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Archive for the ‘antivirals’ Category

Covid 19: some stuff on remdesivir

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remdesivir, somewhat simplified, with its central phosphate group

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://www.nih.gov/news-events/news-releases/antiviral-remdesivir-prevents-disease-progression-monkeys-covid-19

https://en.wikipedia.org/wiki/Antiviral_drug

https://cen.acs.org/biological-chemistry/infectious-disease/Scaling-remdesivir-amid-coronavirus-crisis/98/web/2020/04

https://ama.com.au/ausmed/govt-stands-tamiflu-despite-damning-findings

How coronavirus kills: acute respiratory distress syndrome (ARDS) & Covid-19 treatment (one of the first in an excellent ongoing video series on the Covid-19 pandemic)

Written by stewart henderson

April 21, 2020 at 12:58 pm

Covid 19: hopes, failures, solutions

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under pressure

Covid-19 continues to be devastating, especially in the USA, where there are vastly more cases than anywhere else, and vastly more deaths, though the picture there is complex. The hardest-hit region, the New York area, is seeing devastation in poorer districts such as Queens, where the Elmhurst public hospital is inundated with uninsured, critically ill patients. New York has suffered almost half of US deaths. Some other states and regions, especially physical outliers such as Alaska, Hawaii and the Virgin Islands, have very low numbers, and it would be hard to explain why the spread of cases across the mainland has been so uneven. Of course it’s obvious that there has been no federal leadership on the pandemic.

Here in Australia, where the numbers seem to be improving (we’re 33rd on the list of total cases, down from 18th when I first started paying attention to the list about three weeks ago, and 52nd on the list of total deaths), our conservative federal government is keen to open up the country again, and has released modelling to the effect that the virus will be eliminated from the mainland if we maintain current physical distancing measures, though it’s likely to take weeks rather than months:

The model suggests that every 10 people infected currently spread the virus to five more people, on average. At that level, the virus would eventually be unable to circulate and would die out within Australia.

Sydney Morning Herald, ‘Australia in course to eliminate Covid-19, modelling shows’

Australia’s current reproduction number (R0) is just a little over .5. A maintained R0 of 1 or less will eventually eliminate the virus. Of course, there will be fluctuations in that number, so it will be difficult to project a time when things are ‘all clear’. Another difficulty with modelling is that the number of infected but asymptomatic people is unknown and difficult to estimate. For example, recent Covid-19 testing of the entire crew of the aircraft carrier Theodore Roosevelt found that a substantial majority of those who tested positive were asymptomatic, casting doubt on previous estimates (already worrying for transmission) of one in four cases being asymptomatic.

The asymptomatic/presymptomatic transmission issue was addressed by Bill Gates in this article back in February. It’s what makes SARS-CoV-2 a much more serious threat than the previous SARS and MERS viruses. Gates, in this very important article, also provides an outline of what needs to be done globally to fight this pandemic and to prepare for inevitable future ones. If only…

It’s worth comparing Gates’ call for national and global co-ordination, and more expenditure, in the fields of epidemiology and disease prevention, with another more recent article, also published in the New England Journal of Medicine, which tells a tale of Britain and its NHS, gutted by years, in fact decades of ‘reforms’ and budget cuts:

Thanks to government “reforms” of the NHS, it has become highly decentralized, with over 200 commissioning groups in England that can make independent decisions about staffing and procurement of equipment — far from the monolithic “socialist” health care system it is often assumed to be. The devolved governments in Wales, Scotland, and Northern Ireland have substantial health system autonomy. At a time when central management of staff and resources might be most helpful, the decentralized decision-making structure leads to competition for resources and inconsistent policies.

One can hope that the travesty of this virus, especially in places like the US and the UK, will lead to a rethinking of the importance of a well-funded, centralised, co-ordinating and interventionist government in modern states, with particular emphasis on the healthcare system. But I suspect that, in the USA at least, things will go the other way, and the government-hating and government-blaming will only intensify. I’d love to leave this topic and look at solutions – that’s to say I’d love to focus more on the science, but I’m barely equipped to do so. Still, I like to have a go. A very technical and comprehensive review review of pharmacological treatments has been posted recently on the JAMA website, which includes an account of how SARS-CoV-2 enters host cells and utilises those cells for reproduction.

The review claims that currently the most promising therapy is the antiviral drug remdesivir. So what is it and how does it work? I’ll try to answer that question next time.

References

https://www.news.com.au/world/coronavirus/global/epicentre-of-the-epicentre-this-queens-ny-hospital-is-coronavirus-ground-zero/news-story/6d0213ab9d5dd82fa12339f551be99ce

https://www.theguardian.com/world/ng-interactive/2020/apr/16/coronavirus-map-of-the-us-latest-cases-state-by-state

https://www.smh.com.au/national/australia-on-course-to-eliminate-covid-19-modelling-shows-20200416-p54kjh.html

https://www.nejm.org/doi/full/10.1056/NEJMp2005755?query=recirc_artType_railA_article

https://www.nejm.org/doi/full/10.1056/NEJMp2003762

https://jamanetwork.com/journals/jama/fullarticle/2764727

Written by stewart henderson

April 18, 2020 at 1:18 pm

the science of Covid-19: global collaboration and broad-spectrum antivirals

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not claiming I understand this diagram …. yet

An interesting article in the New Yorker has introduced me to David Ho, whose work on AIDS in the eighties and nineties led Time magazine to name him its person of the year in 1996. Almost forty years on from reporting the first AIDS cases in 1981, Ho continues to fight the disease, which still kills a million people a year. That might shock some people, but out of sight, out of mind, it’s not happening here. Covid-19 has killed about 100,000 in a few months, all over the world, and the global curve is no cause for complacency, to put it mildly. And you can catch it just by breathing. And many researchers have said this is just a rehearsal for the big one. Well, let’s just deal with this one first, and learn from it. People like David Ho are on the front line, desperately seeking new, comprehensive antiviral solutions.

Drug companies, however, have tended to invest in chronic viral infections, such as AIDS and hepatitis B, rather than acute ones which do deadly damage then disappear, as did SARS and MERS. Both these infections were gone before a vaccine was fully developed, so there would have been no return on investment. Many researchers are pointing out that it’s therefore not a task suited to private enterprise, which tends to be competitive rather than collaborative, as well as having other priorities. This article linked to the Johns Hopkins website focuses on some of the problems related to lack of co-ordination regarding messaging and possible treatments. The pandemic is global, it obviously disregards boundaries, so we need to be less nationalistic and proprietorial and more humanistic in response. To quote the article,

As a first step, the biomedical community needs to insist on consistent use of central registries of clinical studies and on early sharing of complete details of both successful and failed studies, and not withhold important scientific evidence as proprietary information.

If adequate testing shows promising results, that information needs to be shared immediately, in a way that can be analysed and the testing replicated. This of course includes methods of analysing and tracking the virus and its proteins. Developing treatments at the moment is tricky due to the apparently huge variation in the responses to infection – from being completely asymptomatic to the other extreme. Drugs may have to vary in toxicity to treat these varying symptoms. With effective collaboration, rigorous testing of treatments doesn’t have to be a slow process – at least it can can be much quicker than it has been before.

Meanwhile, not all health authorities are on the same page regarding physical distancing measures. The USA’s Centers for Disease Control and Prevention (CDC), a federal government agency, has sparked controversy by allowing asymptomatic ‘critical infrastructure’ workers who’ve been exposed to SARS-CoV-2 to return to work under strict guidelines. It’s noteworthy that the US federal government has been pushing a rapid return-to-work scenario for some weeks, though it has often been inconsistent in its messaging. Asymptomatic carriers of the virus are officially estimated at about 25%, though some experts argue that the figure could be as high as 50%. Individuals can also be presymptomatic rather than asymptomatic, and this is difficult to identify due to the variability of the onset of symptoms. In any case there is still the possibility of spread from either group. The lack of precise evidence about asymptomatic transmission tends to make most experts err on the side of reducing the risk. Also, according to this paper, distancing measures have likely reduced the spread of seasonal influenza (particularly virulent this season), especially in countries such as Japan, where there was an early awareness of Covid-19 prevention measures.

Not surprisingly, the advent of this virus, which has brought with it a return of all the unheeded warnings of the past decade or more, has inspired and spurred a lot of interesting new research and approaches to dealing with viruses – long regarded as the most potentially dangerous pathogens out there. The New Yorker article relates some of the history, from the first antiviral drug to be marketed in the early sixties, ‘a repurposed anti-cancer drug put to use as a topical treatment for a herpes infection that attacked the cornea’, to drugs such as ribavirin and acyclovir in the seventies, and then on to breakthroughs in the eighties in the battle against HIV/AIDS. There will be more breakthroughs with this new pandemic, but the point is that the threat of new viral outbreaks has been touted for years, but antiviral research gets limited funding and all but shuts down when there’s no clear and present danger. The current pandemic may or may not convince us that work on broad-spectrum antivirals needs to be ongoing and cannot be subject to private market fluctuations or whims.

Lest I lead people into thinking I have much of a clue as to what broad-spectrum antivirals are, let me assure you… but there’s something of a clue in the name. It should be about finding some common factor in the invasive behaviour of viruses, and what they do to replicate once inside, and using that knowledge to develop or activate agents that will shut down or act against such behaviour. A website called Creative Biolabs has a bit more to say on its front page:

By inhibiting virus replication/reproduction in infected cells or improving cellular defense system, these broad-spectrum antiviral drugs are effective in the clinical treatment of viral infection, as well as for SARS-CoV-2 infection. Mechanisms drugs with broad-spectrum SARS-CoV-2 antiviral activities mainly involve:

– Inhibiting or killing the virus directly

– Interference with virus attachment/membrane fusion

– Preventing the virus from penetrating into cells

– Inhibiting the biosynthesis of the virus

– Inhibiting the assembly and release of the virus

– Enhancing the antiviral ability of the host

From what I can gather, Creative Biolabs is a bonafide life-science company servicing various private pharmaceutical companies as well as government agencies. So hopefully I can learn, from their website and many others, more about broad-spectrum antivirals and any other possible treatments and ventures that might reduce the threat of viral epidemics.

References

https://www.newyorker.com/magazine/2020/04/13/the-quest-for-a-pandemic-pill

https://www.cdc.gov/coronavirus/2019-ncov/community/critical-workers/implementing-safety-practices.html

https://www.healthline.com/health-news/cdc-gives-advice-on-how-to-go-back-to-work-what-the-experts-say#The-bottom-line

https://jamanetwork.com/journals/jama/fullarticle/2764657

https://en.wikipedia.org/wiki/Ribavirin

https://en.wikipedia.org/wiki/Aciclovir

https://sars-cov-2.creative-biolabs.com/broad-spectrum-SARS-CoV-2-antiviral-drug-discovery-service.htm?gclid=CjwKCAjw1cX0BRBmEiwAy9tKHmF2vy7hDpFiRnaLLBvtlpRNy8T5PVg0eAe7OmkX-Zpmc3MIQfHYoBoCBD4QAvD_BwE

https://en.wikipedia.org/wiki/Creative_Biolabs

Written by stewart henderson

April 12, 2020 at 4:03 pm

Posted in antivirals, covid19, virology

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