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Beating the BBB with Mannitol?

Rorthron

Rorthron

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Mannitol has been used IV for increasing the availability of drugs to the brain by increasing the permeability of the Blood-Brain Barrier in extremely high concentrations

Recently, mannitol orally has apparently given positive results in drosophilas.

Now, do you think mannitol could increase the bioavailability of many drugs that might be have its efficacity reduced by not passing through the BBB in adequate amounts? I'm thinking of loperamide as an obvious case, but many others might be affected, which suddenly might become much more active in the presence of even moderate concentrations of mannitol in the blood.
 
No one can say for sure without studies proving the ladder.

However, it doesn't seem likely. It's a common misconception that Loperamide doesn't cross the blood-brain barrier. It does cross the BBB. But it's pumped out quickly by P-Glycoprotein. Since this drug only shrinks Endothelium cells, it might help get more Loperamide into the brain, but P-Glycoprotein would pump it out just like it normally does. Also, bioavailability has nothing to do with the ability to cross the blood-brain barrier. They're two separate mechanisms controlled by different parts of the body.

On topic with the source - I have no idea why this would be a treatment for Parkinsons by itself. Since Parkinsons is caused by the destruction of Dopamine-producing cells and this only allows more of a substance into the brain, it seems this would have no effect on Parkinsons.

Unless it was co-administered with L-DOPA, I see no reason why it would benefit in the treatment of Parkinsons. Maybe this substance allows Dopamine to cross the BBB? Anyways, without actually studying it in depth, no one can say for sure.
 
bio-availability is a different thing than crossing the BBB, related, but not the same thing.

bio availability is what percent of the drug gets absorbed into the blood. then once its in the Blood it can try to cross the Barrier to the Brain. obviously thats kinda over simplifying things, but eh
 
Yes, that's how mannitol has been used: IV administration directly in the artery (and I mentioned that!) but could moderate concentrations (as discussed in the article) could in any way improve the availability of a drug to the CNS? apparently in drosophila models, results suggest so.

Also, as far as I remember, aren't p-GP responsible for blocking only really big molecules? (>500 Da, or so)

This could be easily tested.
 
Rorthron said:
Yes, that's how mannitol has been used: IV administration directly in the artery (and I mentioned that!) but could moderate concentrations (as discussed in the article) could in any way improve the availability of a drug to the CNS? apparently in drosophila models, results suggest so.

Also, as far as I remember, aren't p-GP responsible for blocking only really big molecules? (>500 Da, or so)

This could be easily tested.
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I think what sekio was getting at is that loperamide actually DOES cross the BBB, but p-GP expels it so quickly that it essentially never enters the brain. Even if mannitol does effectively weaken the BBB it wouldn't have much effect on that particular drug.
 
endotropic said:
I think what sekio was getting at is that loperamide actually DOES cross the BBB, but p-GP expels it so quickly that it essentially never enters the brain. Even if mannitol does effectively weaken the BBB it wouldn't have much effect on that particular drug.
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Ok. I do not have any interest on loperamide. I just mentioned it as I remembered reading that it had difficulty passing the BBB (i was wrong, apparently) but what about other drugs? Even drugs we do know that cross it, like morphine, LSD, DOC, DMT, etc. Do you believe that a little (or not so little) mannitol beforehand, could increase the effects of the drug? How much?
 
One can hardly fail to wonder how they knew if their needle was in a fruit-fly vein or not. And one doesn't WANT to get loperamide into the CNS, and have it stay there. At least, if one doesn't want to do a scorched earth job upon one's substantia nigra thus inflicting permanent, severe DA-ergic damage; parkinson's disease etc.
 
Even drugs we do know that cross it, like morphine, LSD, DOC, DMT, etc. Do you believe that a little (or not so little) mannitol beforehand, could increase the effects of the drug? How much?
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I think that you'd need to have huge amounts of mannitol IV. If memory serves the only reason mannitol changes BBB permeability is because it adjusts the osmolality of the blood.

Fruit flies are poor models for human physiology, btw.
 
In the case of loperamide, my guess is that it would indeed increase central activity; probably not much by itself but perhaps significantly when co administered with a p-GP inhibiter.

Correct me if I'm mistaken, my understanding if loperamide was that a little (yet some) crossed the BBB and was then rapidly removed by p-GP, the two limitations coming together to severely limit it's central affects. If loperamide crossed the BBB just fine and p-GP was either the sole or major issue then wouldn't one expect even fairly weak p-GP inhibitors (e.g. quinine) to radically increase the central mu effects? I've bioassayed loperamide with various p-GP inhibitors, fairly extensively with quinine in fact (lop' dose of 36 mg in all trials - lop' alone begins to exhibit central affects in me when the 30 mg line is crossed). Five separate assays over a 2 month period, all performed in the same location at the same time of day and without any other xenobiotics other than nicotine in my system. Assay 1: ~20 mg quinine, a2: ~70 mg, a3: ~250 mg, a4: 650 mg, a5: 1300 mg.

Possible increased central effects were felt in a1 and a2 but these were too mild to grant any certainty. Definite increases were felt in a3, 4 and 5. A3 led to a more-or-less full, if somewhat atypical opioid high that lacked strong euphoria and pin prick pupils but little else. A4 produced a significantly increased 'high' with a small amount of euphoria at times and slightly constricted pupils, a5 provided further pupil constriction but little else. (No nodding, no real euphoria, pupils small but not pinned.

While this assay proved jack, it does illustrate that p-GP inhibition does increase the central opioid effects of loperamide. However, if the removal of lop via p-GP was the main factor in making it an infamously weak central agonist then (given both lop's binding affinity for mu and it's comparative GI opioid effects at 36 mg dosages) you would expect the increase in central effects from a2 through a5 to be much greater, no?

Just to note I have a moderate tolerance to opiates which, over the 2 months these assays took place in, increased ever so slightly. No other loperamide was taken during the 2 months. My general loperamide use includes ~7 additional 'assays' of central effects spread out across a two year period, the very occasional use of loperamide as a relief for food poisoning etc ( <12 mg) and perhaps 10 occasions to help during morphine withdrawal (<16 mg).

Just my two pence...
 
Yeah, I took 60mg last night while deep into withdrawal, after taking dope cut heavily with quinine. No effect.
 
Sekio said:
Don't forget that quinine itself is centrally active as an analgesic.
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Do we know the mechanism by which it produces analgesia? If your good self (or anyone else!) could sling me a link or paper ref, it would be most appreciated.
 
I think the question about loperamide has already been settled, but let me just say this as an aside about mannitol. Overall, I consider mannitol a crude drug, a blunt tool, with dwindling justified uses in modern medicine. I'd always learned its mode of action in raising brain perfusion was by jacking up the osmolar gradient between blood and the tissues surrounding it to unnaturally high levels. Mannitol and things like it work not by disabling the BBB, but by overwhelming it. The glial cells which are thought to create the BBB are kind of like border guards that snatch up certain kinds of large molecules and other foreign bodies. But if millions of refugees crash down a border and stampede across, a good number of them will get away with it, no matter how ready the border patrol is to shoot or arrest people. There have got to be safer ways to get drugs that don't have a BBB visa across than giving people blood thickeners and intravascular volume and pressure (!) boosters, yeesh.

Yes, I understand that mannitol is fluff. Filler. Nothing. Inert. Pump it in, pee it out. Makes a good artificial sweetener in very low doses for this reason. But if you were to take large doses of it (by any ROA) over extended periods of time, wouldn't you also piss away a lot of your more key electrolytes and small charged proteins at an alarming rate that would need some bodybuilder-worthy diligence to repletion?
 
Great point: we don't want to push a bunch of random shit through the BBB, various compounds traversing it in various directions; rather, the goal is to transport a single compound across, hence the advantage of complexed micro/nano particles (as with that one study). The problem/situational reality, though, is that none of this is kitchen chemistry stuff; just obtain some active drugs. :P

ebola
 
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