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Does anyone know what this new drug is?

psuedo resveritol

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#31 niner

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Posted 26 March 2013 - 12:49 AM

I have not done any filtering yet with the resveratrol mixture. It's still on the magnetic stirrer. I'm thinking I should filter it with the same 0.22 μm filter I use on my c60 solution. I happen to have some pure olive oil on hand that I've already run through that filter size. So I figure if I can accurately get some equal volumes, then some weight measurements might give an indication of how much is dissolved. But the milligram scale I have maxes out at 50 grams so I'm limited on the quantity I can deal with. I figure I might get some fairly consistent small volumes to work with using a medicine dropper. I'll play around with a laser pointer before and after filtering and see if I notice any deflection differences. But I want to keep my resveratrol mixing at least another week.


I don't think you'll be able to get an accurate value for resveratrol solubility in olive oil this way. When a compound dissolves in a solvent, it can affect the density of the solvent in non-obvious ways. The volume could either go up, down, or stay roughly the same. You'd probably have better luck weighing the resveratrol that ends up on the filter. You'd need to wash off the olive oil with something that wouldn't dissolve the resveratrol. I'm not sure what would be best there.. An alkane, maybe, like hexane or heptane? It might be enough to just estimate the weight, if there isn't much there.

The point of doing the molar calculation was that if the previous numbers are the max, then the resveratrol is at 1/3 molar concentration as the c60, which means it is probably bonding to a different part of the olive oil. Perhaps it is attracted to the glycerin, and the C60 is attracted to the fatty acid part?


Resveratrol doesn't bond to olive oil. It's just an ordinary solution, where the resveratrol molecules are floating around in the olive oil. It's probably attracted to both parts of the triglyceride. C60, on the other hand, forms a chemical bond with the fatty acid chain.

#32 hav

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Posted 29 March 2013 - 01:46 AM

I don't think you'll be able to get an accurate value for resveratrol solubility in olive oil this way. When a compound dissolves in a solvent, it can affect the density of the solvent in non-obvious ways. The volume could either go up, down, or stay roughly the same. You'd probably have better luck weighing the resveratrol that ends up on the filter. You'd need to wash off the olive oil with something that wouldn't dissolve the resveratrol. I'm not sure what would be best there.. An alkane, maybe, like hexane or heptane? It might be enough to just estimate the weight, if there isn't much there.


Thanks, niner. I had a feeling it wasn't going to be that simple. I may just have to repeat this iteratively until I see a negligible amount of material on the filter. Kind of like a saw when experimenting with c60 concentrations.

Howard

Edited by hav, 29 March 2013 - 01:47 AM.


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#33 hav

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Posted 04 April 2013 - 05:17 PM

Here's an update on my effort to mix 2 g of resveratrol into 100 ml of pre-filtered olive oil. I let it mix on a magnetic stirrer for 2 weeks then let it settle a couple of days. Here's a picture:

Attached File  resv2g_oo100ml.jpg   104.79KB   5 downloads

There's about 1/2 inch of uncloudy oil at the top and about 3/16 inch of settled resveratrol at the bottom. The oil in the middle is cloudy which I assume is some of the undissolved 98% pure resveratrol and some or all of the other 2% impurities in suspension.

I'm going to add some more filtered oil and continue mixing to get a rough idea of what it takes to minimize the amount that settles.

Howard

Edited by hav, 04 April 2013 - 05:18 PM.


#34 niner

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Posted 05 April 2013 - 02:54 AM

Looks like it needs to settle for a couple weeks. If you had a big centrifuge, that would speed it up. You could always filter it. So far, you've tried 20mg/ml, and it looks like that's above the solubility. The question is: How far above? If you could weigh the solid, that would tell you. You could try drinking some of the cloudy stuff- it would be a mixture of dissolved resveratrol and micronized resveratrol. I'd start with a small quantity, if you do. Like one ml.

Edited by niner, 05 April 2013 - 03:00 AM.


#35 hav

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Posted 05 April 2013 - 06:01 PM

It's just a little hype on this study:
http://www.ncbi.nlm....pubmed/23471411

I don't think he was referring to a specific drug. In a few of the articles I've seen snips of he seemed top be referring to an assay to rapidly identify possible SIT1 activators, perhaps from resveratrol analogs with better bioavailability and predicted they'd find one within a couple of years. But they'd still need to test it in vivo to actually prove anything, like the fact that their assay is actually accurate.

Howard


Hi, Bron. No one seems to think that just mixing resveratrol into ordinary vegetable oil actually forms anything different from what would normally form in the digestive tract. I'm just trying to figure out what its oil solubility limit is. And then perhaps see if dissolving it in advance might make it more effective.

Howard

#36 hav

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Posted 05 April 2013 - 06:21 PM

Looks like it needs to settle for a couple weeks. If you had a big centrifuge, that would speed it up. You could always filter it. So far, you've tried 20mg/ml, and it looks like that's above the solubility. The question is: How far above? If you could weigh the solid, that would tell you. You could try drinking some of the cloudy stuff- it would be a mixture of dissolved resveratrol and micronized resveratrol. I'd start with a small quantity, if you do. Like one ml.


I already started remixing with an added 50 ml of oil to see how much the settled amount reduces. That will give me 150 ml of solution to work with, I should be able to easily pour off just the liquid for filtering and get enough of a yield to load up my small centrifuge which has 6 tubes holding 15 ml each. I can then try it starting with one OO capsule full which is pretty close to a ml. I've taken as much as a gram under the tongue before. I certainly don't expect such a small dose to feel anything like that but I agree its better to err on the side of caution and start with baby steps. I'll give it a go in about a week or so.

Howard

#37 niner

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Posted 05 April 2013 - 08:50 PM

It's just a little hype on this study:
http://www.ncbi.nlm....pubmed/23471411

I don't think he was referring to a specific drug. In a few of the articles I've seen snips of he seemed top be referring to an assay to rapidly identify possible SIT1 activators, perhaps from resveratrol analogs with better bioavailability and predicted they'd find one within a couple of years. But they'd still need to test it in vivo to actually prove anything, like the fact that their assay is actually accurate.

Howard


Hi, Bron. No one seems to think that just mixing resveratrol into ordinary vegetable oil actually forms anything different from what would normally form in the digestive tract. I'm just trying to figure out what its oil solubility limit is. And then perhaps see if dissolving it in advance might make it more effective.

Howard


You guys must be communicating telepathically... Bron never said anything here.

#38 cudBwrong

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Posted 10 April 2013 - 12:58 PM

Resveratrol isn't damaged in the stomach. The damage happens primarily in the liver, although there might be some conjugation that happens in the gut as well. It gets absorbed through the gut into general circulation and proceeds directly to the liver. The idea of "swamping" is that if there is a limited number of conjugative enzymes, and they are all busy with the first half of a large dose, the second half of the dose will sneak through. It may or may not actually work that way, but the net effect is as though it does.


Very interesting discussion.

Is there a concern that the larger doses may damage the liver, due to this "swamping" effect?

#39 niner

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Posted 10 April 2013 - 07:13 PM

Is there a concern that the larger doses may damage the liver, due to this "swamping" effect?


No, resveratrol isn't harmful to the liver.

#40 cudBwrong

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Posted 10 April 2013 - 07:36 PM

No, resveratrol isn't harmful to the liver.

If there is no concern regarding the liver, maybe the solution is just to take higher doses and not be too concerned about bypassing the normal circulation to the liver. Of course, it's quite interesting to try to determine the soluability, if only to understand the physical properties a bit better.

This raises important larger issues about dosage. There is a standard protocol, endorsed by the FDA, which describes how to translate dosage used in an animal model to humans for clinical trials. I can't post links yet, but I'm trying to attach a relevant paper from the FASEB journal, Shannon Reagan-Shaw et. al, "Dose Translation From Animal to Human Studies Revisited" doi: 10.1096/fj.07-9574LSF .

The suggestion is to use surface area, not mass equivalents.

The key question is whether the surface area equivalent correlates well in cases like resveratrol, where there are bioavailabilty issues.

I've looked at some resveratrol animal studies where a mass equivalent would give a truly massive human dose, perhaps 20 grams or more in some cases. The clinical trials all seem to be using much lower doses based on surface area. Maybe these trials will not replicate the animal studies because the animal livers are swamped, and the human livers are not.

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  • Attached File  dose.pdf   86.05KB   1 downloads


#41 niner

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Posted 10 April 2013 - 08:55 PM

The key question is whether the surface area equivalent correlates well in cases like resveratrol, where there are bioavailabilty issues.

I've looked at some resveratrol animal studies where a mass equivalent would give a truly massive human dose, perhaps 20 grams or more in some cases. The clinical trials all seem to be using much lower doses based on surface area. Maybe these trials will not replicate the animal studies because the animal livers are swamped, and the human livers are not.


That's a good point. While the general rule of thumb is that the human dose in mg/kg is 1/12 of the mouse dose or 1/6 of the rat dose, those are just rules of thumb. A rule that's generalized over all compounds is bound to have some compounds for which it works poorly. The pharmaceutical industry strives to avoid the sort of phenolic functionality that causes resveratrol to have such poor bioavailability. If the BSA rule is optimized for typical pharmaceuticals, it may or may not work as well for polyphenols. In the final analysis, we need to adjust human doses to balance effectiveness, toxicity, and other concerns anyway. The BSA scaling rule is just a starting point.

#42 hav

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Posted 11 April 2013 - 11:40 PM

No, resveratrol isn't harmful to the liver.

If there is no concern regarding the liver, maybe the solution is just to take higher doses and not be too concerned about bypassing the normal circulation to the liver. Of course, it's quite interesting to try to determine the soluability, if only to understand the physical properties a bit better.


I think taking larger doses is the common wisdom around here. I'm interested in the liver bypass possibilities because it occurs to me that there's quite a large disparity in effects shown in some small dosage studies and I wonder if blood levels are the be all and end all of judging resveratrol bioavailability. Particularly if resveratrol is significantly lipophilic with a possible uptake route that passes through the lymphatic system before hitting the liver and bloodstream. I figure the starting point for that speculation is getting some idea on how oil soluble it is in a long chain triglyceride that takes the route I'm interested in.

Howard
saepe fallitur, dubitare nuquam

#43 cudBwrong

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Posted 13 April 2013 - 05:12 PM

... I wonder if blood levels are the be all and end all of judging resveratrol bioavailability. Particularly if resveratrol is significantly lipophilic with a possible uptake route that passes through the lymphatic system before hitting the liver and bloodstream. I figure the starting point for that speculation is getting some idea on how oil soluble it is in a long chain triglyceride that takes the route I'm interested in.

Howard
saepe fallitur, dubitare nuquam


Now I'm beginning to understand. Thanks for doing this work and sharing the results, and thanks to all the contributors for posting interesting information.

#44 ClarkSims

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Posted 17 April 2013 - 04:20 PM

... I wonder if blood levels are the be all and end all of judging resveratrol bioavailability. Particularly if resveratrol is significantly lipophilic with a possible uptake route that passes through the lymphatic system before hitting the liver and bloodstream. I figure the starting point for that speculation is getting some idea on how oil soluble it is in a long chain triglyceride that takes the route I'm interested in.

Howard
saepe fallitur, dubitare nuquam


Do you know how quickly (or slowly) the lymph circulates? I am guessing it is orders of magnitude slower than the blood, just based on how my feet take a while to get rid of compression marks from elastic socks.

I also had a bruise from a bike accident recently. I could see the blood flowing out of the injury and downstream following the lymph. It seemed to go very slowly. I treated part of the bruise with DMSO, and that part recovered very quickly. I took pictures, but I haven't had time to put up a web page about DMSO and bruises yet.

#45 hav

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Posted 17 April 2013 - 08:18 PM

Do you know how quickly (or slowly) the lymph circulates? I am guessing it is orders of magnitude slower than the blood, just based on how my feet take a while to get rid of compression marks from elastic socks.


Wasn't sure myself but I found a powerpoint on the web site of a Dr Lou Freedman that had some interesting stats on circulation among other things:

Rate of Lymph Formation/Flow (slide #44)
•Thoracic duct- 100 ml/hr.
•Right lymph duct- 20 ml/hr.
•Total lymph flow- 120 ml/hr (2.9 L/day)
•Every day a volume of lymph roughly equal to your entire plasma volume is filtered
...

Blood Flow (slide #108)
•Rest CO = 5.9 L/min
–Coronary-250 ml/min
–Brain-750 ml/min
–Organs-3100 ml/min
–Inactive muscle-650 ml/min
–Active muscle-650 ml/min
–Skin- 500 ml/min

•Exercise = 24 L/min
–Coronary-1000 ml/min
–Brain-750 ml/min
–Organs-600 ml/min
–Inactive muscle-300 ml/min
–Active muscle-20,850 ml/min
–Skin- initially↓, then ↑as body temp ↑


I assume the lymph flow rate is an average throughout a typical day but I understand it goes down during sleep and goes up during exercise and massage.

Howard
saepe fallitur, dubitare nuquam

Edited by hav, 17 April 2013 - 08:20 PM.


#46 maxwatt

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Posted 20 April 2013 - 06:49 PM

Lymph circulation is passive. Blood is pumped by the heart, lymph by the contraction of one's muscles in the course of general activity. There are valves that prevent it from flowing in reverse.

#47 cudBwrong

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Posted 24 April 2013 - 09:32 PM

I think taking larger doses is the common wisdom around here. I'm interested in the liver bypass possibilities because it occurs to me that there's quite a large disparity in effects shown in some small dosage studies and I wonder if blood levels are the be all and end all of judging resveratrol bioavailability. Particularly if resveratrol is significantly lipophilic with a possible uptake route that passes through the lymphatic system before hitting the liver and bloodstream. I figure the starting point for that speculation is getting some idea on how oil soluble it is in a long chain triglyceride that takes the route I'm interested in.

Howard
saepe fallitur, dubitare nuquam


Howard, it seems that your work is related to some of the research on liposomes. I'm posting this link because it's a free full-text article on PLOS One that includes details of their preparation methods.

http://dx.doi.org/10...al.pone.0041438

Edited by cudBwrong, 24 April 2013 - 09:42 PM.


#48 hav

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Posted 25 April 2013 - 05:06 PM

Howard, it seems that your work is related to some of the research on liposomes. I'm posting this link because it's a free full-text article on PLOS One that includes details of their preparation methods.

http://dx.doi.org/10...al.pone.0041438


Thanks so much for that. Its really interesting that their technique can embed up to around 50% of the resveratrol into a lipid. With simple stirring into olive oil I think I'm getting quite a bit less than than that. I haven't taken any measurements yet but it seems that less than 100 mg of resveratrol is dissolving into 100 ml of olive oil.

Howard
saepe fallitur, dubitare nuquam

Edited by hav, 25 April 2013 - 05:07 PM.


#49 ClarkSims

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Posted 27 April 2013 - 05:55 PM

I think taking larger doses is the common wisdom around here. I'm interested in the liver bypass possibilities because it occurs to me that there's quite a large disparity in effects shown in some small dosage studies and I wonder if blood levels are the be all and end all of judging resveratrol bioavailability. Particularly if resveratrol is significantly lipophilic with a possible uptake route that passes through the lymphatic system before hitting the liver and bloodstream. I figure the starting point for that speculation is getting some idea on how oil soluble it is in a long chain triglyceride that takes the route I'm interested in.

Howard
saepe fallitur, dubitare nuquam


I wonder why the body has evolved a separate method for ingesting long chain triglycerides? I can only speculate, that they are rare in nature and were the limiting factor in tissue repair. Therefore the body wanted to maximize their availability and by putting them in slow moving lymph, and not letting the liver break them down. If this is true, then the body should readily incorporate them into the membranes of the cell and cell organelles.

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#50 niner

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Posted 27 April 2013 - 07:11 PM

I wonder why the body has evolved a separate method for ingesting long chain triglycerides? I can only speculate, that they are rare in nature and were the limiting factor in tissue repair. Therefore the body wanted to maximize their availability and by putting them in slow moving lymph, and not letting the liver break them down. If this is true, then the body should readily incorporate them into the membranes of the cell and cell organelles.


I thought that MCTs were digested, but just follow a different absorption pathway. They're still food, and they do occur in nature, albeit not ubiquitously like longer chain triglycerides.




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