RL648_81: Synthesis and Evaluation of Potent KCNQ2/3-specific Channel Activators

Discussion in 'Research News' started by attheedgeofscience, Mar 29, 2016.

    1. Kotve
      Grumpy

      Kotve Member

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      So it does for me, but at a point of a company what is cheaper. 1. finding how to find a fix for all causes or 2. Find a fix for your neck but then forget the 90% of the rest.
       
    2. Silvio Sabo
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      Silvio Sabo Member Benefactor

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      No not really. You test your compound on cells in a petri dish first (usually you use yeast but sometimes even human cells, human cells are harder to work with since they aren't meant to survive outside of the body so you have to supply them with serum that contains lots of stuff like growth factors and so on). Or perhaps even a simple organism like worms or flies (I used to work with worms in a lab by the way).

      Here you generally test lots of different compounds and there is a lot of trial and error perfecting things. But it's not as time consuming as human trials and you don't have to ask for approval before you do something. If you want to test something you just do it. In the case with worms you can pretty much complete an experiment in less than a week. You can perform hundreds of tests in matter of months on single cells or worms. Worms are really great to work with since they have a generation length of just 3-4 days.

      Typically if you work with a simple organism you would first create mutants that are sick and then try your compounds on them and see if they are rescued.

      I actually managed to perform about 10 different experiments - including a life span experiment that took over a month - in the lab regarding statins with statin resistant mutant worms that we created in less then 4 months when I worked on my thesis.

      Then when you have found something that you have a good reason to believe works you test it on mice (this is a little more time consuming). And then after that you apply to go to trials and here is where it gets interesting.

      However before all of this you have to have a compound to test. And that is not a straightforward thing to do.

      You do know that there are other primates than chimps? There are species of monkeys that are a lot smaller and cheaper to use than chimps and they are still more similar to us than mice. And some primates can also be trained to respond to simple questions because of their superior intelligence compared to both mice and dogs.

      And by the way, the reason there aren't so many chimps is because they are pretty much useless to us. So we aren't breading them. But if we started to there would be a lot more of them. Just think of how many cows there are in the world. And they are a lot bigger and eat a lot more.

      I'm not saying that pre-screening should be done on primates but before human trials you can do a test on primates and probably save years of human trials on a drug that is pretty much useless. The tests on animals are usually not regulated the same way as human trials and should therefore take a lot less time (read what I wrote above). The time consuming part is not the actual testing but the bureaucracy of getting approval for going from one phase to the next and then the actual approval by the FDA and sometimes also getting candidates for the trials. And of course the thinking process, it basically boils down to brain work to try solving the puzzle.

      If we look at the case of AUT0063 they probably could have found out it wasn't working before even going to phase I but instead could have focused on the next compound instead of wasting years and a lot of money.
       
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    3. beeeep

      beeeep Member

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      I didn't mean when screening molecules, but before entering phase I in humans. You have to do some tests, and as far as I know for toxicity tests you must use at least two different species.

      Wikipdedia says: "Importantly, the regulatory guidelines of FDA, EMA and other similar international and regional authorities usually require safety testing in at least two mammalian species, including one non-rodent species, prior to human trials authorization."

      Really? I thought there were only two species on earth: Chimps with fur and Chimps without fur (called Humans). ;)
      But honestly, This was in reply to your quote "But I have the opinion that it's far better that a few chimps suffer then hundreds of millions of people". So, that's where the Chimps came from. I'm well aware of other primates (as probably everybody is).
       
    4. Silvio Sabo
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      Silvio Sabo Member Benefactor

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      Toxicity testing in two species is not what I would consider as "tons of tests". The actual testing is straightforward business. This is not something that takes years to do!
       
    5. linearb
      Psychedelic

      linearb Member Benefactor Hall of Fame

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      It strikes me as a little odd to be considering taking an extremely expensive research molecule, with all the risks that come along with being a guinea pig for a drug that's never been tested in humans, when you haven't even attempted RTG which is at least well documented, with its risks assessed.

      RL may have a better side effects profile... or it might not... or it might not work at all.

      I also don't think the "high dose" of RTG is a reasonable concern; if RL is significantly more potent, then the risks appear at lower doses. Think about something like alprazolam (Xanax) compared to diazepam (Valium); Xanax is about 10-20 times more potent. This doesn't make it safer, even though the affective dose is much lower. In fact, in the case of benzo drugs, the more potent they are, the tighter they couple with their receptor, and this seems to cause worse problems with dependence and discontinuation effects.

      All of which is to say, having studied the Kv drugs in mild detail, and having dabbled with RTG... RTG alarms me far less than RL.

      And, with an advance apology for snark, the idea that anyone on this forum could do useful experiments on animals, is laughable.
       
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    6. Bobby B
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      Bobby B Member Benefactor

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      "Thanos Tzounopoulos, Ph.D., Endowed Chair in Auditory Physiology, associate professor of otolaryngology and member of the Auditory Research Group, University of Pittsburgh School of Medicine" and Peter Wipf, Ph.D.,

      Sorry but these two Scientist together know a lot more than you about how drugs work and if they say it will work much better with less sides - then I see no reasons to not believe them.

      Professor T was also on the SF0034 team so he has been studying the subject for some time



      Its okay to be questioning everything and doubting and being so negative and such ..but I would take the word of a few Scientists with Phd and actual experience over yours in this matter.

      @linearb

      Unless you can prove you have relevant background in the field of epilepsy drug development.

      Its not like they are going to sell us RL_81 tomorrow and get filthy rich so they don't have to lie to us.

      The issue is what happens after t- as we saw his email reply..its "out of his hands" so the actual testing process is going to take years if ever..and yes animal testing has been detailed in studies it may not be as good as a real University facility but its certainly a lot better than nothing at all.

      We can also use a primate from day 1 if we want - we don't need approval !..just money for the animal and the first batch.

      They are probably only going to use rats at first so our primate tests will be far better for a drug affecting the brain.
       
    7. Aussie Lea
      Dramaqueen

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      @Bobby B don't take this the wrong way, I mean no offense... but... you don't seem the brightest of people... I would drop this idea of a do it yourself trial before you even begin.
       
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    8. Bobby B
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      Bobby B Member Benefactor

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      @Aussie Lea I see a dog picture so I assume its your animal ..does it mean you don't like the idea of animal experiments ? Is this why we should drop the whole thing and let others harm animals hidden in cages in some lab ?
       
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    9. beeeep

      beeeep Member

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      Sorry to say, but that's NOT what they are saying. hey did preliminary experiments on Chinese ovary hamster cell cultures which evaluated one aspect of the drug. They never said "It will work in humans and is harmless". They designed it to be more harmless, based on some assumptions about why RTG has so many side effects, and they are indeed cautiously optimistic that it might work and has fewer side effects, but they didn't check anything expect that the various compounds they designed (indeed, if you read the paper, they designed quite a few compounds, of which they are probably going to trial more than one) are highly selective towards(Chinese hamster ovary) KCNQ2/3 channels.

      Just read the discussion in the paper (page 18):
      "Although the mechanism by which retigabine-mediated toxicity influences skin and retina
      remains poorly understood, one hypothesis is that UV radiation may cause photodegradation and
      oxidation of retigabine’s aniline ring, which may lead to the formation of colored deposits in skin
      and eyes. The incorporation of electron-withdrawing highly fluorinated substituents significantly
      reduces the highest occupied molecular orbital energy of RL648_81 (-8.33 eV) vs. retigabine (-
      8.06 eV), and thus should render the former compound less prone to formation of reactive
      metabolites".
       
    10. Bobby B
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      Bobby B Member Benefactor

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      who said it will be harmless ? all they say is that it will have less sides effects than RGT for more effect.

      Nothing is harmless

      Why are people so keen on finding excuses to not do anything ? where are the desperate people with T almost killing themselves everyday ?

      If we had 10 other promising T drugs in the pipeline then sure fine ..lets wait a few years all good... but we don't ! besides the longer you wait the more chronic and hard to eliminate T becomes.. even waiting is not the best option here
       
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    11. Aussie Lea
      Dramaqueen

      Aussie Lea Member

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      If you are so keen to try RL, why don't you buy it yourself and be the guinea pig for the rest of us. You should bear some responsibility for the health of others and not let them get the untested drug. You can do whatever you want with your own health but giving other desperate sufferers the chance to harm themselves is irresponsible.
       
    12. AUTHOR
      AUTHOR
      attheedgeofscience
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      attheedgeofscience Member Mighty Benefactor Hall of Fame

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      Hmmm. This is a tinnitus forum - which - pretty much means one thing:

      Cant-Some-one-Else-Just-Do-It.jpg
       
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    13. linearb
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      linearb Member Benefactor Hall of Fame

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      Well, sure, Bobby :) But neither of these professors has, you know, actually said that it will work better with fewer side effects. You seem to be basing all that off of this:
      This is 'potency' measured by by receptor affinity -- which is a useful thing to do, but definitely does not provide evidence that the drug will work as well/better as the existing drug. I can give you a dozen examples of research molecules that appear, on paper and in vitro, to be more potent or selective, which did not pan out in vivo. And, note the "should" in that quote. Again, there are plenty of examples of drugs which were developed to have a lesser side effect profile, which ended up having different or more problematic side effects.

      I don't disagree, and I'd therefore encourage you to email these professors and say "I am considering having a lab synthesize RL81 for me because I think it will work better on my tinnitus with less side effects than RTG, do you agree and think that's a wise thing to do?"

      If they tell you that you should go for it, I'll be happy to independently finance your RL81 experience ;)

      Again, you do not have the expertise, knowledge or experience required to perform useful studies with primates or rats. Do you know what the behavioral correlates of tinnitus are in primates or rats? Have you spent years learning proper protocols for animal studies? Personally, I have at least tangentially worked in an animal research lab at a major university hospital for a period of time (not in any capacity as an animal researcher, mind you) - I've also been a human lab rat in several studies with originated with animal data, and so worked closely with such researchers over a period of months. I would never pretend to have the smallest shred of an idea of how to approach the design and implementation of an animal study.

      The mere fact that you think you could do this with "a couple of monkeys" is very telling. A sample size of two in a tinnitus study tells you almost nothing; you cannot even reliably induce tinnitus in an animal population which is that small.

      I'm sorry to have become a bit vitriolic here, but what you are proposing w/r/t your own body is reckless and ill-advised, and what you are proposing to do with animals is so incredibly unethical and obtuse that I have more than a small suspicion you are trolling.
       
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    14. beeeep

      beeeep Member

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      Obviously, that yellow guy habituated pretty well, just look at him. So why should he risk his health swallowing some untested drug? ;)
       
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    15. Dana
      Busy

      Dana Member Benefactor

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      Maybe it was from the donuts? I will try some.
       
    16. Mithrandir
      Ape-like

      Mithrandir Member

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      We tried Trobalt, we can try the new one whit or without a donut ! :)
       
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    17. Silvio Sabo
      Pooptoast

      Silvio Sabo Member Benefactor

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      I'm sorry to say this but from what I'm reading in your posts you have absolutely no clue of what you are doing. You have as far as I can see no grasp of how to perform any kind of statistical analysis or the basic understanding about the scientific method. I might be wrong but from what you have posted I have come to draw this conclusion. Your heart might be in the right place but you can actually do more harm then good by pursuing this path.

      You have to realize that even if you do everything by the book and in a professional manner just like any other researcher would have done this you will never be taken seriously. All your results will not be worth the paper they are printed on. And what is even worse it might scare away other serious researchers and companies from wanting to work with this.

      You have to understand that researchers are very cautious about their reputation. It's pretty much all they have. All their work and all their results are depending on them being reputable and respected. If you go down this path you might cause some serious damage to tinnitus research! We are battling already to put tinnitus research on the map in competition with other fields such as cancer research and others. It would not be a good thing for tinnitus research if we had a bunch of homemade research wannabes running around.

      Do you really think you can just go to the pet store down the street and buy yourself a few animals and have them in your garage and perform medical experiments on them?! Common, get serious! I advise you to think again about this very long and hard!
       
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    18. Christian78
      Alone

      Christian78 Member

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      i agree

      in personal mail greek doctor said they dont know will they even do testing and if it will take several years
       
    19. Christian78
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      Christian78 Member

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      drug was made becouse he got money to do it, it did not say it will be used!

      and yes waiting 8 years so we see
       
    20. Silvio Sabo
      Pooptoast

      Silvio Sabo Member Benefactor

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      I don't think that people are saying "don't do anything". You can contribute. If you want to do something read up on the subject, reach out to researchers and companies and try to get this stuff to their attention. This is basically what @attheedgeofscience is doing. But let the actual animal and human testing work be done by professionals in professional environments.

      And if you are really keen on doing actual research work I would advise you to get proper education and training and then start looking for funding to found your own lab or join an existing research lab or company. And if your really have the cash or can find investors then start your own company but hire professionals to do the actual work.
       
    21. monacco

      monacco Member

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      If we wait the researchers to do it il will take at list a decade so let @Bobby B do it
       
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    22. Bobby B
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      Bobby B Member Benefactor

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      The goal is to test it for safety and obvious side effects on one primate at 10 times the body dosage then rodents at 100 times.
      Effect on t can be tested on rodents as they are cheap and tests can be repeated with better statistics and better methods Each time .

      If the animal do fine then a short human test will give at least hint if it works on T or not before any other long term unknown new side effects may appear assuming there are some - which we don't know.

      The issue is the long term side effects - this requires constant monitoring of course once the drug is approved in 10 years people aren't going to have blood tested every month so that someone else is going to have it done for them in the approval process.

      Trobalt has a long list of harmful side effects but still people use it .. This RL has a better side effect profile so in theory you can use more and get more effect without the long term issues.

      The idea of getting investors and funding is good @Silvio Sabo why don't YOU go ahead and do just that ?

      We need different approaches here - my DIY approach isn't supposed to replace a professional study but it will be a lot faster than any anything else that's the main goal here .And a lot better than speculation and waiting .

      And once we have more info available in a few years or decade later from the professionals then great at least we didn't wait sitting on our butts and whining on these forums everyday.

      Sending emails to them isn't going to do anything if the drug isn't even tested - this ain't like trobalt big difference here.
       
    23. Alue
      No Mood

      Alue Member

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      Has anyone tried the beer and donut diet to force habituation? You wouldn't even need to test on mice first!
       
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    24. Bobby B
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      Bobby B Member Benefactor

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      Beer is not effective unless it's injected into the ears
      Did you get any results from am101 alue ?
       
    25. Alue
      No Mood

      Alue Member

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      No, or at lest not much of one. I could have gotten the placebo. I do plan on going for the open label round. I hope it's not too late to get some relief. At this point I'm not even looking for a miracle cure, I'd just like it to go down in volume some. A lot of people say they can't hear their T outside or in noisy environments, I think I could settle with that, it would be a big improvement for me.
       
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    26. Silvio Sabo
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      Silvio Sabo Member Benefactor

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      You sir are completely mad. Sure, go right ahead and kill your self some animals with a really expensive Chinese made poison.

      What do you think will happen even if you test the compound on a rodent and/or a non human primate? That is if you don't get yourself arrested for a number of things your will be in violation of, among others patent infringement and animal cruelty. Do you think that you are going to save a decade with that? This stuff will not be approved any sooner because of your experiments, if it ever gets approved that is. The decade consuming part are the HUMAN trials. And I highly doubt that anyone is going to let you preform any experiments on humans.

      Do your really think that you are somehow going to get it approved? A compound which you btw have no right to use in the first place.

      And if you now do test it on yourself, do you really thing it's matter of sending an e-mail to the FDA saying: "Hey! Me and my buddies here have tried this thing we found in a paper online and had it made in some lab in China. It seems to be working, we even tried it on a few rats and a chimp. Can you please approve it?" Are you out of your mind?!

      How do you plan to make it into a drug? Are you going to make pills or are you going to sell it on the street for people to cook in teaspoons and inject in a back alley? What are you going to put in the pills (if you decide to do that) other than the active compound?

      The safety testing in animals is something that a professional lab will do a lot faster and more reliable then you. And btw have you even read the paper? Have you talked to the researchers? Are you sure that the lab in Pittsburgh hasn't already tested the compound in rodents for example?
       
    27. Bobby B
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      Bobby B Member Benefactor

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      Why is this supposed to be a poison ? The lab that will be making it provides high quality research chemicals which I have been using for years without issues.

      You can ask a lab in your country to synthetize it too. They usually don't sell to individuals but there are ways around that obviousely.
      There really isn't any reasons to not be using labs in other countries besides the cost perhaps.

      You don't "make it" into a drug it's a pure chemical you need a precise scale and mix with with food since it's taken orally .
      No need for a filler like a pill since you weight the powder .powder is usually stored in the freezer for pure chemicals.

      You really make this look a lot worse or more complicated than what it is in practice .

      The probability that this molecule will be a success for T are quite high.

      And who cares about the FDA at this stage ?
      They don't need to get involved ever I don't even live in the USA and you too.
       
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    28. Silvio Sabo
      Pooptoast

      Silvio Sabo Member Benefactor

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      Yeah sure, all the regulation and the process of drug approval has been made up just for fun. It's not that complicated really. You just feed your stuff to a few rats and chimp and that's it. Job done!

      Maybe. I truly hope so but so far we don't really know that. Just because it works well in i petri dish or a test tube doesn't have to mean it works in live humans. In fact if you look at statistics it's more likely that it won't work in humans because it's far more common for a potential drug candidate to fail than to succeed.

      Unless you live in some third world country there is probably an FDA equivalent that operates pretty much in the same way.
       
    29. Bobby B
      Fine

      Bobby B Member Benefactor

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      Well we don't own the patent rights to this so why are you even thinking of approval ? That's not the plan here .
      We test it and if it works we keep on testing it until they release it then we buy it officially...

      A test of how life can be during ten years without hearing tinnitus all the time.

      How about that ? Isn't this a worthwhile test to most of us ?
       
    30. Joe Bananas
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      Joe Bananas Member

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