• N&PD Moderators: Skorpio | thegreenhand

Loperamide the OTC fentanyl (reason for no CNS activity)

It was a very useless paper, it had no references on the fact that sterate retarded intestinal absorption, just that sterate was insoluble so that it made parenteral use difficult (again no citation). The bulk of the paper was simpley bitching about the retiredment of the Lexington addiction facility where they could do drug dependecy trials on prison inmates.

And in reply to ^ Yeah, I had no doubt that P-glycoprotein reduces plasma and brain concentrations of opiates, I think there is a lot of evidence out there in the liturature.
 
Your post prompted me to review what is currently known about M6G. Recently, the applied potenital role of M6G has been advanced by human clinical trials comparing it with morphine. Generally, it has been found to be equipotent with morphine, with somewhat slower onset, and significantly reduced sife effects (nausea, emesis, respiratory depression), which agrees with animal studies. We might very well see it in clinical use soon.
As for the receptor binding assays, there is some good evidence M6G may affect a different receptor subtype (though I should mention that the nature of opioid receptor subtypes isn't at all well understood).

So I agree with your point that there isn't evidence that the CYP3A4 inhibition is actually incongruent with perceived greater potency, though I still believe P-gp inhibition is probably the more important function of grapefruit juice (since otherwise I would expect rather altered perceived pharmacokinetics).

Anyhow, could the original poster provide a reference to the putative role of magnesium stearate in inhibiting loperamide's absorption?

The several PGP inhibitors ive seen look potentially dangerous. eg propranolol

There are plenty of inhibitors which should be quite harmless, such as those from dietary sources. Of course, it's not clear they are sufficiently potent. I have thus far found three studies in human subjects confirming the ability of quinidine to allow supraspinal activity of oral loperamide (though one of the studies predicted 16 mg loperamide + 600 mg quinidine would be inferior potency to 30 mg morphine (all oral) based on miosis measurements), so there's no need to worry about the basic feasibility of this.
 
Are any of you guys in the medical or chemical profession?

Coz... wowza...

"The restrigated sublinexed C487 correlates extangilly to the GPG receptors; in a double beer-bound survey results were found to be inconclusive."
 
I have found many commonly available items (herbal extracts, supplements or food items) which are p-glycoprotein inhibitors, but inhibition at the BBB is probably trickier.
 
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but inhibition at the BBB is probably trickier.

Why? these studies cited show that these drugs are effective at doing so. Why would the BBB p-glycoproteins be less sensitive to these inhibitors? I assume that there are different subtypes expressed in endothelial cells vs hepatocytes, for example.
 
^the muscles that cause pupil constriction are controlled by the 3rd cranial nerve, which is part of the peripheral nervous system.
 
loperamide gets you really fucked up if you take like fifty tablets anyway. i did so and passed out on my arm for too long, got a neurapraxia and couldn't move my RIGHT arm for 3 months.. but yeah i was a real loperamide junkie for a while. disbelieve me if you wish.

edit: forgot to say that i also did take a pgp inhibitor (venlafaxine) but i've heard it works without them.
 
I too have had some success using lope recreationally. When I was all out of opiates they did the trick and even gave me a nice, heavy euphoria in the same league as low doses of full µ agonists. So higher doses seems promising. Very much unlike any other opioid I've used though (never tried fentanyl or any of its analogues), it has a very synthetic feel to it...but I would definitely say that it has much more pleasant effects than, say, buprenorphine (never found it very recreational myself but it is the most abused opioid around here, lol). Really like how long it lasts too. I haven't dared to experiment with higher doses than a box at a time though because I fear that would propell me into a severely gay OTC diarrhea med addiction.

It was however a long time ago now since I did it because I'm on maintenance since a year back and thus haven't needed it. I have been wanting to try like 96 mg since 32 mg makes me feel pretty damn good. But that can't be healthy for the intestines, it can't.
 
This topic has already been discussed in considerable detail on various bluelight sub-forums......

Personally, years ago I attempted to achieve a central narcotic effect from loperamide, and with many attempts at dose in concert with many compounds (p.o. quinidine, omeprazole, etc, etc).

End result after various idiotic attempts: Yes, some central activity when induced with a combination of agents I cannot recommend (the barrier is there for a reason), but of a very "dirty" nature (like meperidine, but even 'dirtier' and far less 'enjoyable'; certainly not worth the exposure risks of the facilitating agents, not to mention the worrisome toxicological unknowns).

Point: Even when introduced centrally, the drug is inherently shitty, and (again) a potential toxicological nightmare.........
 
Loperamide and Piperine

new to this site ....although been trolling it for a while. then I came across this thread and I had to post a study I found on Piperine (Black Pepper extract) and its effects on inhibiting PGP. The article also mentions other substances that inhibit this enzyme. thanks, here is the link and i posted the article in case it is taken down for some reason.

http://jpet.aspetjournals.org/content/302/2/645.short

Also see --> http://www.answers.com/topic/piperine

Piperine has also been found to inhibit human CYP3A4 and P-glycoprotein, enzymes important for the metabolism and transport of xenobiotics and metabolites.[9] In animal studies, piperine also inhibited other enzymes important in drug metabolism.[10][11] By inhibiting drug metabolism, piperine may increase the bioavailability of various compounds and alter the effectiveness of some medications.[10] Notably, piperine may enhance bioavailability of curcumin by 2000% in humans.[12] The exact mechanism of piperine's bioavailability enhancing abilities is unknown.[13]

Read more: http://www.answers.com/topic/piperine#ixzz1gC0l77mG


Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4

Rajinder K. Bhardwaj1,2,
Hartmut Glaeser1,
Laurent Becquemont1,
Ulrich Klotz1,
Suresh K. Gupta2 and
Martin F. Fromm1

+ Author Affiliations

1Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (R.K.B., H.G., L.B., U.K., M.F.F.); and 2Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India (R.K.B., S.K.G.)

Prof. Ulrich Klotz, Ph.D., Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Auerbachstrasse 112, D-70376 Stuttgart, Germany. E-mail:[email protected]

Abstract

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC50 values of 15.5 and 74.1 μM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with Ki values of 36 ± 8 (liver 1)/49 ± 6 (liver 2) and 44 ± 10 (liver 1)/77 ± 10 μM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.
Footnotes

This work was supported by the Deutscher Akademischer Austauschdienst (to R.B.; Bonn, Germany), Council of Scientific and Industrial Research (New Delhi, India), the Association Francaise pour la Recherche Therapeutique (www.afrt.org, to L.B., France), the Deutsche Forschungsgemeinschaft (Fr1298/2-1; Bonn, Germany), and the Robert Bosch Foundation (Stuttgart, Germany).

DOI: 10.1124/jpet.102.034728
Abbreviations:

HIV
human immunodeficiency virus
TEER
transepithelial resistance

Received February 12, 2002.
Accepted March 26, 2002.

The American Society for Pharmacology and Experimental Therapeutics

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plug=putting drugs up your ass

that way it would avoid first pass metabolism and possibly make its way to the CNS....

although, in all honesty, if simply plugging loperamide up the ass and drinking grapefruit juice is the solution, i'd think someone would have already done it.

but i am just a dumb ass with no real knowledge, so who knows...i certainly don't discourage some experiments(safe ones, atleast).... :D

ya.
 
its the other way round, after first pass roughly only 10 percent morphine survives, and the other 90 percent is M6G. But i do agree that the potency as an mu agonist of M6G is highly debated. The difference between 100mg of oral morphine and 100mg IM morphine is at 5x more euphoric via IM. Though dont trust everything you hear or read here. a well tolerant individual drank 500mg of oral morphine as ordine syrup and found himself in the ED waking up from a naloxone shot. He said he thought that only 10% of the morphine would be availiable and active, meaning 500mg of oral morphine would be much similar to a dose of 500mg of oral codeine (or ~50mg morphine) much to the amusement of the doctors surrounding him. whatever the activity of the metabolites, theres is less euphoria but plenty of the respiratory depressant effects.
 
100 mg of Loperamide + 1 shaker of black pepper + 1/2 liter of olive oil (extra virgin) + 1/2. Mixing the pure loperamide and polysorbate 80 in alcohol would allow them to. loperamide in the guinea pig ileum acts on mu receptors while in using clonipin, muscle relaxants and tegretol.
 
One shaker of black pepper?! That's a brave guinea pig.
 
"The mean (median) times for 50% and 90% of the radioactivity to arrive at the colon were 7.4 (7.3) hours and 9.6 (9.2) hours, respectively. For the loperamide-simethicone combination... the mean (median) times for 50% and 90% of the radioactivity to arrive at the colon were 9.7 (8.1) hours and 13.3 (9.7) hours, respectively."

So simethicone allows loperamide to linger around longer

"Loperamide 16 mg suppresses adrenocorticotropic hormone (ACTH) and cortisol secretion in individuals who do not have Cushing’s syndrome. Because the suppression of ACTH and cortisol is reversed by administration of naloxone, this effect of loperamide is likely mediated by opiate receptors. When corticotropin-releasing hormone is administered, loperamide does not suppress ACTH release, suggesting that the inhibition of ACTH secretion by loperamide does not occur at the pituitary gland."

Now this is new to me... is this typical of all opiates? This would explain how or beloved rockstars Keith Richards and Mick Jagger are still with us today, amongst others, so long as they dont blow their heads off or snag a hep c infection.
 
Well maybe not 1 whole shaker of black pepper. Using a pepper grinder, gind about 2tsp of fresh black pepper for the max amkunt of pepperdine. Pepperdine is usually mixed and sold in combo with certian supplementandherbs like turmeric. Turmeric wont b absorbed unless its mixed with pepperdine which GREATLY increases bio-availability. Turmeric by itsellf is worthless. Also try taking the amino acid supplement "L-tyrosine" a few hours before taking tramadol. It increases the effects at least twofold for me anyway and i was flying 8 hrs later. Yoy can buy id a health food stores or its in some energy drinks tho not 4hr energy. MERRY CHRISTMAS!
 
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I'm telling you, someone is going to figure out how to make Loperamide inherently abusable albeit probably only yielding a dirty, shitty (no pun intended) high.

I'm waiting for this on Channel 7 nightly news:

Loperamide, no your kids don't have chronic, unending diarrhea - more at 7

Admittedly, the whole premise is hilarious if not intriguing if something could actually come of this. I just can't get past that most likely the yield will be something along the lines of a sketchy opiate like pethidine.
 
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