Archive for the ‘drugs’ Category
adult ADHD – what’s the buzz?
Jacinta: So this is a commissioned piece, sort of, by someone who wants us to look into this disorder (attention deficit hyperactivity disorder, in full), for our sakes and of course for the sake of humanity.
Canto: Sounds like a first world issue to me.
Jacinta: Okay consider yourself lucky you don’t have to scrounge around rubbish heaps for a living, or travel miles on a half-dead donkey to see a medico, or dodge government bullets because you’re an outspoken female…
Canto: Okay okay. So we know that diagnoses of adult ADHD have risen substantially in recent years, in the WEIRD* world, along with autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, PTSD, chronic fatigue syndrome, and others. A lot of work is being created for clinical psychologists, and the waiting lists are getting longer.
Jacinta: So we’ve started by watching a couple of videos, one from CNBC in the US, another from the ABC in Australia. And a few points here about research and reliable info. Avoid social media! And for the most part avoid commercial news and info networks, which are privately owned and often have a commercial-financial agenda. The most reliable sources in the WEIRD world are generally government subsidised and mandated sites (the ABC in Australia, the BBC in Britain, PBS and NPR in the USA, DW (Deutsche Welle) in Germany, France TV and Radio France, for example).
Canto: Well, we’ve broken that rule by starting with this video from CNBC, but it does give a good overview of the symptoms, via field professionals such as Dr Leonard Adler, director of an adult ADHD programme at NYU. The symptoms are divided into two types, those associated with inattentiveness and with hyperactivity, though there are obvious crossovers. Under each type heading, nine more or less connected symptoms are described. For example, symptoms of inattentiveness include ‘forgetfulness in daily activities’, ‘failure to finish tasks’ and ‘losing important things’, and under hyperactivity comes ‘interrupting others’ or ‘trouble with turn-taking’, and ‘being always ‘on the go”. Apparently you need at least five of the nine symptoms in either category to be diagnosed with ADHD, at least in the USA. Personally, I can relate to all of the symptoms some of the time. All of this, by the way, comes from the famous, or infamous, DSM-5, the 5th edition of the diagnostic and statistical manual of mental disorders.
Jacinta: So you may be skeptical, but on the question posed throughout this video: ‘Is ADHD on the rise or is there simply a rise in diagnoses?’, my answer would be ‘yes there is a rise in diagnoses’, but not for the cynical reason you seem to favour – that it’s all about lining the pockets of psychiatrists. Remember we’ve been studying Freud and the post-Freudians, who pioneered the uncovering of disorders due to childhood trauma, sexual repression, unconscious guilt and the like, all in a groping, hit-and-miss sort of way, before anything much was known of neurology, endocrinology or genetics. Now in the 21st century, we can make connections between genetics, family and personal histories and brain processes in a more scientific way – at least slightly. There’s a long way to go. And this has led us to the reality of ongoing behavioural disorders, where previously people were just considered in vague terms as oddballs, eccentrics, psychos, losers or pains in the arse.
Canto: Steady on. I understand that it’s not about having some symptoms sometimes, which we all do, it’s about having a number of them to a degree that it becomes debilitating. And, as more than one expert has said, what’s frustrating to these sufferers is that sometimes, with certain specific tasks, or aspects of their professional lives, they perform perfectly well on a regular basis, while the rest of their lives are a mess of procrastination, disorganisation, impulsivity and the like. But the more I learn about the disorder, the more I wonder about treatment. These symptoms seem so multi-faceted, I can’t imagine how they can be dealt with though drugs. I can’t even begin to imagine the brain chemistry behind such varied behaviour. Surely there’s no medication that’s going to make you more organised or a better listener – never mind both at the same time.
Jacinta: Well, and yet it all has to be about brain chemistry and signalling. What else can it be? And patterns of behaviour – that’s to say, patterns of brain signalling, that have become habitual since childhood. In response to family dynamics and such. No free will, remember. Much that I’ve heard so far indicates that it runs in families. And of course there are prescription medications for the disorder. So we have to look at effectiveness (method of action), cost, availability and any side-effects or downsides. And then there are other treatments such as cognitive behavioural therapy.
Canto: Yeah I’ve heard that medications are expensive, and I doubt that therapy comes cheaply either. But let’s look at the brain of ADHD sufferers and what can be done medically, if anything, to alter it.
Jacinta: Well Britain’s National Health Service has this to say:
Research has identified a number of possible differences in the brains of people with ADHD from those without the condition, although the exact significance of these is not clear. For example, studies involving brain scans have suggested that certain areas of the brain may be smaller in people with ADHD, whereas other areas may be larger. Other studies have suggested that people with ADHD may have an imbalance in the level of neurotransmitters in the brain, or that these chemicals may not work properly.
Canto: Wow, that’s really informative. I like the bit about smaller or larger. Are they talking about brains or dicks? I mean, really…
Jacinta: Hmm. We need to look at research papers. And one thing I note is that researchers don’t readily distinguish ‘Adult ADHD’ because it’s understood to have emerged in childhood, though symptoms might have changed over time. In fact many children may ‘get over it’. Dr Judy Ho, in an interview on ADHD in the USA, quoted that childhood ADHD affects some 5% of the population but the adult version affects some 2.5%, which seems to make sense.
Canto: Well, having checked Google Scholar, I don’t see much in the way of recent research that jumps out. Sheeting home the various symptoms of the disorder to brain chemistry is really difficult…
Jacinta: Well since they do have medications on the market – the NHS describes 5 types- methylphenidate, lisdexamfetamine, dexamfetamine, atomoxetine and guanfacine – and these presumably work on brain chemistry, they must have some idea. ..
Canto: Well these are generally amfetamines, which act as stimulants, speeding up brain functions through the release of hormones and monoamine neurotransmitters such as dopamine and norepinephrine, and this kind of ‘upper’ activity would help with the disorder most associated with ADHD, which is depression, though there are definite downsides related to prolonged use or overuse. Combining, and possibly replacing, such medications with more behavioural-analytical treatments such as Cognitive Behavioural Therapy might be an idea, if there were enough decent therapists around, and if it was affordable, but it’s all a bit hit and miss.
Jacinta: You have to distinguish between proximal causes and ultimate causes. The proximal causes of most of these conditions is hormone levels and neurotransmitter activity, but that says nothing about why those levels are higher in some people than in others. If you don’t know the underlying causes, you’re just treating symptoms – drugging people to behave ‘normally’. But those underlying causes are generally fiendishly difficult to deal with – for example how can you cure an abused childhood, or damage done in the womb?
Canto: But many people with ADHD may just want to be ‘normalised’, to a degree. They know that what’s been done to them can’t be undone, but they just might want those symptoms reduced, to concentrate better, to be more organised, to calm down, whatever.
Jacinta: And given that we’re not that good at tolerating differences, why not give people drugs so they can all be the same, at least tolerably so….
*western ,educated,industrial,rich,democratic
References
ADD/ADHD – What is Attention Deficit Hyperactivity Disorder? (video)
https://www.nhs.uk/conditions/attention-deficit-hyperactivity-disorder-adhd/treatment/
https://www.cdc.gov/ncbddd/adhd/index.html
more oxytocin fantasies: an interminable conversation 3
not sure if this measures a significant difference
Canto: So, as it turns out, the bonobo-oxytocin connection is all the rage on the internet. I mean, there are at least two articles on it. Here’s a quote from a PubMed article called ‘Divergent effects of oxytocin on eye contact in bonobos and chimpanzees’:
Previous studies have shown that bonobos and chimpanzees, humans’ two closest relatives, demonstrate considerable behavioral differences, including that bonobos look more at others’ eyes than chimpanzees. Oxytocin is known to increase attention to another’s eyes in many mammalian species (e.g. dogs, monkeys, and humans), yet this effect has not been tested in any nonhuman great ape species.
Jacinta: Hmm, so how do they know this? Presumably they’ve dosed subjects with oxytocin and measured their eye contact against controls?
Canto: No no, they know that bonobos have more eye contact than chimps, simply from observation. So they might infer from this that bonobos produce more oxytocin naturally than chimps…
Jacinta: So do women produce more oxytocin than men I wonder? I presume women make more eye contact than men.
Canto: Well in this study they dosed both bonobos and chimps with oxytocin, and the effect – more eye contact – was greater in bonobos than chimps. In fact, chimps even tended to avoid eye contact when shown images of conspecifics.
Jacinta: So, it’s a matter of interplay between this hormone/neurotransmitter and social conditioning?
Canto: Maybe, but you’d think that an increase in this supposedly touchy-feely hormone would act against social conditioning. Isn’t this the point of that drug, ecstacy? That it reduces social inhibitions… But presumably nothing is ever so simple. Being poor, I only have access to the abstract of this paper, but another abstract, which looks at the effects of oxytocin and vasopressin on chimps, describes them as neuropeptides, just to confuse matters. The abstract also refers to about a dozen brain regions, as well as specific oxytocin and vasopressin receptors, so it gets pretty complicated.
Jacinta: Okay, vasopressin… from Wikipedia:
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP), or argipressin, is a hormone synthesised from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular hypertonicity (hyperosmolality). AVP has two major functions… etc etc
Canto: Okay thanks for that, let’s stick with oxytocin for now. It’s produced in the hypothalamus, a smallish region buried deep within the brain, just below the larger thalamus and above the even smaller amygdala. It releases and manages a variety of hormones. Brain signals are sent to the hypothalamus, exciting it to release oxytocin and other hormones, which are secreted into the bloodstream by the posterior pituitary gland….
Jacinta: Can you tell me what oxytocin is actually made of? Its structure? The term ‘hormone’ is just a black box to me.
Canto: Okay, here’s a diagram of oxytocin to try and make sense of:
It’s a polypeptide. A peptide is basically an amino acid chain. FYI:
An amino acid is an organic molecule that is made up of a basic amino group (−NH2), an acidic carboxyl group (−COOH), and an organic R group (or side chain) that is unique to each amino acid. The term amino acid is short for α-amino [alpha-amino] carboxylic acid.
Jacinta: So these are coded for, ultimately, by genes?
Canto: Yes, we’re heading backwards here, but each amino acid is encoded by a sequence of three of the four base pairs in our DNA. Anyway oxytocin, among other things is sometimes given to women while in labour. It helps with the contractions apparently. I’ve also heard that the recreational drug ‘ecstasy’, or MDMA, works essentially by releasing oxytocin.
Jacinta: It just so happens I’ve found an interesting 2014 paper published in Neuropsychopharmacology, my new favourite journal, called ‘Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing’, and here’s a quote from the abstract:
Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.
Canto: That is interesting. If that finding can be replicated, I’d say forget the MDMA, dose people with oxytocin. A small but significant increase in feelings of sociability might just be enough to transform our human world.
Jacinta: Hmmm. Small but significant – that sounds a mite contradictory.
Canto: Not the same as significantly small. That slightly significant dose, administered to Messrs Pudding and Pingpong and their enablers, might’ve saved the lives of many Ukrainians, Uyghurs and advocates of multiculturalism, democracy, feminism and other wild and woolly notions. And it doesn’t really transform characters, it just softens their edges.
Jacinta: Yes it’s a nice fantasy – more productive than butchering the butchers, a fantasy I occasionally indulge in. But not workable really.
Canto: Why not? We dosed petrol with lead, and look at how that worked out. It certainly had an effect. In Japan they still use radium baths (at very low levels) for health purposes, even claiming it as a cure for cancer. I’m not sure if oxytocin baths can ever be a thing, but if so I’m sure there will be early adopters.
Jacinta: Well, it’s good to think positively. Oxytocin is often thought of as a bonding hormone between mother and child. The key would be to ensure it facilitates a more general bonding: to cause Mr Pingpong, for example, to see Uyghur, Tibetan, Yi, Limi, and all the other non-Han ethnicities in China as his sisters – or lovers even, revolting as that would be to those peoples.
Canto: Better than being their oppressors and exterminators.
Jacinta: Slightly. But I wonder, quite seriously, if, assuming such a dose of bonding could be effectuated, we could still function as the sometimes rational, problem-solving, highly creative species we indubitably are. Would there be a price to pay for all that oxytocin? And how would this affect all those other hormones and neurotransmitters and all their myriad effects? Humans are notorious for causing extra problems with their solutions, e.g lead, DDT, etc etc.
Canto: Well, there’s no need to worry about the fallout from this solution as yet. I just googled Putin and oxytocin together and came up empty. Obviously we’re way ahead of the curve.
Jacinta: Haha, it’s not a curve these days, it’s a pivot. Get with the program!
References
https://pubmed.ncbi.nlm.nih.gov/33388536/
https://www.yourhormones.info/hormones/oxytocin/
https://www.acs.org/content/acs/en/molecule-of-the-week/archive/o/oxytocin.html
https://www.britannica.com/science/amino-acid
https://www.wsj.com/articles/BL-JRTB-11551
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 – 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: hopes, failures, solutions
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.nejm.org/doi/full/10.1056/NEJMp2005755?query=recirc_artType_railA_article