Why "Horror Drugs" Sold for Billions After the Tragedy (Science of Thalidomide)
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- เผยแพร่เมื่อ 1 ก.ค. 2024
- 👶 You are wrong if you think that the thalidomide tragedy put an end to this molecule. Scientifically - with all due respect to harmed individuals - this molecule proved to be incredibly innovative, unlocking a completely new mechanism of action of "therapeutic glues".
❓ What is thalidomide? Why is one enantiomer safe and the other is not?
In this video, we uncover the history, chemistry, biology and pharmacology of thalidomide and related molecules like lenalidomide.
If you are a science enthusiast or interested in pharmaceuticals in general, this video is for you!
Disclaimer - This channel does not provide medical advice!
No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on TH-cam.
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Note: A page abbreviates cereblon incorrectly as CBRN :)
00:00 Thalidomide - Horror Drug with Massive Profits?
01:35 Origins of thalidomide and Chemie Grünenthal
02:51 Initial findings of thalidomide side effects
03:45 Targeted protein degradation and molecular glues
06:19 Why did they not notice thalidomide side effects?
07:21 Chemistry and synthesis of thalidomide
08:47 Aftermath of thalidomide: Contergan trial
09:40 Thalidomide in the US: Narrowly avoiding a disaster
11:07 Learnings from the tragedy
11:55 Thalidomide benefit in leprosy and multiple myeloma
14:06 Lenalidomide, thalidomide's younger big brother - and lawsuits
16:51 More next-generation cereblon modulators (iberdomide)
17:56 Covalent modification of cereblon
18:40 THANK YOU!
Key references:
- Frances Oldham Kelsey. FDA medical reviewer leaves her mark on history | FDA Consum 2001, 35, 24
- The Thalidomide Syndrome | Scientific American 1962, 207, 29
- THALIDOMIDE AND CONGENITAL ABNORMALITIES | Lancet 1962, 279, 45
- The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement | Int J Mol Sci 2020, 21, 6429
- Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment| Acta Pharmaceutica Sinica B 2022, 12, 3548
- Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in medicine and chemical biology | Cell Chem Biol 2021, 28, 987
- Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice | Blood 2018, 132, 1535
- Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs | PNAS 2015, E1471
- Lawsuit Blames Thalidomide for More Birth Defects | Scientific American 2011
- Antitumor Activity of Thalidomide in Refractory Multiple Myeloma | NEJM 1999, 341, 1565
- Immunomodulatory Drugs for the Treatment of B Cell Malignancies | Int. J. Mol. Sci. 2021, 22(16), 8572
- NPR.org “How A Drugmaker Gamed The System To Keep Generic Competition Away” (2018)
- A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos | J Med Chem 2018, 61, 535
- Cereblon covalent modulation through structure-based design of histidine targeting chemical probes | RSC Chem. Biol. 2022, 3, 1105
Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
- Nicolaou; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures) - วิทยาศาสตร์และเทคโนโลยี
![ภาพนี้ก็ฮาเหมือนกันนะเนี้ย #1 SS8 [ พากย์นรก MEME.EXE ] | easy boy](http://i.ytimg.com/vi/Ytc50m91QK8/mqdefault.jpg)
🎄 Not the most cheerful topic, but as we see there is some connection to Christmas here. Wishing you all a great wrap-up to 2023 and a restful holiday period.
Thanks again to all channel supporters and followers! Let me know any thoughts as always.
www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
Thanks for the info. As a pharmacist, this information is crucial for understanding how important drug safety is, independently the of step in which we are working.
Thanks for watching!
This is my absolutely favourite type of content on yt. Please never stop making these. The more you go into the MOA, the better
Thank you! This video wasnt shown to many viewers for some reason but comments like yours are very encouraging, I will definitely make more in future
Thalidomide is a very good drug for sleep, rivals the barbs, anyone who has tried them will agree
This IS a miracle drug, but they did not practice safety at all! It was only dangerous during a few weeks of pregnacy.
Exactly, although use later in pregnancy did not lead to those obvious malformations but some other detrimental effects as well
Thank you for the excellent video!
Thank you so much for the video, i especially love the part explaining in deep details the biochemical mechanism
Thanks for your comment! Glad you enjoyed this
More drug scandle videos please! Really enjoyed this one
Awesome, thanks. There is some other big and small stuff, I will put on my list for 2024 :)
new total synthesis video
💕💕💕
Love your channel🙏🙏
Thank you 🥰
The fact that the _shape_ of a molecule can be understood and then tailored to suit is very nearly miraculous.
Super cool
I like your videos
Thanks mate!
fascinating stuff
Thanks for making it clear out of the gate that there is no way for pregnant people to ingest this safely!
*Pregnant Women
Very interesting background information, though the chemistry was pretty simple due to a non-complex target molecule. What do you have planned next?
Thanks mate. Yeah the chemistry was pretty modest on this one. I'm gonna mix some easier but visual chemistry, as well as advanced organic synthesis in upcoming vids. Maybe another psychedelic (e.g. salvinorin A) as well in future. I basically have an infinite list of topis I'd like to cover, the question is time to make videos :)
The literature is about to learn how to make these compounds like crazy, trust me...
I'm curious about mechanism of action as sedative. There's little info on how it works on CNS. It would be a good idea to explain this mechanism
Yeah I do agree I actually didnt find much info on this one when researching, I'll check
@@totalsynthesis It would be great to see what's the base mechanism of action which was the reason why this drug was prescribed in first place, and made it so infamous.
@@szalonydoktor I don't think it's really. See here: www.ncbi.nlm.nih.gov/pmc/articles/PMC9780081/
"Sedation is a consistently reported effect in clinical studies of THD (see Millrine and Kishimoto, 2017), including when evaluated for efficacy against CINV (Zhang et al., 2017). It may be speculated that a general reduction in arousal level may reduce perception of nausea (involving thalamo-cortical arousal) but it is less likely to affect vomiting as this can be evoked even under general anaesthesia (Andrews et al., 1990). However, other drugs with sedative/hypnotic activity such as propofol, midazolam and olanzepine also have ‘anti-emetic’ activity in humans (Borgeat et al., 1992; Tarhan et al., 2007; Davis and Sanger, 2020) so could this be the case for THD? Propofol acts on multiple ligand-gated ion channels, including the GABAA, glycine, nicotinic and weakly, 5-HT3 receptors (Trapani et al., 2000). Positive modulation of the inhibitory function of GABAA receptors by propofol (Barann et al., 2000; Trapani et al., 2000) has been demonstrated in the NTS (McDougall et al., 2008) and the AP (Cechetto et al., 2001) and could contribute to a direct anti-emetic effect in post-operative nausea and vomiting and CINV even when propofol is administered at sub-hypnotic doses (e.g., Ewalenko et al., 1996; Gan et al., 1997; Kim et al., 2000). The sedating benzodiazepine medazoline may also be efficacious against post-operative nausea and vomiting (PONV) at sub-hypnotic doses, and like propofol modulates neuronal activity by binding to the GABAA-benzodiazepine receptor complex (Tarhan et al., 2007). Finally, the antipsychotic drug olanzapine, which also causes sedation can inhibit vomiting (Davis and Sanger, 2020 for review). This drug also antagonises activity at multiple receptors (D1, D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, α1 adrenergic, H1 and m1, m2, m3, m4 receptors) many of which may be involved in the mechanisms of vomiting although antagonism of the H1 receptor is most likely responsible for the sedative actions of olanzapine within the cerebral cortex (Davis and Sanger, 2020).
With regards to THD, binding studies (see below) at a range of different receptor and enzyme targets do not suggest an ability to interact with any of the anti-emetic mechanisms suggested for propofol, medazoline or olanzapine (Kanbayashi et al., 1996). Interestingly, in silico studies suggest that THD can dock with the benzodiazepine pocket of the GABAA receptor (Asadollahi et al., 2019). These findings contrast with an inability of THD to bind to this area (Kanbayashi et al., 1996; see below) but do indicate that further studies are needed to look for an ability of THD to modulate GABAA function (see also 6.2, iii).
Neurophysiological and molecular studies of the sedative/hypnotic actions of THD show that it does not appear to involve the cereblon-mediated ubiquitin/proteasome pathway (Hirose et al., 2020). However, a THD-induced depression of cortical excitatory transmission, partially mediated pre-synaptically, was observed in the absence of an effect on inhibitory transmission (ibid). Earlier animal studies differentiated THD from pentobarbital in several ways: i) THD increased slow wave sleep and rapid eye movement sleep at doses which did not induce ataxia; ii) THD did not reduce pre-optic area activity; iii) THD enhanced the sleep-inducing effect of basal forebrain stimulation (Frederickson et al., 1977; Kaitin, 1985). THD has an acute, rapid onset sedative/hypnotic effect with a different profile from barbiturates. The sedative/hypnotic effects in both human and animal studies suggest a central action involving suppression of excitatory neurotransmission which if it occurred in critical parts of pathways receiving stimuli inducing nausea or vomiting (e.g., NTS, AP) could also directly affect induction of nausea and/or vomiting (rather than indirectly through reduced arousal)."
@@totalsynthesis Thank you for your effort. So the answer is "we don't know" 😁. Thought mechanism will be known at this point. I was reading about speculation on THD as H1 antagonist and GABAa agonist many years ago
didnt walter white teach this to his students
7:50
Great work ! To be fair the side effect is very specific, especialy compared to what thoes nazi must have had already tested so it looked safe for them lol
Yep that's absolutely right
This was the first thing that came to mind 😂
Teratogenic drug
Im so annoyed that the only way i noticed this video is your community post.
Man I dont know why but the algo hasnt been liking my past videos, it's not recommending to my subs very much 😂
But thats good feedback for me to continue doing some video-related community posts once in a while
@@totalsynthesis I even have notifications turned on... But keep putting out the amazing content!
thank you!! @@abs0lute-zer061