TrumpLyftAlles | 8 points
Prevuew of study Ivermectin antiviral effectiveness (Argentina 2020-08-19) Youtubehttps://www.youtube.com/watch?v=AAQ1WYjj3Co&feature=youtu.be
[-] TrumpLyftAlles | 2 points
SHIT I introduced a type in the title because I didn't like PREVIEW (shouting). Dammit.
[-] RiskyBiscuit-999 | 3 points
It’s ok we know what you meant!!
[-] TrumpLyftAlles | 1 points
The link takes you to a youtube video posted on 2020-09-19. It was previously posted on 2020-08-19 in Spanish only; this version has English subtitles, which I extracted and posted below. TLATODO: Insert images
PREVIEW of study Ivermectin antiviral effectiveness Argentina
Dr Alejandro Krolewiecki speaking.
Thanks to Héctor Casado, to the Faculty of Engineering and through Liz Nallim and the rector for this invitation to show what we are doing at the Oran Institute.
In a few minutes I propose to present some data that we have already begun to collect about the evaluation of Ivermectin and its potential use in the treatment of covid-19, showing some methodological aspects and some characteristics of drugs with antiviral capacity.
The first question we must answer is whether Ivermectin has antiviral activity against covid and this because, a few months ago, a study was published showing an inhibition of the sars-cov-2 virus in Vero cells in-vitro, in which through a single addition of the drug almost complete reductions were achieved within 48 hours, with an average concentration of 2 to 3 micromoles. And what was found, the image at the bottom, which is extracted from this work, it is a blockage in the importines that move the virus from the cytoplasm to the nucleus of cells. Now this is an in-vitro work.
For those who are not familiar with Ivermectin, It is a drug that our team has been working on for several years, because it is an anthelmintic, that is, it is a drug against helminth parasites, with very wide use, both in human and veterinary medicine. It is the drug of choice for diseases such as: onchocerciasis, scabies, strongyloidiasis, and is being studied for the control of malaria, for its action against mosquitoes. It is a drug of very wide use and and we can see in the upper tables as within the WHO drug donation programs more than 850 million tablets have been distributed, and these are official WHO publications, year by year growing for the treatment of these diseases, river blindness and also, as we see in the photo below they are from Tartagal, for the control of intestinal parasites, which we have been working on.
This study from the Australian group, eventual in-vitro activity, found us already working and with enough developed knowledge. So what happened once this work was published on Vero cells with Ivermectin?
Two currents of thought appeared: one that posited that Ivermectin is the solution for the pandemic and the other opposite saying that the dose needed to control the virus, based on what was seen in those in-vitro experiments, it was too high and also toxic. And, from that, they literally appeared countless works, with publications of anecdotal use, retrospective reports and even fraudulent works, modeling, recommendations for use, recommendations for not use, letters with concerns, skepticism and much criticism, all published without data.
Faced with this, we understood that this in-vitro model posed two important limitations for reaching definitive conclusions: the first is that being a cell culture did not consider the host's immune response, and the second is that it did not take into account a balance between drug concentrations and amounts versus viral load. Given this, we decided to collect data and try to create a proof of concept, for which we hear the call made by the "Ministry of Science and Technology" for the development of projects related to the pandemic and with this in mind, we designed a project who will try to give the first answers and the first thing we meet is that there are very great challenges for the evaluation of antiviral activity regarding acute respiratory infections.
For this we use already published literature, especially on influenza and the difficulties we encountered were that these diseases have very short incubation periods and the symptoms come very fast.
This situation presents limitations for the intervention, because at the time of arrival of patients to the hospital, in most cases the "peak" of the amount of virus has already passed. Therefore, there is little opportunity to measure the effect before entering the immune control phase of the disease. In addition, the symptom scores are not very representative, because according to the host immune response, a person may present a state completely asymptomatic, slightly asymptomatic or very symptomatic, with which, directly measuring symptom scores may not be representative of the antiviral activity of a drug. And finally symptoms and complications are often unrelated to peak viral load and, in many cases, these complications appear when the virus is no longer and I only leave the sequels, as we are seeing right now with complex covid patients.
Faced with this we consider a project that had characteristics of: recruit patients in the early stage of infection, use virological indicators and the use of controls. For this we use the influenza model for viral dynamics, in which the ascent is measured, with a diagram similar to that used in pharmacology, to see at what point in time the viral load peak is reached and from there determine what the area is under the viral load curve. And what is very important, I will show it then what is the "viral decay", ie the fall the slope of the virus elimination fall, beyond of the use of medication and trying to impact on these values with medication.
So, taking this model, we designed a clinical trial. And for that, we needed a specific and predictable measurement about the amount of virus. As part of the consortium that we put together, led by the Institute of Oran, we partner with the Virology Laboratory of the Hospital Garrahan de Buenos Aires, to develop, based on its experience, a viral load meter. This differs from diagnostic tests that are commonly used by PCR, is that it has been designed to present quantitative and non-qualitative results unlike the usual diagnostic tests. When taking a test with international quantification standards, allows us a linearity much more precise, with which, the value that it throws us has a better relation with the other values, allowing to better measure differences between them, in a better way than a quantitative measurement test would.
This test that has been developed, allow us to measure with a dynamic range, using logarithmic base 10 1 to 8, that is, from 10 copies to several million copies, with high precision, high efficiency and also with the ability to measure the amount of human RNA and DNA, to determine what is the presence of the sample of different types of RNA. With this tool developed, we move on to the other component which is to try to determine the concentrations of Ivermectin in tissue. And for this the CIVERTAN Tandil group also participates in this project, the veterinary group, with a very large experience in Ivermectin and with which our group has had many works together.
One of the things we did, as groundwork for the clinical trial, was to do animal experiments using the pig model, that ended a few weeks ago, with which we wanted to see if, when administering the drug with the expected plasma concentrations and that we know of other projects, try to determine and predict how much of this drug is reached in tissues that are of particular importance in what has to do with the infection by covid19, i.e. the nasopharyngeal mucosa (the primary infection site) and the lung, a site of particular importance due to the complications it ends up having.
And what we determined, from these experiments in the pig model, is that they are achieved with the usual oral dose, 0.2 milligrams per kilogram that is 200 micrograms / kilo, at 6 hours, higher concentrations are reached than in plasma, both the lung and the nasopharynx mucosa. It is worth clarifying that the pig model is not the most similar to the human because it has a larger volume of drug distribution, but if the bovine model is similar to the human, in which they had already been made some experiments and showed (at least in lung) concentrations higher than in plasma.
The third element is that, for some years, our group has been working with high doses, and for which other groups such as Smit in Africa have completed studies with triple the dose tested jumping from 200 to 600 micrograms / kg for three days, with good safety indicators.
Our group completed, together with the group from the National Autonomous University of Honduras, other works last year, as you can see in the photos that I show you here, works in children for the treatment of T. trichiura with very good safety data as well and in a collaboration with groups from Spain, France, Italy and Cameroon, we have recently published a systematic review, that in January we have been able to publish, doing a meta-analysis about the safety of Ivermectin at higher than usual doses, with favorable measurement results safety ratio. All this invited us to try to take advantage of this knowledge and apply it in this clinical trial.
[Too long, continued in reply]
[-] TrumpLyftAlles | 2 points
As we had experience with three days, we modeled together with the CIVETAN group from Tandil what would happen with five days of administration, and what we got was that the maximum drug concentration did not reach accumulation levels, with which the a priori safety would be as good as in dosages of 3 days. Starting from this we write a clinical trial, we present it to different ethics committees and after it got approved, we started doing it.
Basically, this clinical trial is based on trying to show a proof of concept about the eventual antiviral effect of Ivermectin against this particular virus (SARS-CoV-2) having virological indicators, incorporating patients with early disease and early in relative terms, because we define five days from the onset of symptoms and, for example, in influenza work, there are studies that are up to 36 hours from the onset of symptoms and also 72 hours. We decided to incorporate symptomatic patients, without requiring intensive therapy, although they need oxygen supplementation.
We maximize the doses, as it is a proof of concept study, to the one with available security data, which are the ones I just showed you, and with drug exposure measurement. The design of a prospective study, open, randomized and controlled. In what has to do with open I mean that patients know whether they take the medication or not, but those who are blind to the treatment received are those in charge of measuring the primary objective, which is the people at Garrahan Hospital measuring viral loads. When the samples are received at Garrahan Hospital, the operator does not know if it comes from a patient who received treatment or an untreated control.
Secondary objectives as always are: security, but also evolution of symptoms, serological response and some PK / PD relationship.
Based on what we did as a statistical calculation to work the proof of concept we need 30 patients treated and 15 controls, with a 2 to 1 randomization. We incorporated adult patients from 18 to 69 years old, as I told you before, up to 5 days of symptoms and that they were not receiving other drugs with potential antiviral activity.
As of today there are four centers open and recruiting in Buenos Aires and we decided to start it in Buenos Aires because that is where, at the time of initiating the design, writing and approval of the studies, the largest number of cases was concentrated and as of today we have 37 patients recruited. Security has been good, with two cases of mild "rash" that we cannot assure that they are related to the treatment but neither can we rule it out and a case of hyponatremia that was reversible. Some very basic data And this the truth is that it is data that we are collecting and that I am gathering day by day, we have a mean viral load of 5 logarithms in the control group against almost 5 in the Ivermectin group.
As you can see, the day of onset of symptoms is around three days in both groups. And in the very preliminary data, there we begin to find very interesting data.
For a moment, forget about the red curve of the controls And just look at the green curve and see the decrease in viral load. And if I were just showing you this curve without the controls, any of you could tell me (and I assure you) that the drug is being very effective. However, when we compare it With the controls, the two groups are behaving in a way relatively similar. Hence, control is so important, since it allows us draw conclusions and that is precisely the group of "untreated". It is also relevant to see how, in this "untreated" group, as day by day the viral load is controlling itself. These are data, I repeat, very preliminary. This is the average of all cases from each of the groups. However we did some analysis a little deeper into this, and before I move on, I show you how, For the construction of our hypothesis, we took the little available literature.
In this work published in the Lancet a few months ago, we were able to verify that it occurs, in blue and red, they are just different data sources in untreated patients, either saliva or endotracheal aspirates, as we could now, with our cases, go reproducing what the literature was showing. And at this point we are probably gathering more information than other groups as regards viral load measured with quantitative methodologies. So another thing we did was measure the viral load reduction day by day and what we find here, we begin to find that, With these data (I repeat) PRELIMINARY, it is that the reduction of viral load in the Ivermectin groups, at each measurement point, it has been a little deeper in contrast to the control groups.
A limitation that we are having, and it can be seen in the box plots that are to our right, it is that there is a large dispersion of viral loads between patients. I can tell you that we have had patients with a baseline viral load count of 200-300 copies and others with more than 10 million, that is, there is a very important variability. And where there is also a high variability and this is data that we already had from our pharmacokinetic studies, it is that Ivermectin is characterized for having a great variability in the maximum concentrations (Cmax) between different individuals.
But I show you this because taking advantage of this information, we did another type of analysis. This analysis that I show you here is for the pharmacokinetic and pharmacodynamic relationship that it is, seeing that slope decrease in viruses, block that and check for any associations between the maximum Ivermectin concentration reached versus this slope of fall.
And even with these few cases that we have analyzable, we already find a high relationship and a highly significant association between those cases that reach a higher concentration of ivermectin in plasma, achieve higher virus clearance, the results of which we need to confirm. So to finish, the preliminary data that we are finding justify completing the study, both because security is good, and because there are trends that would show that there is an activity of the drug against the virus.
The need to have control groups for this type of study was proven and this I think is extensive, not only to Ivermectin, but (due to the characteristics of the virus) to any study that is done on drugs to enhance antiviral activity against this virus.
The results indicate that Antiviral therapies have an early-stage role in infection. Confirmation of the trends we have should be accompanied by confirmatory studies with clinical indicators. These results are optimistic and the other thing that is important, is that there is a very high productive capacity to satisfy the demand for the drug.
To finish, I want to bring you this, which does not come from literature and of medical or biological science and has to do with a problem that we are finding in the middle of the pandemic with many of the eventual treatments. And it has to do with this sociology theory, which has to do with diffusion of innovations and what we are finding in these therapies is that early adopters of these new technologies, in many cases they are ahead of the innovators and are adopting many therapies and recommendations are being reached before developments and science allows us to say that a treatment works or does not work.
This complicates recommendations, confuses people and makes the creation of evidence more complex, because if something it is already recommended it is difficult to implement a research test using control groups. So this theory also shows us and in the literature what shows that the most common errors, in general and not necessarily applied to the development of medical technologies, is to assume that evidence matters to adopters, that publishing innovations before its validation tends to confuse, that communicators are often misused and in that, we researchers are often bad communicators and that proposing unique solutions to problems is often the wrong way.
So, to close, I have to thank many groups and many people, in the consortium that we are working on this, our group is included in the National University of Salta, but also the CIVETAN Tandil, the Garrahan Hospital, the CEMIC of Buenos Aires, the Faculty of Medicine of the National University of La Plata, the Elea-Phoenix Laboratory, the National University of Quilmes, the Muñiz Hospital, the Mundo Sano Foundation and finally to thank the Science and Technology Agency and the Elea Laboratory, which are the funders of this project.
[-] ibexrecurve | 2 points
Thanks for the recap so I didn't have to watch the video!
[-] Haitchpeasauce | 2 points | Sep 23 2020 06:48:14
Thank you for posting the translated transcription.
It is good that they take into account time from onset of symptoms and are cognizant that peak viral load is reached around day 5 from onset (around day 8 from exposure). Timing is essential when we discuss any antiviral therapy for COVID-19, and this virus is extremely replication competent. Earlier is better, prophylaxis is best. In the same way that it is pointless administering Remdesivir when a patient is in the severe immune dysfunction stage, similarly Ivermectin will have less effect when given too late. However IVM may continue to be beneficial with binding to viral proteins, anti-thrombotic or anti-inflammatory effects - something Remdesivir can't do as a nucleoside analog. I would like to see a study combining IVM with other beneficial therapies like steroid, heparin, statins for the severe O2/vented cases.
Interesting thought to consider: RT-PCR might not be the best measure of viral clearance as a measure of success. Naso-pharyngeal swab will pick up neutralised virus and RNA fragments from phagocytosed virus, which will return a positive result. A better way would be to culture the virus from the swab and measure time to negative culture, as well as measure time to resolution of symptoms.
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[-] TrumpLyftAlles | 1 points | Sep 23 2020 08:02:06
A better way would be to culture the virus from the swab and measure time to negative culture, as well as measure time to resolution of symptoms.
I was with you all the way -- you know your stuff! -- until the part I quoted.
You want to put ivermectin in a test tube with a swab of virus-containing mucus? Wouldn't that be invalid because it cuts out the body's immune response? It's a throwback to the Monash 48 hours in vitro study.
Unless I misunderstand. It's very late, and I'm probably missing on 3 of my 4 cylinders.
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[-] Haitchpeasauce | 2 points | Sep 23 2020 09:28:53
Not quite, that would be the same as an in vitro study. I'm suggesting that PCR doesn't indicate the presence of viable virus. You can get positive result and not have replicating viruses in the body. Since the measure we are after is the impact on viral load, PCR isn't actually measuring this.
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