Pharmacology Tilidine - Pharmacology and chemistry

[AlsoTapered]

That's not a truism that's nonsense. Sorry if that sounds harsh, but it's just not true. Several pharmaceutics uni textbooks have entire chapters dealing with the science behind ER/SR technology. It's an extremely complex subject matter that deserves its own subfield of science.
There are entire drug research departments of large, multinational pharmaceutical corporations that do research specifically on how to come up with better formulations. There is an actual science behind it...

I strongly recommend you take a look at the sampled plasma levels of various 'sustained release' formulations. Absolutely none of them produce a steady plasma level, even after chronic consumption.

In fact, I'm keen to see if you can find a single paper which demonstrates a steady plasma level of ANY medicine because I've read several hundred and not found one... which kind of reflects the statement we were taught. Consider it educational.

Think logically - no two people will absorb and metabolize a drug at the same rate so it's an impossible task - the best we can manage is to somewhat reduce variation of plasma levels Different ethnic groups sometimes metabolize drugs at vastly different rates. I've already pointed to one specific metabolic pathway that shows massive differences between certain ethnic groups... and that's just ONE liver. enzyme. Now consider that most drugs are subject to multiple metabolic pathways and their is individual and ethnic variance for them all. Now consider absorption. Their is demonstrated variability in terms of time and overall absorption of a medicine...

It's politics that books teach SR as a fact but it's pretty well documented not to be the case. But no rug manufacturer would wish to draw attention to such a thing. It's not a nice area of science.

SR bupropion (Wellbutrin) is a good one too look at. It turned out that the generic makers copied the release curve the original maker published. Then a significant number of patients suffered seizures because the original manufacturer had, ahem, not been totally honest about their data, Dose dumping is a significant problem.

 

[emkee_reinvented]

There are ways to increase the onset of action of dexedrine, so there is definitely a need for an ER formulation. Well, chemically speaking, all of those compounds are rather boring in my humble view. The only amphetamine that I find truly worth studying is Lisdexamphetamine Dimesylate. I'm trying to figure out since days now what exactly it is in the molecular structure of Lisdexamphetamine Dimesylate which causes the "natural" extended release pharmacokinetic property without the physical alteration of the actual pill to guarantee the ER property. Figuring that out and trying to find methods and possibilities to translate that pharmacokinetic property onto an opioid (basically designing an opioid version of Vyvanse) is an actually worthwile R&D project for which I'd grant a massive budget if I was the CEO or executive chairman (or chairperson if we are supposed to use pc language these days...ugh). Such a vyvanse-like opioid patent would generate billions of dollars in revenue since that'd be the first opioid which is completely impossible to de-retard and the healthcare industry has a desperate demand for such an opioid. 20 years exclusive rights for the sale of such a product...mouth watering

Ruining the slow smooth onset why? That was why I liked it so much. Then again I took it for ADHD. Never exceded my dose, my one experiment ( extracting a lot ) was enough to convince me for me this is a functional stim.

No need to change it imo.

 

[Hexenstahl]

Ruining the slow smooth onset why?

Where did I say that the ER should be ruined?? I was arguing in FAVOUR of ER formulations...

 

[Hexenstahl]

I strongly recommend you take a look at the sampled plasma levels of various 'sustained release' formulations. Absolutely none of them produce a steady plasma level, even after chronic consumption.

In fact, I'm keen to see if you can find a single paper which demonstrates a steady plasma level of ANY medicine because I've read several hundred and not found one... which kind of reflects the statement we were taught. Consider it educational.

Think logically - no two people will absorb and metabolize a drug at the same rate so it's an impossible task - the best we can manage is to somewhat reduce variation of plasma levels Different ethnic groups sometimes metabolize drugs at vastly different rates. I've already pointed to one specific metabolic pathway that shows massive differences between certain ethnic groups... and that's just ONE liver. enzyme. Now consider that most drugs are subject to multiple metabolic pathways and their is individual and ethnic variance for them all. Now consider absorption. Their is demonstrated variability in terms of time and overall absorption of a medicine...

It's politics that books teach SR as a fact but it's pretty well documented not to be the case.

I have never claimed that drugs only qualify as ER when they manage to ensure perfectly steady plasmic levels which is why I don't have to provide you with any such papers because I don't even believe in that definition. That's an arbitrary definition anyway. We humans aren't machines. Even the same person taking the same drug can metabolize a drug a little bit differently from day to day due to factors too numerous to list here. I experience this every day. Sometimes the active high of my Levomethadone lasts me 12h and sometimes "only" eight or so. No matter how good the ER formulation is, ups and downs in blood plasma concentration can't be completely ruled out and it's not even necessary for the drug to be considered ER. What ultimately counts at the end of the day is that the subject taking the drug feels a steady release of the drug. Perhaps in some super abstract ivory tower where researchers get periodically lost in numbers and statistics and end up not being able to see the forest for the trees, an unrealistically perfect line on some graph confirming what that academic armchair theorist has arbitrarily defined as ER/SR, might be important in some sense to him and his fellow researchers, but for purely practical purposes where solving an actual medical problem is more important than pointless hairsplitting semantics, the subjectively felt effect is what counts at the end of the day. When in our clinic 9 out of 10 patients perceive Substitol to give a steady effect for 24h per dose, then that drug counts for all intents and purposes as ER/SR despite that not being perfectly the case on some abstract mathematical level that literally nobody cares about...

Consider it educational.
[...]
Think logically

I really have no interest in arguing with somebody who repeatedly treats me like I'm some mentally retarded idiot with his arrogant and condescending attitude simply because I do not blindly and uncritically conform with his personal ideas and views of how something ought to be. I'm done with this honestly and I'm also out of here. I have no interest in talking with people who cannot get off their high horse and talk at an equal and mutually respectful level with me.

Goodbye...

 

[AlsoTapered]

Wow - well that's me told/ You know more than me after 8 weeks - impressive.

I didn't come up with the idea of SR formulations not working, it's something that is accepted industry-wide. Ask your own pharmacist.

But I can't help wondering if the Dunning-Kruger effect is in action. I, for one, wouldn't study a subject for 2 months and presume to be an expert. I've studied it for 35 years and every single day I realize that their is so much more I don't know.

I assure you I will not bother you again.

 

[Hexenstahl]

Wow - well that's me told/ You know more than me after 8 weeks - impressive.

I didn't come up with the idea of SR formulations not working, it's something that is accepted industry-wide. Ask your own pharmacist.

But I can't help wondering if the Dunning-Kruger effect is in action. I, for one, wouldn't study a subject for 2 months and presume to be an expert. I've studied it for 35 years and every single day I realize that their is so much more I don't know.

I assure you I will not bother you again.

I do NOT claim to know more than anyone. You again manipulatively twisting others' words in their mouth. I'm simply saying what textbooks on pharmaceutics say regarding ER/SR formulations. Open up any chapter outlining the methods and technology of such formulations. I already mentioned two of those (which you very conveniently ignored). Maybe follow your own advice for once and "consider it educational".
There is no industry wide consensus on this. In fact there are various opinions on this topic and not a uniform, collective, monolithic statement saying ER/SR doesn't work because this graph here shows an excess variance of 0.00000X% .

DeathIndustrial88 was absolutely right about you. You have a patronizing attitude that hides behind an appararently helpful mask but really can't wait to always show how supposedly intellectually "superior" you are. I understand now why you actually have been replying to my science related threads. It's not out of a genuine desire to help someone better understand a subject matter, but only to rub under other people's noses how much more you know and how dumb others are. Those replies read totally different now that I'm seeing it through that perspective. If you need that to feel better about yourself, fine go ahead but don't do it in my threads anymore.

Also, next time you promise to give someone something in repayment for help, you should actually try to KEEP that promise and not benefit from it while the other person now sits there empty handed. Thanks to me you have saved $30,000 and what do I get? Nothing. At least say thank you. Is that too much asked?! First time in so many FUCKING years that I'm starting to trust humans again and what happens? I get lied to!
I hope enough people read this here to not ever consider helping you if you ever approach them with a "kind" request. What a fool I was to ever trust you. And I was even dumb enough to tell you personal stuff and my real name.
I should be thankful actually. Life has thrown me that experience to harden me again and be on guard. I was about to become weak...

I assure you I will not bother you again

Yeah I FUCKING hope so! Don't want to ever hear anything back from you! I'm done!

 

[someguyontheinternet]

Deathindustrial also made a bunch of claims about research being corrupt and none of them knowing anything yet does his own "research"

I wonder what papers he reads if scientific publishing isn't reliable

 

[Hexenstahl]

@someguyontheinternet
What are you? AlsoTapered's lapdog or how come you're ALWAYS rushing to his rescue whenever someone argues with him? He can defend himself so stop putting your nose into what is none of your business.

And also, don't you dare maligning behind DI88's back like a snake. If you have something to tell to him or criticize, then tag @DeathIndustrial88 like a grown man and tell it to his face instead of coming here with this whole "Oh I wonder if XYZ hehehe" like some coward. DI88 you have the opportunity to defend yourself if you want.

 

[someguyontheinternet]

I don't know why you think I'm defending anyone

I already told him to his face and I haven't heard back in like 3 days but go ahead and see for yourself. I personally wouldn't trust much of what someone says when they say things like that. Where's he getting the info from, his own lab? Does his fairy godmother whisper in his ear at night about pharmacology?

I generally trust what AlsoTapered has to say because he can always back up his claims with citations, he has a proven track record of doing so. There's some defense for you

Bupe - Why do all Bupe Drs knowingly lie about bupe having little to no side effects and having "no withdrawal"

Yea there is absolutely corruption but not to the degree you imply nor at the areas you seem to think it is. I can tell you haven't had experience in research because you'd have a far different perspective Downplaying is not the same as having a realistic perspective I'm an opioid addict today...

bluelight.org

 

[Hexenstahl]

I don't know why you think I'm defending anyone

Because you're very OBVIOUSLY, in fact visibly doing it. I know why you don't want to admit it. It deflates the ego...

and I haven't heard back in like 3 days

I know DI88 very well. We are actually close friends and I know exactly why he hasn't replied in the last couple days (he hasn't replied to my last email I sent him as well) and I'd like to tell you why he is sometimes absent for longer periods of time but I don't know if I'm allowed to share that personal detail publically. All I can say is that his periodic absence from the forum (in fact all social media and interpersonal social interactions) is health related when he sometimes fails to write back even after a long time and most definitely has nothing to do with him having no arguments. If he wants he can share the reason of his absence but I'd absolutely understand it if he wouldn't want to due to a lack of trust. In fact I recommend against it. I can tell that I deeply regret having ever shared personal stuff with someone here I thought I can trust.

See that's what I find so despicable about some of you people here. You simply start assuming things and don't even shy away from insinuating something about someone in bad faith, which I would excuse if that was based purely on incomplete information. However, my experience here in the last couple weeks has shown me increasingly that people like you couldn't actually care less what the actual reason is because for you people it's simply about being right all the time which doesn't exclude slandering others and talking shit about them just to "win" some argument. Instead of maybe asking oneself if the other side hasn't replied because he is currently busy, or dealing with personal problems or maybe something even happened to him (accident, OD, whatever), or go out of your way and write something like "hey you aight? Haven't heard back from you", your type can't wait to jump and say "baaaahahaa see? SEE?! He hasn't repliiiieeed! Haha what an epic fail I totally mopped the floor with that guy's face woohooo!!!"
It's this infantile and pathetic behaviour that sometimes just makes me wanna quit the social media as there is very often nothing social about it.

 

[AlsoTapered]

Deathindustrial also made a bunch of claims about research being corrupt and none of them knowing anything yet does his own "research"

I wonder what papers he reads if scientific publishing isn't reliable

It is true that trials for new medicines are often designed to hide problems. As the law stands, a pharmaceutical company is under no obligation to publish ALL of their trials. That's why I've always supported;

www.alltrials.net

Many candidates proved to demonstrate problems and so through history we have seen many totally avoidable disasters.

The drug trials that went very, very wrong

Clinical trials that went wrong in recent years have had unexpected and devastating consequences on volunteers

www.independent.co.uk

Now the thing is that a very similar drug to Super-MAB had been trialled a decade earlier and had produced serious toxic symptoms BUT the trial results were never published.

It's not always what's published that's the issue, it's the fact that people are free to publish or not so anyone who reads all of the published papers might still not really get a true idea of the safety or efficacy of a medicine. Often it IS possible to spot dubious trials - I remember Prozac at it's highest prescribable dose was trialled against the lowest dose of amitriptyline prescribed for depression (the latter is also prescribed in low doses for other conditions) so, to no one's surprise, Prozac was shown to be 'equally effective' and thus was granted a market licence.

I've not read much recent stuff on buprenorphine but I do know that it was originally considered as a short-term treatment to reduce the acute symptoms of opiate withdrawal. It wasn't intended to be used for months or years. Of course it's much more profitable if people are simply 'parked' on buprenorphine and I think that is the rub.

At the end of the day medicines are very costly to develop. Even a new formulation of an off-patent compound is a very expensive exercise and it's my experience that ethical considerations rarely count for much. I have seen many examples of medicines and formulations of medicines that looked at as the optimal treatment for a patient are not very good but as a way to make a profit make perfect sense. That amitriptyline is a better antidepressant means that many patients did not obtain the optimal outcome. Now, to be fair, Prozac is much safer in overdose and I'm quite sure that doctors were very happy that such a drug was available BUT it remains to be seen if the dangers of intentional amitriptyline overdose (suicide) are more or less than suicides among people for whom Prozac proved ineffective. Now technically pharmacovigilance by Eli Lilly SHOULD disclose that detail but their was and is no requirement for such a study and to the best of my knowledge nobody has done so in spite of the fact that the numbers are not vanishingly small. So Eli Lilly had a 'blockbuster' with a medicine that truthfully isn't that good.

I'm not quite sure what point was being made about buprenorphine but it's been in the BNF since the late 1980s but it has never been a popular analgesic among UK doctors which, since they prescribe based on previous experience, suggests that they have seen enough negative outcomes to make it a second-line treatment. I'm guessing that nausea is one problem. I know KW Bentley remarked on the issue.

 

[Skorpio]

The issue with dextromoramide is that it's relatively short acting. Sure, the biphasic hl can last up to 22h, but the psychoactive effect of the active metabolite is quite short. People often erroneously think half life equals duration of action. Its long hl guarantees that you won't enter wd for 22h (depending on whether or not you're a fast metabolizer), but the actual duration of action of dextromoramide is quite short and therefore not suitable anymore for maintenance since we have better options. However, those better options are unfortunately completely unavailable for americans (Substitol which is a 24h acting morphine pill and Polamidon which is Levomethadone-HCl, the non-cardiotoxic and even longer acting opioid compound than Methadone) and the vast majority of the world in general. Swiss people have it even better. They have access to extended release heroin pills (Diaphin).


There are ways to increase the onset of action of dexedrine, so there is definitely a need for an ER formulation. Well, chemically speaking, all of those compounds are rather boring in my humble view. The only amphetamine that I find truly worth studying is Lisdexamphetamine Dimesylate. I'm trying to figure out since days now what exactly it is in the molecular structure of Lisdexamphetamine Dimesylate which causes the "natural" extended release pharmacokinetic property without the physical alteration of the actual pill to guarantee the ER property. Figuring that out and trying to find methods and possibilities to translate that pharmacokinetic property onto an opioid (basically designing an opioid version of Vyvanse) is an actually worthwile R&D project for which I'd grant a massive budget if I was the CEO or executive chairman (or chairperson if we are supposed to use pc language these days...ugh). Such a vyvanse-like opioid patent would generate billions of dollars in revenue since that'd be the first opioid which is completely impossible to de-retard and the healthcare industry has a desperate demand for such an opioid. 20 years exclusive rights for the sale of such a product...mouth watering

Remifentanil kind of did the opposite of this; making a fentanyl analog that is cleaved by plasma esterases, so that it has a short half life which is not lengthened by administration of large doses or by other drugs metabolized by the liver.

I guess vyvanse is similar in that it gets cleaved by plasma enzymes (peptidases in this case) which is independant of hepatic metabolism. The difference is that vyvanse is a prodrug, where remifentanil simply becomes inactive after metabolism. It isn't known exactly what enzyme cleaves the lysine, as there are a bunch that do so when measured in isolation, so it is likely multiple, functionally-overlapping enzymes that perform the peptide bond cleavage.

I do remember when hydromorphone sr pills switched over to the OROS system to prevent dose dumping when the pills were consumed with alcohol.

A chemical time release mechanism would make it much harder to tamper with (other than by incubating it in vitro with peptidase enzymes before consumption).

Also for everybody in this thread, please try and assume good faith to the other members of this thread. We all have different levels of knowledge and should be respectful of each of our differences. Everybody benefits when the atmosphere is collegial and we all align with the purpose of answering questions.

 

[AlsoTapered]

I believe a few drugs are metabolized by 'non-specific plasma enzymes' (to borrow a phrase) but remifentanil is kind of unusual because it was possible to lose over 99% of the activity of carfentanil and still end up with a potent opioid. As I understand it, remifentanil is administered as a continuous infusion with the dose constantly being adjusted according to response.

I don't believe, the OROS formulation iused in any UK products but I have to admit that it's a really clever idea. I wonder what the costs are like? It's especially valuable for medicines that aren't taken in a chronic manner but (roughly) just in the day time.

Kind of an odd selection of medicines that it's been applied to but if one can ensure that dose-dumping won't be an issue, it makes titrating a patient up to an effective level a much safer process.

 

[emkee_reinvented]

Where did I say that the ER should be ruined?? I was arguing in FAVOUR of ER formulations...

Maybe you misinterpreted my answer but I favor the IR of dextro-Amfetamine. IMO it allready is slow and smooth acting. Maybe you only experience it when you where used to MethylPhenidate. The first line treatment for ADHD.

Methylphenidate the opposit, that one should due to its Pharmakinetic's alway's be ER. At least for fast metabolizer's like me. Even then it would worry me it would interfere with my sleep. While on IR d-Amphetamine at a herapeutic dosage sleeping would be no problem. But that could be a personal chemistry thing.

 

[Hexenstahl]

Maybe you misinterpreted my answer

Indeed. I misinterpreted your answer and I apologize for that emkee. I'm sorry. English isn't my first language so I hope you can cut me some slack. Strangely I'm also a fast metabolizer when it comes to amps (and stims in general. Cocaine for example only lasts like 20 minutes for me whereas others are always high from anwhere between 30 and 45 minutes), but for some reason I'm a slow metabolizer when it comes to opioids. Odd, isn't it
But hey, I do NOT complain lol. I prefer to metabolize opioids as slowly as possible. In fact I'd like to mass murder the enzymes responsible for metabolizing opioids, so I can take just one dose and be high for the rest of my life lol

 

[DeathIndustrial88]

"someguyontheinternet" apparently needs to find a life.... off the internet.


LOL to see this shit talked about in a thread that has nothing to do with that argument.
I simply stopped responding because A) I had already won the argument anyway, whether or not big pharma & the government falsify information doesn't have jack to do with questions like "So have you ever worked in a lab"? Really? It takes a rocket scientist to sniff out corruption? lol

And also B) I have shit to do & I don't really care about ego, so I actually don't give a fuck to finish an argument with some one who keeps deflecting to nonsense "I'm smarter than you" bullshit. You didn't even have any rebuttals. "Have you worked in a lab" is not a rebuttal to anything I provided. Do you work for big pharma? Cause Idk why any drug users here would wanna defend corrupt pieces of shit like that.

And C) to your comment about "I wonder what papers he reads if scientific publishing isn't reliable"....... Uh you're aware non-US literature exists right? You know like the literature that said tramadol was an opioid for 30 years, while the US's literature said it wasn't?
But of course you'd know I've already mentioned that in that thread, but you were too busy trying to "one up" me that you apparently forgot how to read. And yeah actually I do question the science I read. That doesn't mean ALL of it is incorrect & It's not hard to corroborate it with non-US literature.

Why are you mucking up this thread with this buillshit anyway? What are you, 12?
I'm not gonna keep arguing here either as it has jack shit to do with the topic & I'm not gonna dirty up Hexenstahl's informative post with ego wars. Although I know you'd really like to.


I come here to help people with harm reduction & to learn. Not help "someguyontheinternet" stroke his ego. You know what would be even better for your ego? Maybe getting off the fucking internet for awhile?


@Hexenstahl My beautiful friend, I will speak with you soon! ^_^ Thanks for always having my back! Bullshit like this makes me wanna ditch BL altogether, especially lately.

@Skorpio Much love my friend! You've taught me a lot in the past & you're always sharing knowledge without being condescending about it. I appreciate that.


Now, let's keep this thread clean! I have too much respect for Hexenstahl to muck up her thread with another 10 pages of arguing with somebody. If "someguy..." wants to think he "won" cause I simply stopped giving a shit, then go for it buddy. My life will go on. I got better things to do.

 

[someguyontheinternet]

You want to keep the thread clean yet you post more of the same? Nice

 

[DeathIndustrial88]

LOL

"how dare you defend yourself in the thread I was talking shit about you in"...



Seriously dude, fuck off.

 

[Hexenstahl]

Now, let's keep this thread clean! I have too much respect for Hexenstahl to muck up her thread with another 10 pages of arguing with somebody.

I'm actually considering deleting this thread just like I did with the other two science related threads I created, because sometimes I sometimes feel like this forum doesn't deserve such threads. I mean just look at the replies. For god's sake, instead of all coming together (regardless of anyone's level of knowledge, we are ALL lifelong students.) and COLLABORATING together (the real reason I have created these threads) to discuss, discover, ask, answer and perhaps even create something together, it ends up becoming a childish dick-measurement contest where people just try to show everyone else how right they are and just how much they know in more or less subtle patronizing ways. If then someone dares to voice legitimate criticism, various logical fallacies are used, from appeal to authority to the accomplishment fallacy (muh experience, so shut up you greenhorn), and the worst of all: straight up LIES! Putting words and intentions into my mouth that I have NEVER actually said or meant. A forum with such members does NOT deserve such threads. I'm gonna take these things to an actual chemistry and pharmacology forum (there is a good german one I know of, even though it has like only 5 active members, but at least they are humble and open to being corrected despite having a billion years of experience under their belt, which btw doesn't protect you from being wrong) which is a place better suited for such discussions where people actually collaborate together.

Also funny how AT told me the entire time how ER/SR doesn't exist and is merely a "political" designation, but then when Skorpio literally said the same thing that I said (OROS System) he suddenly turned around and was like "oh uh yeah, that OROS thing...pretty cool stuff mate". So the exact same thing you told me happened in that bupe thread and why you eventually stopped replying to such an hopeless case has repeated itself here. These kind of things just show me that there is some personal ego stroking shit going on behind posting such "educational" replies here and not an actual desire TO TEACH AND BE TAUGHT IN LIKE MANNER.
I think I'll sleep one or two nights over this and then decide whether or not I delete this thread. I have copied my entry post and translated it in german in case I do delete it so I can then post it in the german pharmachem forum.

I will speak with you soon! ^_^

Hey no hurries buddy. Take your time, ok? It ain't like I'm sitting here all day and wondering when doomy-gloomy deathy industrially (hehe I like to cutify other people's names...tehehe ) will finally reply to my emails. So chiiiilllllll


EDIT:
earlier I said "A forum with such members does NOT deserve such threads". That was perhaps not really fair, as 99% of all members I have talked to here ever since I registered are completely fine. It wasn't my intention to generalize. It's just that the remaining 1% are very vocal and acive and can make or break a thread. That's what I wanted to say and not that BL as a whole is responsible. You guys are great, especially the staff!

 

[someguyontheinternet]

Also funny how AT told me the entire time how ER/SR doesn't exist and is merely a "political" designation, but then when Skorpio literally said the same thing that I said (OROS System) he suddenly turned around and was like "oh uh yeah, that OROS thing...pretty cool stuff mate".

The context was dose dumping in terms of consuming the pills with alcohol not that it was creating a constant plasma concentration. Dose dumping in this context is defeating a mechanism that slows release.

Also plasma concentration does not necessarily correlate with perceived effects, I don't use an extended release mitragynine extract but I perceive the same level of benefit for the entire day from one morning dose. The plasma concentration is changing over that time