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Pharmacology How drugs affect the workings of the human body.

 
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  #1  
Old 04-12-2010, 15:58
Revolvingdoo Revolvingdoo is offline
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Blood brain barrier permeation

Hey swimmers, quick question i would love to hear the answer to.

There has been evidence to show that PPI's such as omeprazole allow drugs such as loperamide to permiate the BBB to a degree.

Other substances such as mannitol have a similar effect.

My question or rather topic for discussion I would like to propose would be using various chemicals such as those suggested above to "activate" if you will, what is normally psycho actively inert.

Not just loperamide, but other potential candidates (please, feel free to suggest).

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Please don't use abbreviations. Most people probably don't know what PPI stands for.
  #2  
Old 04-12-2010, 16:59
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Re: Blood brain barrier permeation

I will chime in that the alien who hides under my house has wondered if grinding and soaking Loperamide in DMSO would have any effect in helping the opiate to cross the BBB.
  #3  
Old 04-12-2010, 17:43
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Re: Blood brain barrier permeation

Mr. Hamster was doing some research into various compounds and has discovered two which facilitate transition of the blood/brain barrier.
  1. Piracetam
  2. Mannitol
There are surely others, but these are just two he's uncovered in his research. Mannitol is sometimes used as an additive/filler in some pharmaceuticals, presumably because of it's BBB facilitation.

The hamster hopes that helps.

Be well...
  #4  
Old 05-12-2010, 03:23
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Re: Blood brain barrier permeation

I'll just add that loperamide specifically has multiple considerations. And I don't believe DMSO will work. DMSO may work to get loperamide to absorb through the endothelial layer into the body cavity/blood, but I do not believe it would do anything to aid the passage from there into the brain.

If one actually does get loperamide into the brain, from what I understand it is quickly taken out of the brain by proteins that are designed to excrete drugs called multidrug resistance proteins or P-glycoproteins (Pgp). This should also be a consideration with regards to getting things through the blood brain barrier (bbb). If what one is trying to get through the bbb is a subtrate for Pgp, then it may not be effective just to get it past the bbb as it may be quickly excreted out of the brain before it has the opportunity to illicit a pharmacological effect.

That being said, this is a very interesting thread and I will be watching it for developments.


Also, please remember to define any abbreviations used in posts. I assume the OP means Proton Pump Inhibitors with the use of PPI.
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Old 05-12-2010, 04:35
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Re: Blood brain barrier permeation

I would like to know if there is a way to get substances such as phenethylamine (PEA), Tryptamine (serotonin), Dopamine, and Beta-endorphine to cross the BBB, all these substances have proved quite psychoactive when directly injected into the brain, but yet they are in many foods and do not cause an effect, I assume that is due to innability to cross the BBB.
  #6  
Old 05-12-2010, 05:35
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Re: Blood brain barrier permeation

Quote:
Originally Posted by phenythylamine View Post
I would like to know if there is a way to get substances such as phenethylamine (PEA), Tryptamine (serotonin), Dopamine, and Beta-endorphine to cross the BBB, all these substances have proved quite psychoactive when directly injected into the brain, but yet they are in many foods and do not cause an effect, I assume that is due to innability to cross the BBB.

Mr. Hamster has read that these are pretty short-lived outside the brain and tend to get metabolized fairly quickly before they can even reach the BBB. It's a shame, when they are so close, but so far away.

Be well...
  #7  
Old 05-12-2010, 16:52
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Re: Blood brain barrier permeation

what if there was a way to stop them from getting metabolized?
  #8  
Old 05-12-2010, 17:16
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Re: Blood brain barrier permeation

Quote:
Originally Posted by phenythylamine View Post
Tryptamine (serotonin)
Careful there.. serotonin is 5-hydroxytryptamine, not tryptamine. That hydroxyl group is fundamental for serotonin's mechanism of action.

Quote:
Originally Posted by phenythylamine View Post
yet they are in many foods and do not cause an effect, I assume that is due to innability to cross the BBB.
I'm not sure that the BBB poses much of a problem to these substances, certainly not to phenethylamine or the tryptamines. As wanderer said metabolic instability is probably a far bigger problem, especially for phenethylamine.

There's also the issue of trying to make square pegs fit round holes. Even if PEA levels are elevated massively in the brain this does not necessarily make it an effective stimulant or psychedelic. It is inherently a far weaker stimulant than its alpha-methylated derivative amphetamine. It'll also never be comparable to its ring substituted cousins the 2C-x family in terms of serotonergic activity. These substances may just have a fundamentally limited ability to act as an exogenous ligand for neuronal receptors. Distribution and elimination behavior are secondary.

Quote:
what if there was a way to stop them from getting metabolized?
There is.. monoamine oxidase inhibition. It's effective at massively raising PEA levels in the brain, but the effects are generally still underwhelming compared to other drug compounds. MAOIs are also not particularly safe.

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spot on!
  #9  
Old 05-12-2010, 17:39
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Re: Blood brain barrier permeation

Quote:
Originally Posted by phenythylamine View Post
I would like to know if there is a way to get substances such as phenethylamine (PEA), Tryptamine (serotonin), Dopamine, and Beta-endorphine to cross the BBB
First of all, serotonin is 5-OH-Tryptamine (5-HT), not tryptamine. Tryptamine is 2-(1H-indol-3-yl)ethanamine and serotonin is 3-(2-aminoethyl)-1H-indol-5-ol.

While 5-HT does not cross the blood brain barrier, it's precursor (5-HTP, 2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid) does. Oral administration of this precursor has been shown to induce elevations in brain concentrations of 5-HT. To introduce 5-HT to the brain via oral administration, one would need a combination of enzyme-inhibitors and a pgp-inhibitor. There has been discussion elsewhere on php-inhibition and it should be noted that pgp is a ubiquitous protein in the BBB whose purpose is removal of unwanted substances-- not just 5-HT.. I'll let you figure that one out.

The same is true for dopamine and L-DOPA, but you do not want to elevate dopamine levels throughout the brain-- keep in mind that these neurotransmitter systems are ubiquitous throughout neural tissue, not just in regions that produce psychoactive effects. L-DOPA is used to treat dopaminergic neurotoxicity in the brains of patients with Parkinson's Disease, and the side-effects are unpleasant and permanent.

As for phenethylamine (PEA), there is a great deal of discussion on this forum about oral administration and throughout the scientific literature confirming that it crosses the BBB. I'm not sure why you included this. Enzyme inhibition (MAO) has been shown to enhance oral administration by preventing degredation. Try using the search engine and a good library of scientific literature.

β-Endorpin does not readily cross the BBB, and even if it could what applies to dopamine above applies to β-endorpin here. This neurotransmitter is more ubiquitous than you think. Especially if introduced to the peripheral nervous system (read: oral administration..), you are playing with bigger systems than you want to. It should also be noted that the precursor, pro-opiomelanocortin (POMC), is a shared precursor for adrenocorticotropohormone (ACTH). I don't think you want to be elevating ACTH.
Quote:
all these substances have proved quite psychoactive when directly injected into the brain, but yet they are in many foods and do not cause an effect
Right, altering neurotransmitter tone is the foundation of psychoactivity. The kind of experimentation you are is far more elegant than what you seem to be working towards. Think: an iontophoretic micropipette v. a flood of undirected neurotransmitters; a sewing needle or a baseball bat.
Quote:
I assume that is due to innability to cross the BBB.
In part, but mostly it is their inability to even enter circulation when orally administered, as they are rapidly enzymatically degraded. There is a good reason for this, which you can likely deduce from the above caveats.

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highly informative post!
  #10  
Old 05-12-2010, 17:51
Balzafire Balzafire is offline
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Re: Blood brain barrier permeation

I remember reading about quinine as being a potential candidate for somehow getting Loperamide to cross the BBB. I will try to dig that information up and post it here.
  #11  
Old 05-12-2010, 18:19
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Re: Blood brain barrier permeation

the consensus on craplight seems to be that loperamide does cross the blood brain barrier, but is immediatly expelled by Pgp, the only way to make it active would be to take Pgp inhibitors, but those are not easily accessable as they arnt widely used in medicine, and pgp inhibitors would likely let other things into the brain which may be dangerous.
  #12  
Old 18-12-2010, 20:04
Dope Amine Dope Amine is offline
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Re: Blood brain barrier permeation

What aspect/functionality on loperamide causes its difficulty in reaching those lovely brain mu receptors, whether it be expulsion by Pgp or inability to pass the bbb?

Certainly there are very similar structures that get right through. My guess is that it's that amide group. This could be reduced to an amine using LAH. While that wouldn't be easy and safe kitchen chemistry, it would be a short route from an easily attainable material.



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  #13  
Old 24-02-2011, 02:02
Practical_Toker Practical_Toker is offline
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Re: Blood brain barrier permeation

Quote:
Originally Posted by phenythylamine View Post
the consensus on craplight seems to be that loperamide does cross the blood brain barrier, but is immediatly expelled by Pgp, the only way to make it active would be to take Pgp inhibitors, but those are not easily accessable as they arnt widely used in medicine, and pgp inhibitors would likely let other things into the brain which may be dangerous.
Many OTC medicines and foods inhibit pgp to some extent. Unfortunately I'm having massive trouble in finding the list I had access to so long ago. It's been over a year since I looked into PP inhibition and at the time I was prescribed zoloft. After looking for, and finding, a list of inhibitors I noticed sertraline (Zoloft) on there.
That's when I stopped reading. Having already taken my zoloft for the day and some cimetidine I ate some loperamide. Maybe like 12 of them I can't remember (24mg).
I felt nice and floaty and calm and serene and... Man.. It was actually a surprising feeling! I was not expecting clear opioid effects.
I only tried it this one time for some reason... Oh yea because I wasn't about to waste money on imodium. But yea I'm an opiate intolerant person who's developd a pretty good knowledge of the effects of different opiates over the years. I just don't do them often... Not easy to come by.

Anyway I'm looking for a list such as the one I mentioned. It was a clear and concise listing of known p-gp inhibitors (and substrates too I think. it was so long ago). It was a Wiki stylized table I believe...
But there's no sign of it anymore.

It's like the guvmint don't wantchu knowin this infurmashun! (ignorance is feigned not genuine)

Practical_Toker added 23 Minutes and 27 Seconds later...

According to cueflash.com/decks/Drug_Interactions_2

* Cimetidine: cimetidine is a potent inhibitor of all clinically relevant CYP isozymes and p-glycoprotein.
I have that. I get mad heartburn. Think I have GERD...
Incidentally, too much acid production also has the side effect of diarrhea.
So hell... I'm gonna eat some imodium. I'm just going to try 24mg like last year... Maybe....
Anyway how much cimetidine would be good anyone have any ideas? 400mg all right or up it?

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Read the Site Rules. Self incrimination is not allowed, even if it's legal for you. Please find a creative way to avoid it, do not use SWIM.
Even though you self incriminated the experience report was quite detailed and very interesting, please try to avoid self incrimination in the future however.

Last edited by Practical_Toker; 24-02-2011 at 02:02. Reason: Automerged Doublepost
  #14  
Old 27-02-2011, 00:46
phenythylamine phenythylamine is offline
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Re: Blood brain barrier permeation

^^ thats very interesting, although many here believe loperamide is a lost cause I believe differently, just a german chamomile and MAOIs allow certain substances to be much more active than they usually are, its just a matter of cracking the mystery and I am willing to bet that PGP Inhibitors are the answer here, I would really like 69ron to chime in on this one and provide us with a list of some herbal OTC PGP inhibitors, in the mean time Im going to take a peak around the net and see what I can dig up.

edit--------------------------------------------------------
A list of some herbal PGP inhibitors
-curcumin
-some gensenoids
-piperine
-silymerine (milk thistle)
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Old 27-02-2011, 00:52
Practical_Toker Practical_Toker is offline
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Re: Blood brain barrier permeation

P-gp inhibitors are definitely the answer.
P-gp removes a multitude of toxins from the brain though, so inhibiting it all the time would undoubtedly have negative effects.
However once in a while shouldn't be a problem.
If anybody finds more information on inhibitors let me know. A link to a list is needed.
  #16  
Old 01-03-2011, 14:30
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Re: Blood brain barrier permeation

Quote:
Originally Posted by wanderer View Post
Mr. Hamster was doing some research into various compounds and has discovered two which facilitate transition of the blood/brain barrier.
  1. Piracetam
Could you post the relevant research for this? I'm interested if other -racetams might serve the same purpose.
  #17  
Old 01-03-2011, 18:19
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Re: Blood brain barrier permeation

While he had a spare moment, the hamster noticed this thread looking for a reference to the ability of piracetam to easily cross the blood brain barrier. However, contrary to what he found posted on may heath food related web sites, other brain function and nootropic web sites, he came across a patent which specifically addresses the poor ability of piracetam and its analogs from crossing the BBB.

There is a patent filed speciffically for it's ability to cross the BBB, US Patent #7157421, which describes a mechanism for combining it with another BBB crossing molecule to assist its delivery. The scanned pdf of the patent is attached.

So with a little digging, and a bit of reading the patent, the hamster is humbled and must admit he was incorrect previously. He cannot find the original research paper where he found the information, but thinks this patent pretty well clears it up for him and anyone else who might think that piracetam crosses the BBB easily.

Now some good hamster or chinchilla should spread the word to the snake oil vendors who hawk this stuff as something which can improve memory, brain function, and reverse some brain injury. It can and apparently rather well, only usually when administered intrathecally. Not a ROA the average hamster or chinchilla is likely to perform at home.

The humble hamster admits his error and goes back to running on his wheel.

Be well...
Attached Files
File Type: pdf US7157421.pdf (70.8 KB, 8 views)

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