    Penicillin W –
    Penicillin X – Natural penicillin
    Penicillin Y –
    Penicillin Z –

    Please let me know if you find the missing items.

  • Do Cats Get HIV?

    Blalock-Thomas-Taussig shunt is a surgical technique used in colouring Blue Babies pink.

    Last week we had a baby who was referred for cardiac evaluation come back with a report saying she had Tetralogy of Fallot and needs a BT shunt. The parents had not gotten it done yet. Still, the baby wasn’t blue. Because she was too anaemic to have enough deoxygenated haemoglobin to be cyanotic.

    I had to watch Something the Lord Made that night. It is the heart-touching story of how B(T)T shunt was developed. If you don’t cry with Vivian Thomas at the end, you should probably check your cardiac functioning.

    In the backdrop, there are dogs. Blalock and Thomas would perform their surgical experiments on dogs. Countless dogs who have lost lives for (human and animal) science. Thank you dogs!

    Talking about dogs, there are cats too. I found this post on reddit.

    The Litterbox Hero

    Cats don’t get HIV – it’s Human Immunodeficiency Virus, for viral Lords’ sake. Or maybe there is a Feline Immunodeficiency Virus! And when you read more about it you can find that FIV and even HIV is used in gene therapy.

    Fucking science.

    On the other hand scientists are marching to protect science. And being rational is increasingly being viewed as treacherous and anti-nationalistic.

    People just can’t understand.

    I had just figured out a name for the problem one of our patients who got his tissues necrosed after an IM diclo injection had. It was Nicolau Syndrome (or livedoid dermatitis or embolia cutis medicamentosa – remember the name that can make you sound really good).

    And there walked in a patient who had worked too much and was having pain in the forearms and knees. He had to get an injection. It didn’t matter to him whether I gave him 3 mL normal saline or 20 mg morphine. They just have to get injected. Good luck talking them out with Nicolau Syndrome or even anaphylaxis.

    When the pleasures and shortcuts are so tempting, why would people prefer the rigour of science or protocols.