So let’s finally talk about peptides. And I don’t mean peptides as chemists and biologists understand them (short chains of amino acids) I mean “Peptides!”, the hot new wonder drugs that you can order by mail. Oh man.

The first barrier to writing about this situation, for someone like me, is that difference in terms. For a chemist, “peptide” has a pretty clear definition: any relatively short chain of amino acids, and when they get longer we go ahead and call them “proteins”, although the dividing line is a matter of personal opinion. So the number of different possible peptides is just ridiculously huge. If you just pick (say) a ten-amino-acid chain with the 20 common amino acids, that’s twenty to the tenth power, which is over ten trillion possibilities. For comparison, it has been about ten trillion seconds since Homo sapiens emerged as a separate species.

And since that number is large and contains multitudes, there are lots of physiologically active peptides and an even much more gigantic mass of them that biologically do nothing at all. As you digest any particular piece of protein (being from Arkansas, I recommend a plate of barbecue or fried catfish) the enzymes in your stomach and small intestine are producing huge numbers of progressively shorter peptide chains as they break down that food on the way to stuff that will be absorbed into the bloodstream. And this is while every living cell is making progressively longer peptide chains off the ribosomes, building back up the proteins needed for life. This is why I I had a puzzled look on my face when I first saw people talking excitedly about how they were taking “peptides” as if that were a well-defined category that everyone knew about.

Mentioning digestion brings up the question of stability. Your body is also awash with enzymes (proteins themselves!) that do a terrific job of breaking down peptide bonds. So the lifetime of any random protein string in the blood is probably going to be limited, but the subject of today’s post is not random peptides. Nope, it’s amazing wonder peptides ordered from suppliers who mail them directly to your house, stuff that will variously energize your waking hours, cure your diseases, melt your fat deposits, build your muscles, grow your hair, and extend your lifespan. You’re not going to be taking these things orally, because unless a really substantial amount of engineering has gone into it, any given peptide is going get the same treatment from your digestive system as a chicken breast does, i.e. a complete teardown. These mail-order peptides are injectable items.

At one point that would have severely limited their use, but the advent of the GLP-1 drugs (proteins as well, which are largely but not exclusively injectables) has made this more acceptable, at least among people who don’t know someone who has to inject insulin (which needless to say is a small protein itself). So the times have come around to make this a real business opportunity, which many suppliers are enthusiastically leaning into.

How about the science? It’s the biggest mixed bag you ever saw. There’s no doubt at all that there are some extremely biologically active peptides out there, and more such things are being discovered all the time. In fact, there’s a whole field devoted to looking at peptides that are too short to have been studied by the usual analyses, and those folks are turning up all sorts of activities that we never even appreciated were there. So that’s the first point: there are indeed a whole range of physical and medical effects to be found in these things.

Unfortunately, point two is that we barely have any of these effects worked out - at least not to the degree that you would want before you start injecting them into your leg. We’re still finding things out about extremely well known active proteins like insulin, much less more recent discoveries. That lack of knowledge extends - and how - both to their on-target effects (assuming that the target or targets are reasonably well known, which isn’t always the case) and to their off-target toxicities. 

And there are going to be plenty of cases where yes, Peptide X sure does do that thing you’re interested in, but it turns out that you can’t do That Thing without doing other things that you are surely not interested in. A number of “peptides of abuse” these days, for example, seem to be targeting human growth hormone pathways and associated ones, so let’s use that as an example. The pitch is often something like “Here’s the signal your body uses to build muscle! Take it directly and get going today!”, and with HGH there’s also been a longstanding subculture that treats it as a Fountain of Youth signal of some kind. “Replenish your growth hormone levels”, the idea is, “and dial back the biological clock!”

But growth hormone (and I shouldn’t have to say this) is powerful stuff, and it doesn’t just go tell your muscles to swell up. It affects bone tissue and many other tissues as well. I would invite anyone looking to maximize their growth hormone levels to look up a condition called acromegaly, which is what you get when your body keeps on making more growth hormone than you strictly need. Bones in the hands, feet, and head enlarge, and you get all sorts of side effects like joint pain, high blood pressure, type II diabetes, and other things that are probably not mentioned in the peptide supplier’s brochure. 

Excess growth hormone also increases the risk of some types of cancer, and that is a general problem with any attempt to (re)activate cellular growth pathways. Cancer, when you get right down to it, is a disease of unrestrained cellular growth, and there are a lot of different pathways that can lead to it. Stimulating cell growth out of the blue with systemic injections of synthetic hormone-like peptides is (in my view, and it ain’t just me) an invitation to greater tumor risk. And that’s just for starters. 

There are two very good pieces over at Stat right now on this topic. One, by physician Vikas Patel, describes a patient who is discontinuing her statin therapy - very inadvisably, given the clinical presentation described - but is enthusiastic about “BPC-157” as an injectable peptide for her knee pain. Says Patel:

My patient is refusing a drug studied in 170,000 people because of side effects that a 124,000-person analysis just confirmed do not exist — while injecting a compound studied in 14 humans, from unregulated sources, based on the recommendation of someone who profits from selling it. She’s probably not the only one. And those using it believe they are “doing their own research.”

The other one (by Sarah Hood) relates all this to RFJ Jr.’s advocacy. The flip side of “the government shouldn’t be able to force me to vaccinate my kids” is “I should have the right to take whatever medicines I want to without the government getting in my way”. That’s what we’re seeing here. I would bet that many peptide customers see themselves as free agents who have done their own research and are taking their health into their own hands - and dodging past Big Med and the old fossils at the regulatory agencies while they’re at it. But as that article points out (and as I’m doing today), what they’re actually doing is rolling the dice after falling for sales pitches aimed at exactly this sort of customer.

That dice rolling doesn’t just end at the unknown mechanisms of action, the lack of human data, and the lack of information about potential side effects. You’re also ordered from suppliers whose manufacturing standards you are in no position whatsoever to check, no matter how much of a free health warrior you might be. You don’t have an LC/MS or an NMR machine in your garage, so you can’t be sure what it is you’re really injecting, how pure it is, or to what extent it’s already deteriorated on standing. There is no one at the other end of the deal who cares very much, either, believe me. Human nature being what it is in this fallen world, you actually need regulatory agencies to force people to care about these issues by threatening them with severe punishments if they don’t.

In my own view (and it ain’t just me) you also have regulatory agencies to force people to show that their drugs actually have some benefit before they can sell them, too. But that’s going further and further out of fashion. Can’t get ahold of the New Hotness to inject into your upper thigh if there are a bunch of stick-in-the-mud folks asking for human data, infringing on your freedom and all. What a time to be alive.

This weekend brought news that the Russian opposition leader Alexei Navalny was poisoned in prison by the compound epibatidine. That is not (to put it delicately) the first thing one would have expected, so I wanted to give a little background on this compound first.

It’s a toxin isolated from a frog species found in Ecuador and Peru (and a few of its relatives), and like all poison frogs it is a very festive-looking creature indeed. That is of course a warning to potential predators, as with many brightly colored species around the world, a little evolutionary message to any hungry onlooker that they can afford to be so bright and prominent for a very good reason that you should have had a chance to learn by now. Many such frogs are used by native groups in the New World jungles as arrow-poison sources, although this particular species doesn’t seem to be.

It has a simple structure with one rather unusual feature, that 2-chloropyridine group. You do see halogenated natural products, but more often from marine organisms where chlorine and bromine are more easily available. An even weirder-looking related alkaloid with the same group in it (phantasmidine) is also found at lower concentrations in the frogs. Unfortunately, the biosynthesis of these compounds has not yet really been worked out (to my knowledge). It is known, as with most other poison dart frogs, that if you raise them in captivity they do not produce the toxin: there is something in their natural diet or environment that allows for it that is not found under terrarium conditions. Even under jungle conditions, sometimes one population of frogs will have the toxin while another in a different location does not.

It is very likely that the frogs do not have the ability to produce the compound on their own, but instead acquire it from their diet of local insects, etc. and then sequester the epibatidine in their skin. This has been documented with both birds and frogs with another such case, batrachotoxin - that one is chemically distinct from epibatidine and is found in a different genus of frogs, but it’s likely a similar underlying story. Not knowing the exact species that produce these compounds has made studying the chemical pathways behind them rather difficult!

And as with all such compounds, an immediate question is how the creatures that produce or sequester them manage to avoid poisoning themselves. Edit: here's how they do it, apparently, by co-evolving a mutant form of the receptor. This does not come without a cost, it seems. Another paper reports that this Epibatidine works as a ligand for both the muscarinic and nicotinic receptors - it’s an agonist, substituting for the natural ligand acetylcholine, and in general messing with the cholinergic system is going to lead to some strong effects. If you strongly block such signaling, you have replicated the mode of action of nerve gas, and if you strongly enhance it (as in this case) you can get a range of effects including analgesia and muscle paralysis. That latter one is especially unwelcome in the respiratory and cardiovascular system, clearly, and there is no antidote. The compound’s pharmacologic window between interesting pain relief qualities and seizures-n’-death is unfortunately quite narrow. 

People have tried to widen it, most notably Abbott (AbbVie) in the 1990s. They did a lot of work in this area looking for a nonopioid pain compound and took a chemical cousin of epibatidine (ABT-594, tebanicline) into human trials. They had definitely gotten rid of the “death” side effect by that point, as the FDA tends to insist on, but the window between analgesia and the remaining side effects was still too small. These included nausea, vomiting, impaired coordination, and apparently rather weird dreams as well. People were dropping out of the treatment group in the Phase II with alarming frequency, and the compound was abandoned. There are still a number of possible opportunities in the selective-nicotinergic-agonist area, but realizing selective cholinergic agonists is a problem that stretches back many decades and no general solutions have been found.

OK, back to the present day. The presence of the compound in Navalny’s body seems to be beyond dispute. He died two years ago in a “special regime” prison in Siberia, and his body was returned to his mother. Numerous toxicological examinations have confirmed the epibatidine, which does not undergo much metabolism in the human body. That along with its unusual structure make it very easy to identify. I am in agreement with those who believe that this was a deliberate choice by Vladimir Putin’s regime. After all, they had tried to kill Navalny in 2020 with what was obviously a Russian-manufactured nerve agent, and that was after previous chemical attacks in 2017 and 2019. The use of a tropical frog poison in Siberia is to me a grim joke and a statement that this was obviously an unnatural death that was carried out by people with obvious knowledge of human poisons. You don’t need the frogs: epibatidine itself is not that hard to synthesize in the lab by a variety of published routes. It can be made in quantity by any competent organic chemist who knows enough to take the proper precautions, and Russia as a country has a great many skilled organic chemists.

The Russian military and security services have been experts in poisoning people with exotic materials for a long, long time. They know exactly what they are doing from a chemical point of view, even if some of their assassins have not been particularly competent or well-informed themselves. Some have speculated that the authorities wanted to try out the epibatidine route to see how well it worked, but let’s be realistic: they could have done that on all sorts of other Siberian prison inmates without anyone ever hearing about it. I don’t think that the Russian state services have many review-board problems when it comes to running human trials. 

No, this was murder, obvious murder, and it was set up to be an obvious murder. Vladimir Putin is a corrupt, lawless poisoner, and he has had no qualms about demonstrating this over and over. He’ll order it done again the next time the opportunity presents itself.

Here’s an oddity that I’m glad was put to the test of a controlled trial. It seems that retrospective studies on cancer immunotherapy patients had suggested that there might be an advantage to giving the infusions earlier in the day, so this team took 210 non-small-cell lung cancer patients and divided them into two groups. One got the infustion early in the day (from 7:30 AM to 2 PM), and the other later (from 3 PM to 8 PM). Some of the patients were taking sintilimab and others pembrolizumab. 

The results are surprisingly strong: the early-infusion group had a median progression-free survival (PFS) of 11.3 months, while the late-infusion group’s median PFS was 5.7 months. Overall survival was median 28 months and 16.8 months for the two groups, and both results were (as they sound!) highly statistically significant. I’d be willing to bet that even the organizers of this trial weren’t expecting readouts this definitive. Subgroup analysis showed that this held for people taking either of the immunotherapy drugs mentioned. 

So what’s going on here? Some circadian-rhythm explanation seems inevitable here. The team found that the early-infusion group had increased levels of T cells (and increased levels of activated ones, on top of that), but the connection is between that and diurnal timing is still unclear. That is going to be a very interesting thing to figure out. I am certainly willing to believe nearly anything about the immune system at this point! The first step will be to replicate this effect, of course, and it’s an easy enough intervention that I hope that we see this happening soon. 

Here, thanks to Milkshake over at Org Prep Daily, is an example of what the scientific literature is slowly turning into under the onslaught of chatbots. The Royal Society of Chemistry journal Sustainable Energy and Fuels has a paper in it that's been up for a while (published in August of 2024) with the unremarkable title of "Critical insights into eutectic molten hydroxide electrolysis for sustainable green hydrogen production". It's not a topic that I pay that much attention to, and it's not a journal that I think I've ever read a paper from anyway. So why am I noting it here?

Well, try to read the thing. Just try. It starts off sounding pedestrian but sane, but that doesn't last:

Embarking on a journey at the intersection of innovation and sustainability, this research review delves into the realm of hydrogen gas production through a lens of unprecedented possibilities. Driven by concerns over environmental impact and the ever-increasing demand for clean energy, the focus shifts towards the electrochemical process of splitting steam for hydrogen production via eutectic molten hydroxide electrolysis. This exploration is not merely a scientific pursuit; it is a quest to redefine our energy landscape. Imagine a novel reference electrode, a stable companion crafted from the fusion of Ni/Ni(OH)₂ and an ionic membrane. . .Through meticulous exploration and theoretical contemplation, this review sets out to redefine the boundaries of hydrogen gas production, laying the groundwork for a sustainable energy future. This review transcends the ordinary, unlocking the secrets that propel us toward a cleaner, brighter tomorrow.

Helloooo, chatbot. The whole damn thing is written like this, and the adjective-laden prose really starts to grate in the context of a supposed scientific article. But who am I kidding? This crap would grate in the context of an ad for a used-car lot. Everything is novel and exciting and unique and transformative and unusual and important, and the preferred chatbot verbs (like "delve") get a real workout along the way, too. The whole thing ends up sounding like the grandiose fantasies of someone who has either taken a not-very-entertaining recreational drug or has had a (hopefully temporary) injury to their centers of speech. Maybe both. Some sections flutter back down into reality, but then you get things like this:

In the captivating domain of electrochemical exploration, the platinum electrode assumes the spotlight. A meticulous cyclic voltammetry analysis at 550 °C, immersed in molten NaOH, unveils the nuanced interplay of redox peaks, symbolic of the reduction of a delicate oxide film enveloping the platinum wire's surface.¹³⁵Fig. 3(D) presents the cyclic voltammograms from Ge et al.'s study¹³⁵ employing platinum as the working electrode. Each peak narrates a unique story: the cathodic current peak C₁ signifies the poetic reduction of the oxide film; the captivating surge in cathodic current at C₂ (−0.4 V) unfolds a ballet of hydrogen gas evolution; the anodic current peak O₁ depicts the stoic oxidation of the oxide film, and the enchanting O₂ serves as a crescendo harmonizing with the birth of oxygen gas. The saga continues beyond platinum, venturing into the realm of noble nickel. Its cyclic voltammetry narrative in molten NaOH reveals a tapestry of redox peaks akin to its platinum counterpart. The cathodic sonnet at C₃ serenades the reduction of a wispy oxide film caressing the nickel surface. 

The authors, if that's the word we're looking for, are from eight different locations ranging from Penn State through Nottingham, Morocco, Moscow, Sarajevo, Islamabad and more. But there is nowhere on earth where people talk (or write) like this, or at least there shouldn't be. The authors never should have let this manuscript go out in this form, and needless to say, neither should the editors. If that's the word we're looking for. Come on, people: if you're going to use the automatic word-rearrangers, at least try to cover your tracks a tiny bit.

This is what we have to look forward to? Journals filling up with this bilge, this useless wordy debris? Gosh, that's going to work out great with all those machine-learning algorithms for collating human knowledge - just wait until we pour these buckets of sludge into them. That'll produce all kinds of captivating insights for us to delve into. Oh, God.

Louie was in a shelter near me.   Could we help him?  We could.  Look at that sweet face. He went to the vet to get his first rescue checkup.    I think he had something to say.   The vet groomer fit him in Monday morning to be groomed.  He's all cleaned up and ready to go!
He did not want to get bloodwork done though.  He went to my friend who took care of him over the weekend.  He wanted her to help. 

Louie will be neutered on Wednesday, and then he will see the ophthalmologist next week.  He has two cherry eyes and they will need to be repaired.  A new life just began for this boy.  💙  WELCOME TO PVPC LOUIE!