Diprenorphine in response to fentanyl analogue overdose?

[Transcendence]

Naxolone has been historically very effective as an emergency opiate antagonist. But with the widespread distribution of aburdly potent fentanyl analogs it is now common for an overdose to be unresponsive to multiple doses of naxolone. Has there been any push to approve diprenorphine for use in humans? Is there any reason for it not to be used besides that it has traditionally been overkill for opiates in medical use? I guess it's a partial agonist but I don't really understand what that entails in practice? Is not its antagonist activity greater than its agonism at any dose?

 

[kleinerkiffer]

I feel like this is more suited for Neuroscience and Pharmacology discussion, so I'll move the thread there
OD -> N&PD

 

[tacodude]

You make a good point in the need of antagonists with high affinity that can knock off fentanyl type compounds or even bupe if an infant ingest it or something as because as far as I know there's no good way to reverse bupenorphine. Even though it's not as big of a risk it's a much more serious risk if a baby is overdosing rather than a person who has taken one pill too many or made a shot that was just a bit too big.

 

[clubcard]

It's a low efficacy partial agonist, not an inverse agonist or an antagonist. The side-effects are really unpleasant; emesis, aperience, sedation & hallucinations (few people enjoy κ mediated ASCs). For someone who's been unlucky enough to be downed by etorphine or carfentanil, it can be life saving but that doesn't mean they walk away, they still end up in hospital. Ironically, it appears that their is only 1 producer and they only sell it as a kit with etorphine as Immobilon™.

Research is still going on with it: https://pdfs.semanticscholar.org/a38d/624be1c4825ed9386c3a946a8b93e162a6e2.pdf

 

[S.J.B.]

But with the widespread distribution of aburdly potent fentanyl analogs it is now common for an overdose to be unresponsive to multiple doses of naxolone.

I have heard this many times in breathless media reports, but is it accurate? Canada, especially western Canada, has had a big problem with fentanyl and its analogues for the past few years yet there have been zero overdose deaths at any supervised injection site in the country. My sense is that if there were actually a bunch of "treatment resistant" overdoses going on then a few people would have died. It would be interesting to see evidence one way or the other.

 

[Limpet_Chicken]

Just look at (not that it's likely still there anymore after I spotted it and reported it to mods from in aus drug focal forum)

Some cunting rat bastard shilling for 'carfentanil 99.9% pure powder'

Load of ads, etc. in the post, email, that sort of crap. Just imagine what'll happen if somebody did receive un-diluted, pure carfy powder. They'd be lucky to survive merely opening the container, or weighing it on a mg scale to use volumetric dilution in liquid form, etc.

That would literally be supplying a product deadlier than VX nerve agent. Only difference is VX is a thick, viscous liquid, and primarily a contact agent, rather than hazard, in CW contexts,due to it's vapour pressure. And probably easier to hand than a fine powder of an even more highly toxic opioid like carfentanil, which would send invisible, microscopic little puffs of micro-fine dust up into the air opening a vial or worse, a baggie. Tiny bits could already BE on the outside from the supplier, enough to ensure death on touch to anybody picking it up while donning gloves; to say absolutely nothing of the danger posed to the postal workers. Say a package with a gram of carfentanil powder in it is seized, and someone drops a vial, enough is going to end up in the air, especially if they try and clear up the powder with a brush and pan, etc. floating around and people dropping like flies.

A bit on the outside of a package...postie could end up OD'ed.

The sheer number of things able to go wrong in a corpse-factory sort of way with an opioid as potent as carfentanil,it's fucked up. And I take a really, really REALLY dim view of people cooking any but the lowest potency fentanyl derivatives, and then only for themselves, and nobody else's use, certainly not sale.

 

[clubcard]

I have heard this many times in breathless media reports, but is it accurate? Canada, especially western Canada, has had a big problem with fentanyl and its analogues for the past few years yet there have been zero overdose deaths at any supervised injection site in the country. My sense is that if there were actually a bunch of "treatment resistant" overdoses going on then a few people would have died. It would be interesting to see evidence one way or the other.

I have been in contact with HR workers in Toronto concerning this precise issue. While naltrexone & nalmefene oral formats have licences, reformulation would cost a lot of money and the duration would be an issue. While it seems intuitive that the N-allyl analogue of nalmefene, 17-allyl-4,5α-epoxy-6-methylmorphinan-3,14-diol would be of utility (KI values ? 0.12, δ 10, κ 0.94 cloned human receptors) and in spite of the fact that potent opioids will pour onto our streets for decades, nobody is going to invest the $2.6 billion (average cost to licence with an average of 7 years remaining on patent) it would take to produce it. I suspect cost would be lower than average but still, there's about a 30 year gap between a need recognized and a need being met when it comes to those dependant on opiates. In 1976 Bentley suggested that buprenorphine would be useful in substitution therapy! I believe that Randox is developing specific spot tests (1 drop from pin onto paper) using ELISA but so many possible analogues haven't turned up yet so no reference samples.

Many are obviously synthetically complex but it looks like bulk buyers are using Wiki as their reference! Even a cursory glance through Google Patents turns up the fact that Janssen really did exhaustively test every single moiety & every single bioisostere. Just 1 patent instantly doubles the number of possible homologues (thus not containing a controlled scaffold) while confirming the CHARMM calculations. Thiazole, isothiazole, oxazole, triazole... I'm also advised that like BDPC & C-8813... I'm just pointing out the sheer impossibly of legislating against the numerous high-potency open-chain (read synthetically simple using common reagents) opioids. With their short duration and low unit price ($2 deals!), they will drain every single penny from the dependent. Then of course, substitution therapy is not an option and I've heard too many chemists ending up with huge habits and were still in acute withdrawal 12 months later. It's a 1 way street.

I think we need to be looking hard at the acetylmethadol derivatives of the piperidinospiro homologues of methadone. With a potency in the ballpark of these open-chain opioids (x212 M), peak activity at the 6 hour mark and a T? of 20.5 hours, it's got to be a strong candidate. If 3 doses per week is sufficient (as per ORLAAM) then the cost of supervised consumption goes down for everyone. I would imagine it would not be abusable I have no idea how effective it would be at blockading the street stuff but at least it means that it isn't a 1 way street. I'm not interested in apportioning blame for people using street drugs, I'm just interested in finding a way out. Of course, here we consider it to be a medical issue, not a legal issue.

 

[Limpet_Chicken]

There were issues with some of the methadols, and ORLAAM, with Q-T wave prolongation, rememberl

Why the piperidinylspiro-derivatives of 'done? a seriously high potency on weight basis would stop things too, like people who are seriously tolerant, potentially needing so much with methadone itself that long QT could become an issue.

 

[Transcendence]

Just look at (not that it's likely still there anymore after I spotted it and reported it to mods from in aus drug focal forum)

Some cunting rat bastard shilling for 'carfentanil 99.9% pure powder'

Load of ads, etc. in the post, email, that sort of crap. Just imagine what'll happen if somebody did receive un-diluted, pure carfy powder. They'd be lucky to survive merely opening the container, or weighing it on a mg scale to use volumetric dilution in liquid form, etc.

That would literally be supplying a product deadlier than VX nerve agent. Only difference is VX is a thick, viscous liquid, and primarily a contact agent, rather than hazard, in CW contexts,due to it's vapour pressure. And probably easier to hand than a fine powder of an even more highly toxic opioid like carfentanil, which would send invisible, microscopic little puffs of micro-fine dust up into the air opening a vial or worse, a baggie. Tiny bits could already BE on the outside from the supplier, enough to ensure death on touch to anybody picking it up while donning gloves; to say absolutely nothing of the danger posed to the postal workers. Say a package with a gram of carfentanil powder in it is seized, and someone drops a vial, enough is going to end up in the air, especially if they try and clear up the powder with a brush and pan, etc. floating around and people dropping like flies.

A bit on the outside of a package...postie could end up OD'ed.

The sheer number of things able to go wrong in a corpse-factory sort of way with an opioid as potent as carfentanil,it's fucked up. And I take a really, really REALLY dim view of people cooking any but the lowest potency fentanyl derivatives, and then only for themselves, and nobody else's use, certainly not sale.

This is a good point that has been worrying me in the back of my mind for a while now. I don't believe that carfentanil has been sold illicitly on the street until the last couple years. It used to be only a concern for large wildlife veterinarians and a morbid curiosity for everyone else. In my naivety, I honestly did not think that even the most unscrupulous dealer would risk messing with it. It could easily be used as a chemical weapon.

How long until something like the 2′-fluoro derivative of ohmefentanyl (approximately 20x the potency of carfentanil becomes available? For now it's harder to synthesize than the other fentanyl analogues but easier synthesis routes are discovered all the time. As it stands, you would have a much better chance surviving exposure to VX agents than something stronger than carfent. The emergency antidote to nerve agents are available in every pharmacy, but I do not think that any amount of narcan would reverse an ohmefentanyl overdose in time.

 

[sekio]

It seems self-evident, but I don't think anyone at street level sells pure or near-pure fentanyl or carfentanyl analogues. You probably have to climb the food chain a little bit.

Remember that for the longest time the dope game was a balancing act - "how much can I cut this product before people won't buy it". Now that fentanyl is around people have gotten used to the idea that you can cut your product way more while retaining activity. They don't go distributing 100mg doses of pure fentanyl, if you're lucky you might get 5mg of fentanyl and 95mg of caffeine or other bulking agent. The margins for carfentanyl are even lower, even at the "high level", what people sell to the people who cut and deal it, I don't think there's more than 1% by weight. Certainly not the stuff I've seen.

 

[clubcard]

There were issues with some of the methadols, and ORLAAM, with Q-T wave prolongation, rememberl

Why the piperidinylspiro-derivatives of 'done? a seriously high potency on weight basis would stop things too, like people who are seriously tolerant, potentially needing so much with methadone itself that long QT could become an issue.

No - there was an issue with the N,N-dinor metabolite of ORLAAM. Methadone has a convenient ketone to deal with that (imine), ORLAAM doesn't. The hERG IC50 for the chiral, long acting compound is in several of Janssen's works and even a carfentanil head would be long dead before the EC50 QTc was reached, much less the TdP images that he was kind enough to feature. Since those animals were sacrificed (how we lie), better to use the data.

I'm flatly refusing to touch a microtome for the rest of my life; I'm going to Jorge Tejada.

 

[novaveritas]

No - there was an issue with the N,N-dinor metabolite of ORLAAM. Methadone has a convenient ketone to deal with that (imine), ORLAAM doesn't. The hERG IC50 for the chiral, long acting compound is in several of Janssen's works and even a carfentanil head would be long dead before the EC50 QTc was reached, much less the TdP images that he was kind enough to feature. Since those animals were sacrificed (how we lie), better to use the data.

I'm flatly refusing to touch a microtome for the rest of my life; I'm going to Jorge Tejada.

Methadone causes Q-T prolongation and is black boxed for arrythmia. MMT patients are at increased risk of cardio sides like QTP, VA VF and sudden death. The risk of sudden death is around one in 5000 per patient per year. So much for you ridiculous theory about a convenient ketone. Both methadone enantiomers interact with K v11.1 but the more mu potent R is less active, but not by enough to make enantiopure R methadone viable for this reason alone.
I am not going to blow smoke up your ass you are dangerous for all the wrong reasons and a poster child for Dunning-Kruger. I expect you now to throw a petulant hissy fit. At least you are flatly refusing to use a monotone for the rest of your life but getting into bed with HLS instead is not great..

http://www.innovationsincrm.com/car...163-qt-prolongation-arrhythmia-risk-methadone

 

[Neithman]

here in germany we commonly get levomethadone.
Methadone is around but is getting more rare as more patients want the enantiomer pure product.

 

[clubcard]

Methadone causes Q-T prolongation and is black boxed for arrythmia. MMT patients are at increased risk of cardio sides like QTP, VA VF and sudden death. The risk of sudden death is around one in 5000 per patient per year. So much for you ridiculous theory about a convenient ketone. Both methadone enantiomers interact with K v11.1 but the more mu potent R is less active, but not by enough to make enantiopure R methadone viable for this reason alone.
I am not going to blow smoke up your ass you are dangerous for all the wrong reasons and a poster child for Dunning-Kruger. I expect you now to throw a petulant hissy fit. At least you are flatly refusing to use a monotone for the rest of your life but getting into bed with HLS instead is not great..

http://www.innovationsincrm.com/car...163-qt-prolongation-arrhythmia-risk-methadone

Long QT (QTc) is asymptomatic. It's the risk of it developing into torsades de pointe (TdP) that leads to cardiovascular events. You might want to look at the long list of meds that carry the same risks. I believe that the (R) isomer causes less hERG (human Ether-?-go-go related gene CCR5(?)) proliferation which certainly fits in with the German model. AFAIK quite a lot of quite mainstream medications carry black-box warnings, primarily to divest the licensor from legal comeback rather than as an absolute measure of risk. There are about a dozen other meds you simply cannot give concomitantly with methadone - a VERY good reason for a black box. Don't confuse a safety issue with a litigious issue. I don't know if all consumption is supervised but we've seen juice turning up on the street and people pulling a blue because their seemingly unrelated meds interacted. You might want to read that specific black box because it does make it clear that there are multiple issues. Methadone and client noncompliance is kind of common. No hissy fit. Always glad to put in the effort to expand knowledge to the best of my ability.

Don't forget, most medicines are only prescribed across quite a narrow dose range near the bottom of their Tw (which makes sense) and for pain methadone comes as 5mg tablets and you take 1 or 2 and I don't think that there is a measurable increase in morbidity in that range. For substitution therapy I believe people have been given upto a gram a day. Certainly we maintained people on the 100s of mgs a day on the methadone bus. The risk/benefit at those 'heroic' doses is an experience thing, I just handed out brown bags and packed sin-bins. That old 'the dose makes the poison' sentiment is sadly true for juice. I wonder how safe Prozac would be if the dose was 1-200 tablets a day? I mention Prozac since that is just 1 example of a drug pretty safe at sane doses but could cause serious harm if their were no maximum dose; and because it's an example of a drug that interacts with methadone. It's not the things one would necessarily consider. Here we would generally consider that if someone as a habit that REALLY needs that kind of dose then it's pretty certain that the risk/benefit will side with scripting - but our doctors are EXPECTED to know. With no specific dose limitation, a challenge dose & a blood test is occasionally used. I believe there are several patents for compounds with no therapeutic value but the proportion of metabolites indicates CYP450 activity. So, long answer but LC is pretty clued up - all of that applies unsaid to him (or her, I don't know).

Still, if you can replace 1g for under 5mg given thrice weekly, it opens up new vistas and we are going to need them. Crude though the techniques were back then (K channel wasn't backed up with hERG), I'm pretty sure that an optimized route to 3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] (CAS 95195-98-5) would be worth the cost of patenting it. I was offered 'a deal' by Santa Cruz at only $12400 for 5 grams... wow, maybe they did go via the patent route? EP0445974A2 is not much better. WO2002085354A1?

Wow - can anyone spot a natural compound or an intermediate produced in bulk? Finding the best way to this one is going to be lots of fun. Start looking at every single med to see if you can find that rather complex moiety or anything close.

Mods - I hope you can see that in no way is this discussion of practical synthesis of a drug of abuse. It's a question of IF the stuff can be produced at all.

 

[Neithman]

Long QT (QTc) is asymptomatic. It's the risk of it developing into torsades de pointe (TdP) that leads to cardiovascular events. You might want to look at the long list of meds that carry the same risks. I believe that the (R) isomer causes less hERG (human Ether-?-go-go related gene CCR5(?)) proliferation which certainly fits in with the German model. AFAIK quite a lot of quite mainstream medications carry black-box warnings, primarily to divest the licensor from legal comeback rather than as an absolute measure of risk. There are about a dozen other meds you simply cannot give concomitantly with methadone - a VERY good reason for a black box. Don't confuse a safety issue with a litigious issue. I don't know if all consumption is supervised but we've seen juice turning up on the street and people pulling a blue because their seemingly unrelated meds interacted. You might want to read that specific black box because it does make it clear that there are multiple issues. Methadone and client noncompliance is kind of common. No hissy fit. Always glad to put in the effort to expand knowledge to the best of my ability.

Here in germany we have the take-home model.This means if your drug test are negative for 2-3 months you get 1 week prescriptions of your mainentance drug which are methadone,levomethadone,buprenorphine and morphine sulphate.
I even get my morphine for take home,800 mg daily but rarely take 800 mg.This is why alot of methadone and buprenorphine shows up on the street.
We even have Diacetylmorphine for maintenance here in germany but you cant get this for take home also only for injection users as you have to inject it right on the spot in the maintenance clinic,but even this rarely shows up on the street,which is a gem of course and relatively expensive but is 100% pure diacetylmorphine.

 

[DotChem]

..

I'm pretty sure that an optimized route to 3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] (CAS 95195-98-5) would be worth the cost of patenting it. ​

patenting the compound or the synthetic route?..

 

[Limpet_Chicken]

I've often thought that, regarding potency range comparison between V-series agents and various fentanyls, one could easily get away with a comparison and say weight for weight, that it takes a LOT less of the more potent fentanyl derivatives than the V-series nerve agents to off someone.

(especially as typical exposure route for V-agents, outside direct administration as a weapon of assassination, is dermal, the V agents, unlike sarin and most G-agents are thick, viscous liquids, used for their persistence, as area denial weapons.) Whilst fentanyls are liable to be injected, or at least, vaped and directly inhaled.)

IIRC via inhalational or dermal exposure, using VX as the prototypical member of it's class, a dose required to kill a 70kg adult male human is around 10mg, to reach the LD:50.

Thats way, way less toxic than even fentanyl itself, to anyone nontolerant to opioids, 0.5,mg would be pretty reliable, and 1mg pretty certain without treatment to off someone.

Although of course, given the choice of a cholinergic crisis, and massive opioid OD, I know how I'd rather go out, if keeping on living were not an option, in an either-or situation. Cholinergic storms are most unpleasant. Have been 'got' by an anticholinesterase of botanical origin once, as well as bitten by a Latrodectus spider (a brown widow, in this case. Normally she was just fine, very docile, but whilst feeding her just after she'd laid two egg sacks, she, understandably, was not in the best mood)

Got really pissy, nipped me one, and for the next good many days, I was in absolute agony. The venom is not entirely dissimilar from the effects of an anticholinesterase, in that alpha-latrotoxin causes a prolonged, massive and uncontrolled release of acetylcholine, although without inhibiting cholinesterases.

Could barely hobble a few feet to the bog, needed a LOT of opioids, antimuscarinic agents helped (scopolamine), and enough muscle relaxers to near knock me out cold, or ideally, go the whole hog and black me out (tizanidine being the agent in question), could do little but lie on a bed, pissing in a bottle for the first several days until hobbling a few feet on crutches to the bog was possible, along with large doses of a combination of nitrazepam and chlormethiazole, to ensure that I wasn't awake to suffer through as much of what was avoidable, as possible.

 

[clubcard]

There is no shortage of hugely toxic agents and we still cannot match nature. Botulinum toxin & gelsemium still beat our semi-synthetics like some of the epibatidine analogues or fully synthetic agents like the organophosphate/carbamate agents; neither of which touch 2,3,7,8-Tetrachlorodibenzodioxin dimethyl mercury or indeed a whole basket of heavy metal organometalics BTW. But when you try to weaponize them, THEN you realize why certain choices were made. The V stands for venomous with good reason. It describes the action of getting a toxin into the body. Along with energetic materials, it's 2 fields if chemistry I assiduously avoid. I have used several 4:4:4 compounds (fine chemical supplier shorthand for especially hazardous materials) and Dess-Martin periodinane, methyl fluorosulfonate & dimethyl zinc stand out. Accidents happen.

It looks like there MAY eventually be a more active replacement for naloxone and I've seen several pretty potent antagonists. The problem is that we know how doctors think. If they have been using naloxne reliably for a quarter of a century, they won't be won over by a new, in-patent alternative costing vastly more easily. Sadly, for the investment in development to be made, a lot of (ideally English speaking white males between the ages of 16 & 45) people dying because naloxone failed. For the medicinal chemistry minded, it would appear that you need a phenolic moiety (or bioisostere) to engender antagonist activity.

I think we will be seeing an increase in deaths not due to acute toxicity but because such strong agonists MAY cause permanent physiological changes. That their appears to be a ceiling dose and that the seemingly permanent acute phase of abstinence syndrome for people who have reached that ceiling is seemingly unreported. We know of specific opioids that have a ceiling effect but until self-experimentation with highly potent opioids took place, I don't think we were in a position to discover these facts. It just appears to be the case that we really could have a 1-way-street drug of abuse taking hold. If anyone can suggest alternatives to the semi-rigid 3,3-diphenylheptanone class then that would be great. Thienorphine may or may not be of benefit but if we have a potent, long-acting full agonist in place then we have something. I might add that along with the synthesis, there are a number of other novel aspects to the class that WOULD allow it to be patented.

 

[Limpet_Chicken]

It seems to me, logical that there will be a rate-limited far-extreme degree of supramaximal stimulation of most receptors, before their ligands are depleted, intracellular second messenger pathways placed under demands they cannot meet, or would be, were it not for their being unable to meet such demands,

Essentially, saturation bombing, there is only so much ion flux, or metabotropic gene transcription, second messenger recruitment etc, and on-off kinetics, that a human nervous system can take.

Just look at alpha-latrotoxin as a good example IMO, causing uncontrollable acetylcholine release, but without affecting it's degradation. Enough administered, and there will be no more target to bind, and a maximal degree of supra-maximal ACh release in response to that ligand realized.

Used to be into 'energetics' as a kid, definitely, but that was when first starting out. What kid DOESN'T want a rocket launcher to play with, or to find a derelict car in which to place a FAE charge...? Every kid loves a big buggering great bang, all the more if the kid is the one to have engineered the kablooey

It's just that MOST kids can't go beyond fireworks, or reverse-engineering them; and never get to go through a phase of 'can I nitrate it with mixed acid' or 'perchlorate time'.

As for toxins, I'm INTERESTED, certainly, doesn't mean I've a desire to go round poisoning people. The molecular mechanisms of action, in the field of toxicology as a whole, are quite fascinating. And things like the fact human beings not only managed to deduce the structure of, but pull off a stereochemically correct synthesis of palytoxin, the secondmost-lethal nonproteinaceous toxin known thus far to man, with the not dissimilar maitotoxin coming in at no.1, both marine in origin, dinoflagellates or zoanthid coral polyps.

Palytoxin is MASSIVE, structurally, hundreds of stereocenters, a big, sodding great long macrocyclic polyol polyether with some stereoactive bridged heterocycles in the linear chain that look like a bastard to synthesize full stop.

(2S,3R,5R,6E,8R,9S)-10-[(2R,3R,4R,5S,6R)-6-[(1S,2R,3S,4S,5R,11S)-11-{[(1R,3S,5S,7R)-5-[(8S)-9-[(2R,3R,4R,5R,6S)-6-[(2S,3S,4E,6S,9R,10R)-10-[(2S,4R,5S,6R)-6-[(2R,3R)-4-[(2R,3S,4R,5R,6S)-6-[(2S,3Z,5E,8R,9S,10R,12Z,17S,18R,19R,20R)-20-{[(2R,3R,4R,5S,6R)-6-[(1Z,3R,4R)-5-[(1S,3R,5R,7R)-7-{2-[(2R,3R,5S)-5-(aminomethyl)-3-hydroxyoxolan-2-yl]ethyl}-2,6-dioxabicyclo[3.2.1]octan-3-yl]-3,4-dihydroxypent-1-en-1-yl]-3,4,5-trihydroxyoxan-2-yl]methyl}-2,8,9,10,17,18,19-heptahydroxy-14-methylidenehenicosa-3,5,12-trien-1-yl]-3,4,5-trihydroxyoxan-2-yl]-2,3-dihydroxybutyl]-4,5-dihydroxyoxan-2-yl]-2,6,9,10-tetrahydroxy-3-methyldec-4-en-1-yl]-3,4,5,6-tetrahydroxyoxan-2-yl]-8-hydroxynonyl]-1,3-dimethyl-6,8-dioxabicyclo[3.2.1]octan-7-yl]methyl}-1,2,3,4,5-pentahydroxydodecyl]-3,4,5-trihydroxyoxan-2-yl]-2,5,8,9-tetrahydroxy-N-[(1E)-2-[(3-hydroxypropyl)-C-hydroxycarbonimidoyl]eth-1-en-1-yl]-3,7-dimethyldec-6-enimidic acid

For short.

And we actually managed to pull it off, putting it together in segments. Took something 5-6 years IIRC. Although that might just have been for elucidation of the structure.

The mode of action is novel too, turns Na+/K+-ATPase into an ion channel locked into a conformation that allows passive diffusion of Na and K into and out of cells without restriction, result-frying the ion gradient extra-crispy critter, as well as being an ultrapotent vasoconstrictor. Treatment, if it's to save someone, needs to be immediate in case of any significant exposure, due to the vasoactive effects, and using a vasodilator injected directly into the heart.

Although that isn't aid against the generalized and powerful cytotoxic effects, system-wide. The second-deadliest toxin, proteins aside, by weight, that we know of, and also very, very fast acting. Cases exist, of people who've had the zoanthid, Palythoa toxica, in their aquaria, and decided to kill the polyps off by throwing boiling water over them. Resulting in an aerosolized palytoxin-laced cloud that at least, allowed the poor polyps to get their own back at the bastards who just tossed boiling hot water on them. Hospitalized at least one such nasty little git.

Just being interested in the mechanisms, doesn't mean one is out to poison anybody.

 

[clubcard]

Well Botulinum toxin has medical utility so it isn't like we can't put them to good use. That the mass is given in Kilodaltons give some idea of the complexity. I can't remember which member it was but a French developed nerve agent (2,3-dimethyl-5,6-dihydro-2H-1,4,2-oxazaphosphinine 2-oxide) which the lowest LD50 of the class but kind of risky to work around. As I have mentioned, things not usually primarily considered to be toxins like dioxin are actually REALLY dangerous. It's kind of unlikely that people will ever come across the organophosphate/carbamate/organosilanes but things like HF are quite common and quite brutal.

I've just remembered what really soured me on the subject. I met a Swedish chemist in Amsterdam who had worked on agents that covalently (irreversibly) bound to the benzodiazepine site for his government. The idea was that non-lethal doses would cause the maximum amount of assets to treat. I mean, he had gone through some fentanyl analogues that did the same which on consideration is what made me consider the ceiling effect of opiates. He did mention how simple they were chemically but I kind of switched off. I mean a nice guy. Lived in The Netherlands so he could legally access cannabis to treat his MS which he developed quite suddenly at the age of 28. I think that in retrospect, he suspected that he had been contaminated so I suppose it's seeing what they do when they don't kill.

I think getting blown up twice and seeing the bits of people scattered around in the second event is an easy A-B to draw. That time it most certainly was not my fault.