Carfentanil has killed hostages and even moose!

carfentanil

Source: Vancouver, Royal Canadian Mounted Police

Carfentanil is a potent opioid, one of many molecules from the Pandora’s box of organic chemistry labs.  Derived from fentanyl, another synthetic morphine-like compound,  carfentanil has been deliberately introduced into samples of  heroin. Frontline emergency responders have been advised to wear masks and gloves to avoid ingesting minute amounts of the drug. It’s also been described as a substance designed to knock out elephants.

I will describe a couple of related stories from the research literature that have not been mentioned in the news recently, and of course since unlike newspapers, I don’t mind losing readers by dwelling on chemistry,  I will also take a closer look at the molecule. 🙂

hostageOn October 23, 2002, more than 800 people attending a stage show in Moscow were taken hostage by about 50 Chechen rebels. After the latter threatened to blow up everyone in there if their political demands were not met, 3 days later, the Russian military stormed the theatre. To subdue the rebels, an unidentified “gas” was introduced through the ventilation system about 15 minutes before the soldiers moved in.  Things however did not go according to plan. After the “rescue”, the hostages had to be taken to the hospital. Due to wrong assumptions about the nature of the “gas”, many patients were given ineffective treatments and died. But a couple of doctors noticed that the patients showed classic signs of opioid intoxication: pinpoint pupils, unconsciousness and depressed breathing. The opioid hypothesis was supported by the fact that naloxone was able to save those who received the same drug that’s typically used in opioid-related emergencies. Later, the Russian health minister tried to assure the public that the  mixture used during the military intervention was not lethal. They admitted that the aerosol included an opioid, specifically a fentanyl-derivative (likely carfentanil). But convinced of the opioid’s harmlessness, they tried to pin the blame for all of the 127 deaths on the conditions experienced by hostages during the 3 days of captivity.

What else was in the opioid mixture? German chemists found it contained halothane, an anaesthetic, but that wasn’t the fatal ingredient. According to a report of three medical toxicologists from the Good Samaritan Regional Medical Center, the problem was rooted in the Russians’ underestimation of carfentanil’s potency. They had extrapolated rat models that did not apply to humans.  In addition, the Russians didn’t take into account that a ventilation system will not evenly distribute an aerosol.

What kind of a job does carfentanil do on large mammals? The Quebec Environment Ministry did a 10-year study in the late 1980s to 1990s involving carfentanil and free- ranging moose. A dose of 3 mg of carfentanil was mixed with xylazine and injected into 69 different animals. The xylazine was included to smooth out induction and recovery.  Although 3 mg represents only only 7.1 parts per billion for moose with an average mass of 422 kg, most animals slowed down in only 6 minutes and were immobilized in half an hour. Four moose however died. So if in reading the news you became under the impression that for large mammals carfentanil is innocuous, well the reality is that it could be lethal for them too even in small doses, albeit in a smaller percentage of cases compared to humans. As a result of the study, carfentanil is no longer used on moose, but is still mixed with xylazine on some animals who are less sensitive to minute amounts of the opioid.

Opioids can act on several opiate receptors in the central nervous system. To date there are three known varieties of such receptors known as μ , κ and σ. Carfentanil is a strong agonist specific to a pair of μ type receptors known as μ1 and μ2, leading to, among other things, intense euphoria. Interacting with μ1 also leads to analgesic effects, whereas bonding to μ2 leads to respiratory depression, which is the cause of death when the drug kills.

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The morphine rule consists of structural criteria for a molecule to have morphine-like effects. The rule applies to natural opiates but no longer to all opioids.

Carfentanil is more potent than fentanyl, which is in turn is far stronger than morphine. Fentanyl was first synthesized from demerol(pethidine)-analogues in the 1960s. Until that point pharmacologists were under the false impression that to act like morphine a drug had to have a quaternary carbon linked to an aromatic ring and to have that quaternary carbon linked to a tertiary amine via a pair of CH2 groups. But fentanyl has only a tertiary carbon, and it is not directly bonded to an aromatic group. It became the first drug to violate the so-called morphine rule, and yet ironically it was stronger than most of the opioids that stuck to the rule.

fentanyl

A comparison of the structures of the two opioids. Carfentanil has an ester group on a carbon that is quaternary and not tertiary. (See green, circled carbon in each case.) Like all opiates both have a carbon linked to tertiary amine (asterisk) separated by a pair of Ch2 groups(green dots). Carfentanil violates the morphine rule by not having its quaternary carbon directly linked to an aromatic ring.

In contrast, carfentanil is like the traditional opiates in that it has a quaternary carbon, one created by the addition of a methyl ester group on that carbon—the only difference in structure between the two molecules. But like fentanyl, it still violates the morphine rule because the carbon is not directly linked to an aromatic ring.

Sources:

Unexpected “gas” casualties in Moscow: A medical toxicology perspective  Annals of emergency medicine May 2003Volume 41, Issue 5, Pages 700–705
http://www.annemergmed.com/article/S0196-0644(03)00109-4/abstract

Unintentional opioid overdose deaths in New York City, 2005–2010: A place-based approach to reduce risk Original International Journal of Drug Policy 25 (2014) 569–574 reveals that carfentanil was a factor in unintentional drug overdose-deaths in a study involving such cases in 2010 to 2014.

RELATIVE EFFICIENCY OF SUCCINYLCHOLINE, XYLAZINE, AND  CARFENTANIL/XYLAZINE MIXTURES TO IMMOBILIZE FREE-RANGING MOOSE   Journal of Wildlife Diseases, 35(1):38-48 http://www.bioone.org/doi/pdf/10.7589/0090-3558-35.1.38
Restraint and Handling of Wild and Domestic Animals 2008 By Murray E. Fowler

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UV: Practical and Philosophical Perspectives

In the same manner that the frequency of visible light plays a role in the color we perceive, or in the way a broadcasting radio frequency characterizes a particular radio station, the specific frequency of ultraviolet light(UV) affects its behavior towards living cells.

Before elaborating on that point, let’s look at some characteristics and origin of UV.  Ultraviolet radiation has a frequency in the range of  7.5 x 1014 to 3 x 1016 Hz (cycles per second),  corresponding to wavelengths of 400 to 10 nanometers. Converting from frequency to wavelength is just a matter of dividing the speed of light in m/s by the frequency in Hz and then multiplying by a billion to get the answer in a value equivalent to a billionth of a meter.

uv

From chemguide.co.uk

In all atoms, electrons can get promoted to higher energy levels. In those of the sun’s most abundant element, hydrogen, when a previously excited electron falls to the second level from either the 3rd,  4th 5th or 6th levels, photons of red, blue-green, blue or violet frequencies are emitted. But because there is a much bigger gap between the 1st and second levels, the photons released are of the ultraviolet variety. Ultraviolet will also result, and will do so at progressively shorter wavelengths,  if an electron calls directly from the mentioned excited levels to the ground state. What gives electrons the jolt of energy in the first place? It comes from the heat at the sun’s surface. The temperature is nowhere near as intense as it at the core where fusion releases gamma, but at about 5800 oC, it’s enough to generate the excitations leading to ultraviolet emissions.  UV is invisible to our eyes but can be seen not only by insects but by at least some species of hummingbirds, pigeons, rats, cyprinid fishes and goldfish.

fish

The cones of the giant dani are sensitive to UV.

The UV emitted by the sun constitutes about 10% of all the electromagnetic radiation that reaches our planet from our star. The UVC-type rarely reaches our planet’s surface thanks to the absorption by oxygen(O2) which generates atomic oxygen, which in turn bonds to an undissociated molecule, yielding ozone, O3. The latter absorbs other frequencies of UVC and some lower-frequency of ultraviolet dubbed UVB. This is a good thing because UVC is the most deleterious biologically and would probably prevent most forms of land life from evolving. Having said that,  I should point out that UVB is energetic enough to cause skin cancer. UVA, my namesake, can’t directly affect DNA molecules, but it’s still a threat because it is the most abundant form of ultraviolet(around 95%) at the earth’s surface and because it causes other molecules to produce free radicals. These reactive atoms that contain unpaired electrons can then move on to attack genetic material. According to Consumer Reports (July 2016), 28 of 65 sunscreen products they tested failed to meet SPF(sun-protection-factor) claims on the label. Nine products protected either fairly  or poorly against UVB.

The ozone layer has been compromised by atomic chlorine and other halogens from our use of certain coolants. As a result more UVB reaches the surface of Earth. A series of protocols(see chart) has controlled the emission of ozone-attacking catalysts and has curtailed the depletion of the vital stratospheric UV-filter. The long residence time of atomic chlorine, however, means that overall there is still significantly less ozone over the Antarctic and a little less globally

From the latest report (2014)on the status of global ozone levels:

Depletion of the global ozone layer increased gradually in the 1980s and reached a maximum of about 5% in the early 1990s. The depletion has lessened since then and now is about 3% averaged over the globe. The average depletion exceeds the natural year-to-year variations of global total ozone.

Notice what we have done in describing ultraviolet light. We have mentioned some associated metrics, its origins and its interactions with oxygen, ozone and biomolecules, all of which are important and practical for us. But what do we know about its essence? Some philosophers such as Philip Goff argue that there are aspects of matter that play a key role determining the nature of consciousness. According to this modern form of panpsychism,  although those aspects can be scientifically investigated, it will take a revolution comparable to that of relativity in physics in order to understand consciousness in all living organisms.

Of course ultraviolet light is a form of energy and not matter. But the two are intimately associated and in special circumstances even interconvertible. So if our understanding of matter may some day be radically rethought, the same may be true of ultraviolet and of all energy forms.What we’ve learned so far is experimentally verified, but the shield of our current mind-frames, theories and instrumentation constantly filter other truths.

Other Sources:

American Zoologist. Ultraviolet Vision in Vertebrates 1., 32:544-554 (1992)http://0-az.oxfordjournals.org.mercury.concordia.ca/content/amzoo/32/4/544.full.pdf

Cone-based vision of rats for ultraviolet and visible lights. Experimental Biology. http://jeb.biologists.org/content/204/14/2439

Methods Enzymol. 2000; 319:359-66.
Photocarcinogenesis: UVA vs UVB.

Earth System Research Laboratory

Chemical Sciences Division

Philosophy of Mind: An Overview
https://philosophynow.org/issues/87/Philosophy_of_Mind_An_Overview

http://www.philipgoffphilosophy.com/