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⫸STICKY⫷ ⫸OD library vs. gettin' nerdy with Pubmed⫷

kleinerkiffer

kleinerkiffer

Bluelight Crew
Joined
Dec 9, 2012
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This is a place to post interesting papers and articles with the main topic being Drugs and Pharmacology, but other topics/fields like neuroscience and biology are gladly appreciated as well :D

I'll start with a really interesting story about why it's important to keep an eye on reaction temperature and how a drug impurity helped with Parkinsons research:
https://arstechnica.com/science/201...g-people-but-kickstarted-parkinsons-research/
 
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Haven't read the link you posted, but I'm pretty sure I don't need to.

Case of the frozen addicts, right? MPTP formation after elimination of propionic anhydride when the reaction producing a prodine analog (similar to the pethidines, ketobemidones etc.) was short-cut in order to hurry up formation of a batch, by increasing the heat the rxn was conducted at.

Unfortunately, it resulted in elimination of the ester, dehydration to the tetrahydropyridine, MPTP, which fries dopaminergic neurons in the substantia nigra, causing instant uber-parkinsons from hell.

Am I right?

I like the premise of this thread. IMO it ought to be made a sticky if we can make it take off.

And of course, regular updates on sci-hub addresses, when those Elsevier cockgarglers get another court order and make the creatrix of sci-hub need to get off her arse in order to give them the middle finger and shout 'oi fuck off yeh wiggy cuntocks=D' and rehost it.

One would think, surely, that whilst Elsevier and their ilk are as grasping and greedy as the day is long and faecal matter stinks of 4-methylindole, they are not so STUPID as to actually believe participating in a protracted, costly game of whack-a-mole with someone based in eastern europe who they cannot lay a finger on, bar shutting down individual hosts, will EVER 'win the war on terror.....greedy grasping shitbags of journal publishing houses that is, being terrorized. Sorry, this time, you lose, you lost before you ever started bitching, and you just have to put up with being owned. Sorry, but up yours, thats the way its going to be=D
 
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Knew it. IMO getting this sort of thing up and loaded with useful material, which I'll do myself when I run into useful/interesting papers, it's a good idea, to get more advanced material out of the sole realm of NSPD. Some might feel they lack the level of knowledge to participate, feel shy of entering.

Basically, to get it out there, or out here, in here, whichever way one wants to put it=D.

Suggested format of full text papers is posting the sci-hub links, or direct links to copies hosted somewhere, of the full texts.
 
^I think we shouldn't post sci-hub links etc due to copyright problems

If anyone reading this thread has problems understanding some mechanism or other things don't be afraid to ask and we'll try to explain it as best as we can :)
 
This one might be particularly interesting for people with chronic pain, there's only been a study on mice, but nevertheless sounds very promising.
Painkillers crafted with a part of the wrinkle-smoothing drug Botox provide long-term pain relief in mice.

Researchers added the modified Botox to molecules that target pain-messaging nerve cells. Mice given a single spinal injection of the new drugs showed signs of pain relief for the full duration of the experiments, around three weeks, researchers report online July 18 in Science Translational Medicine. Such painkillers could potentially one day be developed for humans as alternatives to more addictive drugs, such as opioids.

Created by the bacterium Clostridium botulinum, botulinum toxin causes the food poisoning disease botulism. Botox, which is made from the toxin, is often injected into people to iron out worry lines and has been used to treat conditions that involve overactive muscles, such as repetitive neck spasms or overactive bladder (SN: 4/5/08, p. 213). The toxin has also been used to reduce the frequency of migraines.

Biochemist Bazbek Davletov of the University of Sheffield in England and colleagues focused on botulinum toxin because it can stop certain nerve cells from communicating with one another for up to five months with each injection. And “you locally inject less than a millionth of a gram, which is helpful to avoid any immune response,” he says.

Davletov and colleagues created their new drugs with a process he describes as a “molecular Lego system.” Taking the part of the botulinum toxin that blocks nerve cells from sending messages, the team attached the piece to one of two molecules that target neurons that relay pain information. The researchers removed the part of the toxin, found in Botox, that binds to muscle-controlling nerve cells.

In the new study, the scientists injected SP-BOT, a botulinum toxin-based pain reliever they’d made previously, into the spinal fluid of male mice with pain due to nerve damage. SP-BOT provided pain relief starting around three days after the injection and lasted through the rest of the experiment. In another experiment, SP-BOT also mollified pain from inflammation due to a different injury.

The researchers also created a new formula, called DERM-BOT, which targets nerve cell opioid receptors with dermorphin, a natural opioid secreted from the skin of a South American tree frog. DERM-BOT injected in mice with nerve damage kicked in right away and then provided pain relief to the rodents for over three weeks. The drug was also likewise effective in lessening pain from injuries that produced inflammation.

The team gauged the painkillers’ effectiveness by poking the animals’ paws with plastic filaments of different diameters. Mice in pain withdrew their paws from the finer filaments, Davletov says, while mice with pain relief didn’t withdraw until prodded by the thicker filaments, the same behavior seen in healthy mice.

Injecting the drugs into healthy mice caused no mobility issues, the researchers found, indicating that the drugs did not target muscle-controlling nerve cells as Botox does.

Neuroscientist Luana Colloca of the University of Maryland, Baltimore, who was not part of the study, says the drugs are promising candidates for further research in humans. Short-term painkillers, including morphine, may require multiple daily doses, and a body can build up tolerance and require higher doses for relief, she says. “One single administration lasting for several months can reduce the risk of dependence and addiction.”

But the drugs should be tested in female animals, Colloca adds. “We truly need to know if this data apply also to women in pain.”
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https://www.sciencenews.org/article/how-variation-botox-could-be-used-treat-pain

The article can be found here: http://stm.sciencemag.org/content/10/450/eaar7384 it's just the abstract, but there are ways around the paywall
 
So you are prescribed or use benzodiazepines regularly and develop an infection that requires an antibiotic. Something you might want to mention to your doctor, as many are unaware.

  • Fluoroquinolone antibiotics [ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin)] compete directly with benzodiazepines for the benzodiazepine receptor site displacing benzodiazepines and precipitating an acute withdrawal effect.
    .
  • Benzodiazepine dose-tapering and/or cessation might be associated with GABAergic underactivity but rebound neuro-excitation following fluoroquinolone exposure.
    .
  • Alterations in the GABAA?benzodiazepine receptor complex (during benzodiazepine tolerance/dependency status) may increase fluoroquinolone-induced stimulation of the receptor complex.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435654/
 
APAP/ Acetaminophen/ Paracetamol overdose and toxicity is a large problem and only growing in the states since we add it to Everything OTC, as well as most of our oxycodone, hydrocodone, tramadol & codeine. Though along with SAMe and parenteral N-AcetylCysteine a new substance is showing promise:

Co-administration of fresh grape fruit juice (GFJ) and bergamottin prevented paracetamol induced hepatotoxicity after paracetamol overdose in rats.

In conclusion, GFJ and BGT prevented PAR-induced hepatotoxicity after PAR overdose in rats, and this calls for appropriate observation studies in humans.
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https://www.ncbi.nlm.nih.gov/pubmed/28962403
 
"Despite the widespread consumption of ethanol, mechanisms underlying its anesthetic effects remain uncertain. n-Alcohols induce anesthesia up to a specific chain length and then lose potency—an observation known as the “chain-length cutoff effect.” This cutoff effect is thought to be mediated by alcohol binding sites on proteins such as ion channels, but where these sites are for long-chain alcohols and how they mediate a cutoff remain poorly defined. In animals, the enzyme phospholipase D (PLD) has been shown to generate alcohol metabolites (e.g., phosphatidylethanol) with a cutoff, but no phenotype has been shown connecting PLD to an anesthetic effect. Here we show loss of PLD blocks ethanol-mediated hyperactivity in Drosophila melanogaster (fruit fly), demonstrating that PLD mediates behavioral responses to alcohol in vivo. Furthermore, the metabolite phosphatidylethanol directly competes for the endogenous PLD product phosphatidic acid at lipid-binding sites within potassium channels [e.g., TWIK-related K+ channel type 1 (K2P2.1, TREK-1)]. This gives rise to a PLD-dependent cutoff in TREK-1. We propose an alcohol pathway where PLD produces lipid-alcohol metabolites that bind to and regulate downstream effector molecules including lipid-regulated potassium channels."
https://www.sciencedirect.com/science/article/pii/S0022283618310441?via=ihub
 
You though GCPRs (G protein-coupled receptors) are difficult enough? Welcome to the world of 'Functional selectivity':
Humans express more than 800 G protein–coupled receptors (GPCRs), through which myriad physiological, immune, and neurophysiological processes are regulated (1). These receptors are embedded in the cell's plasma membrane and bind to extracellular chemical stimuli (agonists). This interaction induces conformational changes in the receptor that converge at intracellular sites that bind to either heterotrimeric guanine nucleotide–binding proteins (G proteins) or to β-arrestin proteins that block G protein binding and lead to receptor desensitization and internalization, as well as provide a scaffold for protein regulatory complexes that control gene expression (2). Many agonists induce functionally selective or biased states of the receptor, wherein one pathway is activated with greater efficacy than another (3). Thus, GPCRs are not simple on-off switches, but can adopt multiple conformational states to control diverse processes. On page 1106 of this issue, Liu et al. (4) provide clues as to how a GPCR called the β2-adrenergic receptor (β2AR) can tune its conformation to achieve a balance of functional outcomes, as directed by the chemical structure of the receptor agonist.
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http://science.sciencemag.org/content/335/6072/1055
 
Jekyl Anhydride said:
So you are prescribed or use benzodiazepines regularly and develop an infection that requires an antibiotic. Something you might want to mention to your doctor, as many are unaware.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435654/
Click to expand...

Ibe mentioned this before. Ibuprofen (and other nsaids, surely) also compete for ga a receptors, albeit at a low level

I avoid certain antibiotics and ibuprofen now, which doesn't leave many otc options.

I'll try to post a link, thoughtge info is a u da rly outthere, even though it's oddly not well known

Having problems quoting , however this study confirms the above, and even list the antagonistic potency of
the nsaids. Ibuprofen is low on the list

https://www.ncbi.nlm.nih.gov/m/pubmed/8388990/
Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxacin, enoxacin, and pipemidic acid), known to be gamma-aminobutyric acid (GABA) antagonists, fully reversed the inhibitory effect of GABA on [35S]t-butylbicyclophosphorothionate ([35S] TBPS) binding to rat brain membranes in vitro. Twelve indomethacin/ibuprofen-like arylalkanoic acid (AAA) anti-inflammatory drugs alone had no effect on [35S]TBPS binding, or on its inhibition by GABA, but potentiated the GABA-antagonistic effects of the four quinolones. Felbinac (4-biphenylacetic acid) was most potent in this respect (EC50 = 110 nM, together with 5 microM norfloxacin), followed by flurbiprofen > anirolac > metiazinic acid > tolmetin = ketoprofen = fenbufen = indomethacin > fenoprofen > ibuprofen = (+)-naproxen = sulindac. Other anti-inflammatory analgesic drugs, including aspirin, diclofenac, diflunisal, meclofenamic acid, mefenamic acid, nambumetone, phenacetin, piroxicam, and phenylbutazone, failed to potentiate the GABA-antagonistic effect of norfloxacin. Felbinac (1 microM) increased the GABA-antagonistic potencies of norfloxacin and enoxacin about 26-fold, while increasing those of ciprofloxacin and pipemidic acid 7-fold and 2.3-fold, respectively. Using subsaturating concentrations of the four quinolones, concentration-response curves for felbinac yielded EC50 values ranging from 110 nM with 5 microM norfloxacin to 1.3 microM with 100 microM pipemidic acid. Three other piperazinoquinolone antibacterial agents (amifloxacin, difloxacin, and fleroxacin) and four nonpiperazinoquinolone anti-bacterial agents (oxolinic acid, cinoxacin, nalidixic acid, and piromidic acid) were much weaker GABA antagonists and were not significantly potentiated by felbinac. All other known GABAA receptor blockers tested, including R 5135, pitrazepin, bicuculline, SR 95531, strychnine, D-tubocurarine, thebaine, securinine, theophylline, and caffeine, were not potentiated by felbinac. Our results suggest that norfloxacin and related piperazinoquinolones, acting at GABAA receptors, may induce a high affinity binding site for indomethacin/ibuprofen-like anti-inflammatory agents (the AAA site) that, when occupied, reciprocally increases the affinities of the quinolones for GABAA receptors. The AAA binding site may be a new site in the GABAA receptor complex.
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I've gone ahead, merged your posts and added the quote :)
 
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Some great news for people abusing opioids
Researchers at the University of Washington have developed a cellphone app, called Second Chance, that uses sonar to monitor someone's breathing rate and sense when an opioid overdose has occurred. The app accurately detects overdose-related symptoms about 90 percent of the time and can track someone's breathing from up to 3 feet away. The team will publish its results Jan. 9 in Science Translational Medicine.
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https://medicalxpress.com/news/2019-01-smartphone-app-opioid-overdose-precursors.html
 
^ Apple/ Androids should be loading that on phones straight out the factory!

The future of pain control?? No fun but gets the job done??

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

AT-121 suppressed oxycodone’s reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.
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http://stm.sciencemag.org/content/10/456/eaar3483
 
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