Posts Tagged ‘remdesivir’
covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors
from The Lancet, ‘the four horsemen of a viral apocalpse’
Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence.
Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication.
Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised.
Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):
Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.
They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males.
Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels.
Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool.
Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function.
Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus.
Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.
Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect.
Canto: Hmm. Is that protectionism?
Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.
Canto: Very CCP.
Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:
We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.
So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment:
We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.
They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.
Canto: Potential? You’d think they’d be onto all this by now.
Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients.
Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….
Jacinta: Yes I’ll try, maybe next time.
References
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK
Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions
Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool
Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability
Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC
amhf.org.au/covid_19
https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
Covid-19: remdesivir, masks, vaccine trials, arrhythmias
So to Dr Seheult’s coronavirus update 77, where he looks again at the antiviral drug remdesivir. A preliminary report from the New England Journal of Medicine describes results from trials comparing remdesivir with placebo in covid-19 patients at various levels of treatment, i.e, those receiving oxygen, those not receiving oxygen, those receiving high-flow oxygen or ‘noninvasive mechanical ventilation’, and those receiving full mechanical ventilation or ECMO (extracorporeal membrane oxygenation), and the finding was that remdesivir only made a statistically significant difference in the oxygen-receiving patients, which is more or less an intermediate phase. This may be due to the larger sample size that fell into this category. There were apparently small benefits in the non-oxygen category, but nothing in the more serious patient categories. The report’s conclusion:
These preliminary findings support the use of remdesivir for patients who are hospitalised with Covid-19 and require supplemental oxygen therapy. However, given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient.
So remdesivir appears to be just one of many agents and therapeutics in the armamentarium of health authorities dealing with this pandemic, which over the past few months appear to have been utilised to reduce mortality and improve recovery times since the early phase of the outbreak in the USA, to judge from figures comparing, say, New York with Texas and Florida.
The update also discusses heat-treating the interior of police vehicles as a disinfectant, using a computer program. Basically a system has been devised to heat-treat unoccupied vehicles for 15 minutes to 133 degrees fahrenheit, long enough and hot enough to kill 99% of known pathogens, including SARS-CoV2, and it’s already being rolled out for police SUVs. Interesting, and obviously adaptive to other circumstances. The rest of the update discusses promising approaches as of the end of May, including convalescent plasma therapy, which I hope to look at later.
Update 78 starts with face masks. We here in South Australia have only suffered 459 cases in total, with 457 recovered and only 4 deaths. The majority of cases by far occurred in the early stages (March-April), and much has opened up since then, and the wearing of masks has always been optional here. However, the virus has had a resurgence in Australia’s more populated eastern states, so we’re on alert, and there’s been a partial closing down again. Still, most people I notice aren’t wearing masks. In the USA there seems to have been some prevarication from authorities like the CDC on mask-wearing, but with a further understanding, especially of asymptomatic and pre-symptomatic cases, they came out more strongly in favour of cloth masks ‘in public settings where other physical distancing measures are difficult to maintain (e.g. grocery stores and pharmacies), especially in areas of significant community-based transmission’. The WHO’s guidelines aren’t so strict possibly because they’re dealing with a broader base in which effective face masks are less readily available and need to be prioritised.
Also related to masking is a New England Journal of Medicine article on aerosols and droplets generated by speech, which have been implicated in Covid-19 transmission. A simple experiment was conducted using laser light scattering to illuminate droplets from a speaker without a mask, and then with one, and the difference was quite dramatic. Update 78 shows the video, and it’s worth a thousand words.
This update also highlights a website which I intend to explore further, especially as I seem to be spending a lot of time in the world of disease, pathogens and the fight against them. It’s called Regulatory Focus, and there’s a further link to its covid-19 therapeutics tracker, which tracks all the research and studies, of antivirals, monoclonal antibodies and any other medications that might relate in any way to the pandemic, and another link takes us to the covid-19 vaccine tracker. It provides information on phase trials, the vaccine type, the institutions and sponsors involved, etc.
In update 79, Dr Seheult picks out a few of the vaccine trials that seem to show most promise and are most likely to be available by 2021. First is the Moderna mRNA-1273 candidate, which will inject mRNA to produce proteins that generate an immune response. Now the standard clinical trial process for testing a vaccine involves three phases. Phase 1 tests primarily for safety, phase 2 largely looks at appropriate dosage, and phase 3 is the final, large human population trial. These phases have been fast-tracked more than ever before, as is well known, sometimes without the usual animal testing, which would generally raise ethical issues, but that doesn’t seem to be happening for covid-19 trials. The University of Oxford candidate is ‘a chimpanzee adenovirus vaccine vector called AZD1222’. It injects an epitope for an antigen into the patient. An epitope is a region of an antigen that antibodies detect and bind to. Other candidates come from the Merck company, Johnson & Johnson and Pfizer.
Update 80 deals with a very controversial issue, which is possible research industry malpractice, in the form of massaged results relating to a relatively small company, Surgisphere. Interestingly, it involves an overstatement of deaths here in Australia, among other inconsistencies, which have led to retractions of papers on hydroxychloroquine and chloroquine in prestigious journals such as the Lancet and NEJM. It seems that the papers may have exaggerated negative effects from the use of these anti-malaria medications, with or without the addition of a macrolide (a class of antibiotics), which has just added to the controversy surrounding them. There’s also a question about the use of the anti-parasite drug ivermectin, and some common heart medications, due to these now-retracted results.
Interestingly, update 81, posted back on June 9, highlights Australia as still succeeding in keeping numbers down as we head into winter. That’s not the case today (August 11). It goes on to introduce another website, Covid-trials.org, comprising data on ‘over 1400 trials’ (now over 1900) worldwide relating to covid-19, including ‘alternative therapy’ and ‘traditional Chinese medicine’. Hmmm. And of course all the more promising treatments. This and the previously mentioned vaccine and therapeutics trackers provide a wealth of ongoing detail about the who, the how, the what, the how much, etc.
The update also describes a trial of hydroxychloroquine ‘as post-exposure prophylaxis’ published in NEJM. 821 people known to be exposed to the virus were treated with either hydroxychloroquine or a placebo, and then tested for the virus. The result was a non-statistically significant prophylactic effect. There were minor gastrointestinal side-effects in the hydroxychloroquine group, but no cardiac arrhythmias, often associated with the drug. Dr Seheult explains something about these arrhythmias, which is interesting enough for me to dwell on.
When we look at an electrocardiogram (ECG) we find something like the drawing here, with a P-wave, and a T-wave at the end. Some medications can cause a prolonged QTc (the c stands for ‘corrected’), and in combination with others, this can result in cardiac arrhythmias, which generally have two types, as shown in the illustration at the top of this post – an over-fast beat (tachycardia) or a too-slow one (bradycardia).
So, although the positive effects of hydroxychloroquine in this study were minor, there may have been a greater benefit from adding zinc to the treatment, as Seheult suggests, because the drug acts as a zinc ionophore. An ionophore is a fat-soluble transporter material which can carry non-fat-soluble minerals like zinc through the fatty cellular membrane. Zinc inhibits the RNA-dependent RNA polymerase of the coronavirus, but it seems that as of mid-June no full-blown studies had been done to show a benefit, or otherwise, from the combination.
References
Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico
Coronavirus Pandemic Update 78: Mask Controversy; Vaccine Update for COVID-19
Coronavirus Pandemic Update 79: COVID-19 Vaccines to Keep an Eye On – mRNA, Antigen, Others
Coronavirus Pandemic Update 80: COVID-19 Retractions & Data (Hydroxychloroquine, ACE Inhibitors)
Coronavirus Pandemic Update 81: New Data on Hydroxychloroquine Side Effects & Prevention of COVID-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
https://jamanetwork.com/journals/jama/article-abstract/2766943
https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker
https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-therapeutics-tracker
Covid-19 – conspiracies, remdesivir
Canto: So, getting back to Covid-19, I want to look at two unrelated issues – the limited approval of remdesivir as a treatment, and the claim by the US government that the virus escaped from a lab in Wuhan. What do you think?
Jacinta: Well let me briefly address the second matter – I haven’t yet looked into the claim, but I will say that, IMHO, the current US federal government is possibly the largest misinformation machine on the globe at present, and I won’t be happy till I see every member of that non-administration in jail.
Canto: Okay, be prepared for a life of misery. I agree though, that Pompeo is a slimeball, and it’s very likely that this is largely designed as another blame-shifting distraction by the US maladministration. I don’t remember hearing about this from any news source before Pompeo announced it.
Jacinta: Well it’s interesting that, in investigating this, we have to contend with, and generally ignore, two of the most untrustworthy governmental sources of information on Earth, the USA and China. So thank dog for independent journalists, scientists and investigators. We need them so much at this time. The Washington Post has a 2000-word article on the issue, posted on May 1, undoubtedly in response to moves by Frumpy & co to get the US public to blame China for the pandemic. The article describes an assessment from the US intelligence community:
While asserting that the pathogen was not man-made or genetically altered, the statement pointedly declined to rule out the possibility that the virus had escaped from the complex of laboratories in Wuhan that has been at the forefront of global research into bat-borne viruses linked to multiple epidemics over the past decade.
Canto: ‘Pointedly declining to rule out’ means very little. They’re making a point of saying it’s possible? Isn’t it more likely to have come from the ‘wet markets’ – wet with blood that is – as a result of that traditional Chinese fondness for dining and medicating on exotica?
Jacinta: ‘Murky’ is how the WaPo describes the origins. Some scientists are saying it’s highly likely to have been ‘naturally transmitted’, others, not so sure. But the thing is, the scientists are the ones to trust on this, certainly not the Chinese or US governments. And even then you need to check those scientists’ allegiances.
Canto: I should also point out, as so many scientists are doing, that now is not the time for playing the blame game. Knowledge is power, and we need to be pooling our global resources, and our knowledge, to combat this and future pandemics. We need to try and build trust, not to sow distrust. And this isn’t to say that accidents can’t and don’t happen in virology and microbiology labs around the world, including in the USA.
Jacinta: The WaPo also has much to say about renowned virologist Shi Zhengli, team leader at the Wuhan Institute of Virology, which is being targeted by the Trump administration’s propaganda campaign. According to Shi, ‘the institute never possessed the SARS-CoV-2 virus’, while Wuhan’s health commission has found, or claimed, that the first person who died of the virus purchased goods at the Huanan Seafood Wholesale Market.
Canto: So it may have come from seafood?
Jacinta: Don’t know. Probably they sold more than seafood there, or it was part of a wider market. Anyway, many virologists, including US scientists who’ve worked with her, vouch for Shi’s extreme rigour and brilliance. But clearly that won’t stop the US government’s attempt at character assassination. I’ve heard they’re trying to say, or infer, that the virus was engineered at the Wuhan lab – and no doubt millions of Yanks will believe this brilliant theory, that the virus was engineered by mad scientists and then let loose to kill thousands of their own people before being unleashed upon the world – to be followed up by Chinese chem-trails, no doubt.
Canto: And not just Yanks. Anyway let’s move on to a happier topic. Remdesivir.
Jacinta: Well the news is that the FDA in the USA has issued an Emergency Use Authorisation for remdesivir, and the Gilead company which owns this pharmaceutical, has issued a company statement (on May 5), and here’s a quote:
Gilead’s overarching goal is to make remdesivir both accessible and affordable to governments and patients around the world, where authorized by regulatory authorities…. Gilead is in discussions with some of the world’s leading chemical and pharmaceutical manufacturing companies about their ability, under voluntary licenses, to produce remdesivir for Europe, Asia and the developing world through at least 2022.
I’ve listened to an interview with Gilead’s CEO Daniel O’Day, and he was making all the right caring-and-sharing noises…
Canto: Can we revisit what remdesivir is and does?
Jacinta: Of course. For starters it’s not a cure, it’s essentially ‘an investigational antiviral drug’ (I’m quoting again from the company statement) which, O’Day is careful to point out, ‘has not been approved by the FDA for any use’ (meaning presumably besides this emergency use). He also admits that the drug is the subject of multiple ongoing clinical trials and ‘the safety and efficacy of remdesivir for the treatment of COVID-19 are not yet established’. It’s a nucleoside analogue, one of many that have been formulated over the years, and dozens have been approved for use in treating viruses, cancers, bacterial and other pathogens. Nucleoside (and nucleotide) analogues are designed to resemble naturally occurring molecules used to build the RNA and DNA so essential to our biology. Some of the best-known nucleosides are cytidine, thymidine, uridine, guanosine, adenosine and inosine. The difference between a nucleoside and a nucleotide is that nucleosides are nucleobases linked to a sugar molecule while nucleotides are linked to phosphate groups (oxygen and phosphorus).
Canto: And the key is that in creating an analogue which functions differently from the real thing, they’re trying to obstruct the replication of the pathogen that takes up this analogue, right?
Jacinta: Yes, you’re getting it. Remdesivir actually has several modifications to the nucleoside structure while still functioning as an analogue – that’s to say it still manages to trick the virus into utilising it, and so becoming dysfunctional in terms of replication. A professor of chemistry and biochemistry, Katherine Seley-Radtke, describes the process in relatively simple terms:
Remdesivir works when the enzyme replicating the genetic material for a new generation of viruses accidentally grabs this nucleoside analogue rather than the natural molecule and incorporates it into the growing RNA strand. Doing this essentially blocks the rest of the RNA from being replicated; this in turn prevents the virus from multiplying.
She writes that remdesivir is a three-times-modified version of the adenosine molecule. Firstly, it’s a ‘prodrug’, in that it has to be modified in the body before it becomes active. The active form has three phosphate groups and is then recognised by the RNA polymerase enzyme of the virus. The second modification is a carbon-nitrogen group attached to the sugar, which is the key to terminating the RNA strand’s production. The third modification is a little change to the molecule’s chemical bond, replacing one nitrogen with a carbon, which prevents one of the enzymes of the virus from recognising and excising ‘foreign’ nucleosides. Remdesivir’s modified adenoside remains in the RNA chain, ultimately terminating further production. Got all that?
Canto: I refuse to confirm or deny. But I can read too. There’s a proper clinical trial of the drug being conducted in the USA at present, and other trials elsewhere. Preliminary results show faster recovery in a statistically significant number of patients, but it isn’t a cure, and will likely be part of a cocktail of treatments as other and hopefully even better antivirals are formulated. This follows the approach to treating other dangerous viruses such as hepatitis C and HIV. It’s about getting the death rate, and the badly-affected rate, down. This is as important as a vaccine, at present.
Jacinta: And I’ve heard it’s quite a tricky drug to manufacture, so getting supplies up and sharing expertise globally will be key factors in saving lives.
References
https://theconversation.com/remdesivir-explained-what-makes-this-drug-work-against-viruses-137751
Covid 19: some stuff on remdesivir
Canto: So there’s this promising new antiviral drug that researchers are working on. Remdesivir. Terrible name. Why not something more hard-hitting like rambovir or rockyvir?
Jacinta: Well I’m not sure it’s an American drug, and I don’t think it’s new. It’s new for Covid-19. Everything’s new for Covid-19. And here we should repeat the standard caveat: ‘No specific agent has yet been demonstrated to be clinically effective in the management of Covid-19’.
Canto: Well done. So I’m reading this online article from a week or so ago – and a week’s a long time in Covid-19 – on the website of the Medical Journal of Australia, and it tells me that the antimicrobial remdesivir is ‘an investigational nucleotide prodrug’ – glad it’s not one of them antidrugs – and was used on the first diagnosed Covid-19 sufferer in the US. So maybe it is American. The article doesn’t say anything about its effect on the patient, but apparently it was first developed as a potential therapy for Ebola, and there’s some laboratory evidence that it can inhibit the replication of SARS-CoV-2.
Jacinta: That’s right, so four clinical trials have already begun in the US to test the effects of remdesivir, and another two are registered in China.
Canto: Well according to this media release only yesterday (April 17) from the National Institutes of Health (NIH) in the USA, they’ve already been testing the drug on poor old rhesus macaques…
Jacinta: They infected em? Bastards.
Canto: History is written by the victors my friend. And also by those who can actually write. Anyway, they responded very well to early treatment with reduced clinical signs and lung damage in a study designed to simulate treatment procedures for human patients in a hospital setting…
Jacinta: That’s nice. They got to sleep in real beds, like middle-class macaques.
Canto: Maybe. Of course, none of this has been peer-reviewed yet, but it’s very promising. But let me give you the total lowdown. You know that there have to be control groups, right?
Jacinta: Uhhh – uh-o. So… Let me see, they were all infected with the virus, but only some got the remdesivir, right?
Canto: Well of course they had to make the comparison. So they had two groups of six rhesus macaques, and they infected both groups with SARS-CoV-2. Then 12 hours later the treatment group received an injection of remdesivir. Sorry about the other group. After that the treatment group received a booster injection every day for the next six days. The initial treatment was timed to more or less coincide with the animals’ highest projected viral load. They first examined the animals 12 hours after initial treatment, and the treatment seemed pretty effective, only one still showed some mild symptoms, while in the control group they all displayed ‘rapid and difficult breathing’ …
Jacinta: Called dyspnoea in medical lingo.
Canto: Thank you. So the study continued for seven days, and over that time the treated monkeys were found to have significantly less virus in, and damage to, their lungs than the untreated.
Jacinta: So what happened to the untreated monkeys after that?
Canto: I might say ‘don’t ask, don’t tell’, but I think it’s reasonable to assume that after seven days they were treated with remdesivir and recovered. And that they chose a short, seven-day testing period so as not to endanger any monkey lives?
Jacinta: Hmmm. I don’t know too much about monkey business… Anyway, this remdesivir is obviouly promising and we must watch out for the results of other trials. But what is this remdesivir? What exactly is an antiviral, or a ‘nucleotide prodrug’, and do they all act in the same way? I know they’re not vaccines, they don’t induce antibodies, so how do they suppress the infection?
Canto: Okay, so our first stop on our info crawl is Wikipedia. Think of antivirals as a counterpart to antibiotics, aimed at viruses rather than bacterial pathogens, except that, unlike most antibiotics, their aim is to suppress rather than to kill the pathogen.
Jacinta: Really? Why not aim to kill the virus?
Canto: I don’t know, perhaps that’s not so easy with viruses. Anyway, while most antivirals target specific viruses, some are broad-spectrum, and I suppose remdesivir is one of those, since it was also successful against MERS, another coronavirus, and was first developed to combat Ebola virus, which isn’t a coronavirus as far as I know.
Jacinta: Remdesivir was earlier described as a nucleotide prodrug. A nucleotide is the basic structural unit of a nucleic acid such as RNA. A prodrug is by definition an inactive biological or pharmacological compound that can be converted within the body to have active drug properties. So the field of antiviral drug research has developed a lot, especially as a result of the HIV epidemic, and those that followed. All of this has expanded our knowledge of how viruses enter hosts and proliferate. SARS-CoV-2 is a set of RNA nucleotides surrounded by a protein capsid, or capsule, over which is a lipid envelope. It enters the host via the spike protein, and through this membrane fusion it infects host T lymphocytes – white blood cells that form a part of our immune system.
Canto: Yes, and trying to describe it all in lay terms – so that we understand it – is damn difficult. We know remdesivir has been somewhat effective for a broad spectrum of action against RNA viruses, and I note in this abstract that it’s ‘a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps)’ My guess is this means it acts like a nucleotide, inhibiting these RDRps. An RNA polymerase, I’m learning, is an enzyme (a type of protein) that’s ‘responsible for copying a DNA sequence into an RNA sequence, during the process of transcription’. But maybe an RNA-dependent RNA polymerase works on RNA, in the absence of DNA. So presumably remdesivir inhibits this essential enzyme from carrying out the transcription process that replicates the virus.
Jacinta: Maybe. By the way, as we travel the net on our info crawl, we’ve discovered some amazing stuff, such as this Covid-19 pandemic series of ongoing videos from a source called MedCram that began in late January and traces the spread, and the drama. The series begins with these words: ‘one of the things that’s in the news and hopefully goes away real soon is the coronavirus epidemic from 2019…’ That, to me, was more compelling than any advertising hook I’ve ever read.
Canto: Yes I’m keen to watch the whole series. Anyway, I believe remdesivir, also called RDV, has been used in an unauthorised way on human subjects already, and news from this Chemical and Engineering News website is that, understandably, interest in the drug and in scaling up production is reaching fever pitch, with a lot of pressure on Gilead, the company that presumably has a patent on RDV.
Jacinta: Of course, as we’ve already pointed out, this is exactly not the time for one private company to get precious about its rights to profit. Scaling up, assuming the drug’s effectiveness can be confirmed, should involve multiple labs in multiple countries. Having said that, producing a drug like RDV, described as a ‘medium complexity project’ compared to an apparently simpler drug such as the antimalarial drug hydrochloroquine, already involves a chain of companies and suppliers in a multi-step process. Every step in the process would need to be efficient, to prevent bottlenecks. Scaling-up also raises questions – remember Tamiflu? Our government stockpiled it in vast amounts in spite of damning analyses by the Cochrane Collaboration and others about its limited effectiveness and problematic side-effects. We don’t yet have proper analysis of RDV’s effectiveness, and we don’t know how much of it might be required, because nobody can predict the eventual course of this pandemic.
Canto: All true, but right now people are dying, and this is clearly the worst pandemic in more than a century. There are of course candidates other than RDV, it would be unwise to focus on just one, but public and private resources should be combined to bring any possible effective treatment to fruition. That’s what I reckon.
References
https://www.mja.com.au/journal/2020/clinical-presentation-and-management-covid-19
https://en.wikipedia.org/wiki/Antiviral_drug
https://ama.com.au/ausmed/govt-stands-tamiflu-despite-damning-findings