Drugs and Poisons

Suicide do's and dont's: Seven drugs, poisons, and other chemicals that are great to kill yourself with, provided you are into that sort of thing

2008-09-20T12:16:00.014-04:00

Obligatory Disclaimer: The intention of this post is not to provide instructions on how to end your life. If you are seeking such information, there are plenty of places to find it on the Internet.

My personal view (since you obviously want to know) on suicide is that sometimes it's okay, particularly as a means of relieving terminal pain and suffering. However, it does bum me out when someone with a potentially treatable mental illness takes their life. I'm not saying that drugs can fix everyone, or even really 'fix' people at all, but they do have the potential to increase an individual's quality of life.

Anyway, if you're thinking about kicking your own bucket, perhaps I could humbly suggest two things? First, do some research. The Wikipedia article on sucide isn't a bad place to start. Or maybe it is, I'm not an expert. Second, there's this thing called the National Suicide Prevention Lifeline. It's capitalized because it's important! If you want to give them a call, their number is 1-800-273-TALK. Just saying.

Okay, back to drugs. To complement my previous post, here are the "do's" of chemical-based suicide. I've kept it to single chemicals, so effective synergistic combos like ethanol and Valium have been excluded.

7. Old school tricyclic antidepressants

As far as prescription drugs go, these suckers are pretty darn toxic. They are associated with a higher rate of death in the event of an overdose relative to the newer nontricyclic antidepressants (e.g. SSRIs such as Zoloft or Prozac) [1]. In this regard, of all the tricyclics, desipramine (aka Norpramin or Pertofrane) is apparently the most 'effective'.

6. General anaesthetics

Ever been put under? They tell you to start counting down from 10, and you're out cold at 8. If your anesthesiologist is actually a highly deceptive, remarkably agile, incredibly intelligent, and yet stunningly incompetent grizzly bear, then it's likely that your heart stops around 2. Acquisition may be a challenge, but otherwise it's probably just a matter of making sure you push enough to shut your brain (and heart, and lungs) down permanently.

5. Any narcotic solvent (diethyl ether, chloroform, benzene, etc.)

The American government just had to go and make it confusing, but from a pharmacological standpoint, a narcotic is essentially any substance that in appreciably large quantities produces euphoria, stupor, and/or coma. Up the dose a little bit more, and add death to that list.

4. gamma-Hydroxybutyrate (GHB)

A big ol' bolus will cause rapid unconsciousness, respiratory depression, and heart failure. Vomiting and convulsions may occur but generally only while you're unconscious, so no biggie. In short, a big mess for whoever cleans you up but a built-in fail-safe (aspirating on your vomit) as far as ending things goes.

3. Opioids (heroin, morphine, fentanyl, etc.)

The primary purpose of these drugs are to numb pain, which is a good place to start when you're looking to meet the reaper.

2. Barbiturates

The number one choice of doctors who end their lives [2].

1. Carbon monoxide

Puts you to sleep before it knocks you off, is readily available (see: gas ovens, running vehicles in the garage, etc.), and you don't even have to swallow or inject something. There's a reason they make detectors for it.

[1] Kapur S, Mieczkowski T, Mann JJ. (1992). Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 268(24): 3441-3445.
[2] Hawton K, Clements A, Simkin S, Malmberg A. (2000). Doctors who kill themselves: a study of the methods used for suicide. QJM 93(6): 351-357. (link)

Suicide do's and dont's: Eight drugs, poisons, and other chemicals that you shouldn't use to kill yourself

2008-09-02T20:22:00.003-04:00

I did a post on this topic when I first started this blog, but it needed improvement. Behold, improvement!

8. Sodium chloride (table salt)
Yeah, you read me right. Pretty much anything will kill you, if you get enough of it into you. This includes good ol' NaCl. You're probably looking at drinking a couple of gallons of salt water, and you'll puke long before you get most of that into you.

7. Methanol (wood alcohol)
It might work, and you get to get drunk while you're at it. But if it doesn't work, you'll end up blind and with holes in your brain.

6. Any radioactive substance
Even if you somehow manage to get your hands on something that is sufficiently radioactive to dose yourself with thousands of rems, dying is still going to take you at the very minimum a couple of days chock full of intense nausea and diarrhea.

5. Strychnine
As I discussed previously, a painful and terrifying way to die. You remain fully conscious and coherent as you experience repeated bouts of violent convulsions until finally your lungs stop working and you asphyxiate. Woo.

4. Any carcinogen with low acute toxicity
You'll need to a get a lot of it into you, which is a pain, and if you don't finish the job, you end up with cancer a couple of years (or more) down the road. I suppose the cancer might kill you, but that's an awfully roundabout and terribly painful and potentially very slow and agonizing way of ending things, don't you think?

3. Corrosive substances
These include common household chemicals like bleach, oven cleaner (sodium hydroxide), chlorine for the pool, and of course, that muriatic acid you have stockpiled in the garage. Some people seem to think that drinking one of these chemicals would be a good way to meet the reaper. Those people are wrong. Being strongly acidic or strongly alkaline, these chemicals will corrode anything organic, including your mouth, esophagus, and stomach. Then, I theorize, all of your stomach acid will escape into the trunk of your body, dissolving your internal organs. That doesn't sound terrible at all.

2. Paraquat
Paraquat is a herbicide found in many weed control products (e.g. Gramoxone). If you drink enough of it, you'll experience the joys of multisystem organ failure with death occurring within hours to a few days. However, should you fail to drink enough of it, it will selectively accumulate and persist in your lungs and slowly eat away at them while you spend several weeks gasping for breath in terrible pain before you expire. There is currently no antidote, and even people who manage to get lung transplants find that their new lungs are eventually destroyed as well, since the poison also hangs out in the fat surrounding them. Sadly, it is widely used as a means of suicide in many parts of the world.

1. Acetaminophen
Also known as paracetamol and Tylenol, acetaminophen is the most common cause of intentional self-poisoning in adults in many countries on account of it being widely available and cheap as hell. What doesn't appear to be widely available is the knowledge that this analgesic is highly toxic to pretty much just the liver and kidneys. Even if you take enough to destroy these organs, it can take up to two weeks to actually die. The pain is apparently excruciating.

Listeriolysin O - Basically why listeriosis sucks so bad

2008-08-22T16:48:00.003-04:00

Every so often, the narcissistic tendencies of Listeria monocytogenes get to be too much for this annoying Gram-positive bacterium to bear, and it decides to make the news by causing a listeriosis outbreak. Typically this involves a major food manufacturer having to recall a product that has become contaminated with the bug. The media loves bacterial narcissism.

Based on what I've read (Wikipedia, obviously), listeriosis is fairly uncommon and largely associated with infants, old people, and those with compromised immune systems. It's actually more common in animals, particularly cows and stuff. Wikipedia also points out that although L. monocytogenes was first described in 1926, it wasn't identified as a cause of foodborne disease until 1981 (in Halifax, Nova Scotia, of all places). Listeriosis often presents as a flu-like illness (fever, puking, feeling like you're gonna puke, and getting the runs) that eventually subsides or else worsens into such fun things as septicemia (blood poisoning), encephalitis/meningitis (brain/brain membrane inflammation), corneal (eye) ulcer (Google Image or bust!), or pneumonia.

Listeriolysin O (LLO) is a protein toxin secreted by L. monocytogenes that helps the bacterium get inside cells, where it can reproduce like crazy while remaining hidden from the the immune system [1]. The entire process starts with the bacterium tricking white blood cells into engulfing it into a container called a phagosome. At this point, LLO creates a hole in the phagosome, permitting the bacteria to escape its container into the cytoplasm of the cell, where it can start dividing like a mofo.

Here's the really cool part. LLO is activated only under the more acidic conditions it encounters within a phagosome, so once it forms a pore and spills out along with the bacterium into the more basic cytoplasm, it's activity is reduced [1]. This means that LLO won't form pores in the plasma (outer) membrane of the cell, which would likely kill it, thus ensuring the maintenance of a nice little cell incubator for Listeria to multiply in.

[1] Schnupf P, Portnoy DA. Listeriolysin O: a phagosome-specific lysin. (2007). Microbes Infect. 9(10):1176-1187.

Diisopropyl fluorophosphate (DFP) - Sarin's little brother

2008-08-15T12:26:00.005-04:00

Organophosphates are a class of chemical compounds that possess a phosphate atom bound to a couple of oxygen atoms. They include among their ranks such essential-for-life biochemicals as nucleic acids and ATP, as well as life-ending insecticides, herbicides, and nerve agents.

Nerve agents kill you by inhibiting an enzyme called acetylcholinesterase, which hangs out wherever nerves from your brain/spinal cord connect with your muscles in order to tell them what to do. When the nervous system wishes a muscle to bend to its will (lol), a neurotransmitter (chemical facilitator of communication between nerve and muscle) called acetylcholine is released from nerves and binds to sites on muscle to cause them to contract. Normally, acetylcholinesterase then breaks down the acetylcholine so that the muscle can relax. Organophosphates bind to a special site on acetylcholinesterase and prevent it from breaking down acetylcholine, resulting in prolonged muscle contraction (i.e. being paralyzed). Since you need muscles to breathe, organophosphates are somewhat problematic, causing asphyxiation and death death death.

Diisopropyl fluorophosphate (DFP) is an organosphate nerve gas; an insecticide gone wrong, if you will. It was originally developed by a British dude named Bernard Charles Saunders, who was trying to break into the exciting world of chemical warfare products (aren't we all). In a major setback for Mr. Saunders, DFP was found to be less toxic than similar compounds like tabun or sarin. However, he stuck with his little toxic friend, and eventually figured out that it could be mixed with mustard gas to produce a mixture with a sufficiently low enough melting point to be used in cold weather, which was apparently a big deal at the time. Mustard gas: Now able to blister you to hell all year round.

Since DFP resembles much more toxic chemical agents (taurin, sarin, soman, cyclosarin, etc.), it has been used by military forces as a substitute for such agents in training drills and top-secret experiments and stuff. DFP is actually a structural analog of sarin, meaning that it contains the same atoms but they are arranged differently.

DFP has been used by eye doctors and vets to produce miosis (constriction of the pupil of the eye), which is beneficial to the treatment of chronic glaucoma and some other stuff. Neuroscience researchers have been known to play around with it since it inhibits acetylcholinesterase and so can be used to induce delayed peripheral neuropathy, permitting this condition to be studied.

Persin - Exploring the secret pharmacological life of the humble avocado

2008-07-24T23:14:00.003-04:00

An important message for the under-the-table pet feeders of the world: If you feed your animal friend a bunch of avocado, it may get very sick [1]. This is thanks to a toxin called persin, which is found in both the fruit and leaves of the avocado tree (Persea americana). Persin is an polyketide that is made via the same biochemical pathways that the avocado plant uses to make its delicious, delicious fatty acids. In fact, it closely resembles linoleic acid, an essential omega-6 fatty acid.

For some reason, persin is usually harmless to humans (though it may be responsible for some avocado allergies) but can seriously mess with all sorts of other animals including birds, mammals (other than us), and fish. Lactating rodents and livestock that eat avocado leaves often develop udder-related problems such as inflammation and wonky milk secretion [2]. Avocado consumption has also been linked to heart damage (necrosis of myocardial fibres) in several mammals. This sort of selective toxicity is actually fairly common among drugs. For example, penicillin is pretty darn safe for humans (provided you aren't allergic), but it kills off guinea pigs like a gator in a...well, guinea pig factory. Keep this in mind the next time your little furry bundle of joy and frequent excretion gets an infection and requires black market antibiotics.

Persin is also capable of harming fungi and insects, particularly those species that infect/eat the avocado plant (e.g. Colletotrichum gloeosporioides, which also attacks citrus fruits and papayas). This may explain why the compound exists in the first place!

In keeping with its toxic nature, persin is capable of killing breast cancer cells (hooray!). Not only that, it can boost the effects of tamoxifen, a popular breast cancer drug [3]. This synergistic effect is thought to be in part due to persin messing with steroid hormone receptor signaling so as to make breast cancer cells more susceptible to the estrogen receptor modulatory effects of tamoxifen.

[1] Buoro IB, Nyamwange SB, Chai D, Munyua SM. (1994). Putative avocado toxicity in two dogs. Onderstepoort J Vet Res. 61(1):107-109.
[2] Oelrichs PB, Ng JC, Seawright AA, Ward A, Schäffeler L, MacLeod JK. (1995). Isolation and identification of a compound from avocado (Persea americana) leaves which causes necrosis of the acinar epithelium of the lactating mammary gland and the myocardium. Nat Toxins. 3(5):344-349.
[3] Roberts CG, Gurisik E, Biden TJ, Sutherland RL, Butt AJ. (2007). Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism. Mol Cancer Ther. 6(10):2777-2785.

Je suis le lazy, so here are some free toxin review articles to read

2008-07-12T21:59:00.007-04:00

I'm so not feeling the whole let's read a couple of papers and write a sweet-ass blog post vibe this evening, so instead I've decided to compile a list of comprehensive, well written, and most importantly, free review articles covering various types of toxins (poisons produced by living things). Think of it as if I've expertly written an entire series of concise posts, while avoiding any attempts at wit or humorous digression, and then lumped them together according to type into nice looking articles that I've linked below.

Bennett JW, Klich M. Mycotoxins. Clin Microbiol Rev. 2003 Jul;16(3):497-516. Review.

Van Dolah FM. Marine algal toxins: origins, health effects, and their increased occurrence. Environ Health Perspect. 2000 Mar;108 Suppl 1:133-41. Review.

Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev. 2004 Jan;84(1):41-68. Review.

Kini RM. Anticoagulant proteins from snake venoms: structure, function and mechanism. Biochem J. 2006 Aug 1;397(3):377-87. Review.

Daly JW. The chemistry of poisons in amphibian skin. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):9-13. Review.

Middlebrook JL, Dorland RB. Bacterial toxins: cellular mechanisms of action. Microbiol Rev. 1984 Sep;48(3):199-221. Review.

Can watermelon help keep your cucumber crisp?

2008-07-06T14:24:00.002-04:00

Word is on the street that watermelon (Citrullus lanatus), God's gift to summertime family reunions, may produce a Viagra-like effect. As a commenter on reddit put it: "They cool you above and fire you up down below."

This effect is apparently made possible by an amino acid called citrulline, which is found in both the rind and flesh of the watermelon. It's also found in mammals, where it is present as a free molecule in the liver as an intermediate in the urea cycle (toxic ammonia in blood -> urea in kidney -> you pee it out) and occasionally found incorporated into proteins. As it is not coded by DNA, it must be produced via the post-translational (occurring after a protein is synthesized from amino acids) modification of arginine, a structurally related amino acid. This process is called citrullination, and it occurs primarily in proteins found in myelin or involved in keratinization (deposition of keratin in skin, hair, and nails). Insufficient citrullination of these proteins has been implicated in some autoimmune diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis.

Anyway, back to this watermelon = possible stiffy business. Following the consumption of watermelon, the citrulline it contains is enzymatically converted into arginine, which in turn is broken down to release a gas called nitric oxide (NO). NO causes the smooth muscle within the walls of blood vessels to relax, leading to dilation of affected vessels and increased blood flow through them. Increased blood flow to the penis leads to an erection. Sounds good, right?

Now here's the thing. Lots of substances can dilate blood vessels, including alcohol and chocolate. We synthesize citrulline in our guts from glutamine, a much more common amino acid. Dairy products, meat, seafood, bread, oatmeal, nuts, seeds, and lentils all contain decent amounts of arginine, which is what citrulline is converted to before it becomes NO. Viagra is so good at doing what it does because it acts on a particular enzyme that opposes the action of NO and is found almost exclusively in the penis. Just because something dilates blood vessels and increases blood flow doesn't mean its going to produce a woody.

The way I figure it, either the researchers at Texas A&M wanted some publicity and so went out of their way to mention that watermelon could potentially be used to treat erectile dysfunction, or the media decided to concentrate on the sex and ignore the science. Possibly both.

It should be mentioned that even if this whole watermelon boner thing is bogus, drugs that relax blood vessels are important for the treatment of many cardiovascular issues such as angina and hypertension. Citrulline is currently used to treat inherited urea cycle disorders and may eventually find use as a means of boosting the citrullination of proteins implicated in autoimmune diseases.

- Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Bénazeth S, Cynober L. Almost all about citrulline in mammals. Amino Acids. 2005 Nov;29(3):177-205. Review.

Orellanine - How normal-looking mushrooms can be way poisonous

2008-06-19T21:34:00.004-04:00

Orellanine is a nephrotoxic (nephros is Greek for kidney, you do the math) dipyridine possessing positively charged nitrogen atoms that is produced by several species of mushrooms belonging to the genus Cortinarius. Members of this genus are gilled mushrooms that grow in association with plants (i.e. are mycorrhizal) and have their gills protectively covered by a cottony cortina (veil or curtain, not to be confused with the Google Image-hogging vehicle of the same name) that spans between their pileus (cap) and stipe (stem) when they are but wee little shroomies. Known producers of the toxin include C. rubellus (deadly webcap), C. orellanus (fool's webcap), and a bunch more. Some of these are found in Europe, others in North America (most commonly in the fall), meaning that no one in the Western world is safe. These poisonous species are occasionally confused with edible or psychedelic mushrooms, resulting in sweet, sweet natural selection.

It has been estimated that the consumption of only 100 grams (about 3.5 ounces) of fresh C. orellanus is necessary to utterly destroy ones' kidney! Orellanine kills people by accumulating in the renal tubules of their kidneys and somehow selectively damaging this part of the organs to the point that they stop working (acute renal failure), an event that usually takes two to three weeks after the onset of symptoms to occur (okay, make that delayed acute renal failure). Unusually, the onset of symptoms (initially and unfortunately flu-like in nature) is typically delayed up to 3 to 4 days after mushroom consumption in severe cases, and up to three weeks in milder cases. If they don't die outright, about one-third to half of all those poisoned by orellanine develop chronic renal failure and may require dialysis or kidney transplant.

Like aflatoxins, which are mycotoxins produced by Aspergillus moulds that rank among the most carcinogenic chemicals known to man, orellanine is fluorescent, making it a blast at glow-in-the-dark mini putt. Similarly-structured substances include the herbicides paraquat and diquat, which are both toxic to humans. Paraquat is particularly nasty, accumulating in and causing progressive destruction of the lungs in a manner similar to how orellanine savages the kidneys.

- Berger KJ, Guss DA. Mycotoxins revisited: Part II. J Emerg Med. 2005 Feb;28(2):175-83. Review.
- Nilsson UA, Nyström J, Buvall L, Ebefors K, Björnson-Granqvist A, Holmdahl J, Haraldsson B. The fungal nephrotoxin orellanine simultaneously increases oxidative stress and down-regulates cellular defenses. Free Radic Biol Med. 2008 Apr 15;44(8):1562-9. Epub 2008 Jan 31.

Agaritine - Raw button mushrooms and The Cancer

2008-06-13T16:47:00.003-04:00

Ah, the dichotomy of mycophagy. That statement sounded pretty darn impressive, didn't it? Admit it, you were a little impressed. Morels, truffles, and king boletes are arguably among the most saporous and sought-after foods out there, while false morels, Amanitas (which include the aptly-named Death cap and Destroying angel), and the Lethal webcaps will generally kill you if you eat them.

Then there's the genus Agaricus. It includes a number of species known to be at least mildly poisonous, as well as several others that are consumed around the world on a daily basis. The common store mushroom, Agaricus bisporus, also known as the commercial mushroom and the button mushroom, is by far the most popular of these, with hundreds of millions of the little guys being produced and consumed annually. The cream-coloured bundle of succulence (yeah, you read that right) that is sold today is actually a mutant strain discovered in Pennsylvania in 1926. The original cultivated strain was a light brown, but at the time white was very trendy. Another familiar strain of A. bisporus is the Portobello mushroom, which has retained the brown colour but is much larger with a thick cap and stem, enabling it to be strangely consumed in burger form.

Other wild species of Agaricus that people eat include A. campestris (the field mushroom), A. arvensis (the horse mushroom), and A. augustus (called the "prince", although I suspect the "emperor" might fit better). These are good eating, but don't go hunting for 'em unless you're an expert. And by that I mean a trained mycologist, not some dude who read a book and "hasn't got sick yet".

All species of Agaricus contain hydrazines, which are compounds that contain two bonded nitrogen atoms. Of these, which include in their ranks such luminaries as gyromitrin and monomethylhydrazine, the most abundant is an aromatic hydrazine known as agaritine.

The vast majority of hydrazines are known carcinogens. Agaritine is rapidly broken down by animal enzymes to form 4-(hydroxymethyl)phenylhydrazine (HMPH) and 4-(hydroxymethyl)benzenediazonium ions (HMBD), both of which are very unstable and have been shown to be carcinogenic. Extracts of A. bisporus have been shown to damage DNA in test tubes (Ames test) and it has been demonstrated that mice display a significant increase in the incidence of several types of tumours after they are fed uncooked mushrooms. As there is currently insufficient evidence to conclude otherwise, agaritine is presently only suspected to cause cancer in humans.

It should be noted that agaritine and its derivatives are likely degraded by heat, so cooking your mushrooms would be expected to lower the risk of developing cancer. If such a risk is real. But honestly, raw mushrooms can't compete with ones that have been sauteed in butter.

- Kondo K, Watanabe A, Akiyama H, Maitani T. The metabolisms of agaritine, a mushroom hydrazine in mice. Food Chem Toxicol. 2008 Mar;46(3):854-62. Epub 2007 Dec 3.

Retapamulin - How a mushroom fights bacteria

2008-05-25T22:28:00.005-04:00

Pleurotus mutilus (also called Clitopilus scyphoides) is delicate cream-coloured edible ectomycorrhizal gilled mushroom that makes an antibacterial compound quite aptly called pleuromutilin.

Like many other antibiotics, pleuromutilin and its lab-born derivatives carry out bacterial genocide by binding to bacterial ribosomes and inhibiting protein synthesis (which is what ribosomes do). This is accomplished by their binding to a domain of 23S rRNA (ribosomes = protein + rRNA), not bound by any other type of similar-acting antibiotic, and directly preventing the binding of the components (peptidyl transferase and amino acid-carrying tRNAs) binding necessary for the formation of proteins. Their unique site of action means that cross-resistance to other antibiotics is non-existent, making them effective against things like MRSA.

Retapamulin (Altabax, Altargo) is a topical semisynthetic pleuromutilin derivative formulated as an ointment and indicated for the treatment of superficial bacterial skin infections such as impetigo and those resulting from wounds. It works well against Gram-positive bacteria, but not much else. Other pleuromutilins that are out there include tiamulin and valnemulin, which are both used by veterinarians to treat infected pigs.

- Yan K, Madden L, Choudhry AE, Voigt CS, Copeland RA, Gontarek RR. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother. 2006 Nov;50(11):3875-81. Epub 2006 Aug 28.
- Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs. 2008;68(6):855-73.

Aztreonam - The lonely monobactam from a purple bacterium

2008-05-17T13:09:00.006-04:00

I appear to be on a bit of an obscure antibiotic kick right now, so bear with me!

In 1928, a Scotsman named Alex Fleming discovered that a mould contaminating one of his Petri plate-based bacterial cultures was dissolving the bacterial colonies around it as it grew. Fortunately for us all, he decided to play around with the mould and managed to extract an antibacterial substance that he boringly named penicillin, after the genus of mould that produced it. It was subsequently shown to be highly effective at treating bacterial infections in humans. World War II came along, spurring the development of a means of mass-production of the drug and ultimately saving the lives of a huge number of infected Allied soldiers. Penicillin went on to revolutionize the treatment of bacterial infections worldwide. The functional group in penicillin that enables it to smite bacteria is the beta-lactam ring. This ring is only four-sided, making it relatively unstable and permitting it to bind to and inactivate an enzyme necessary to make a strong bacterial cell wall. Affected bacteria with wussed-out walls are killed by the uncontrolled buildup of osmotic pressure, which generally causes them to pop/burst/rupture.

Approximately one zillion derivatives of penicillin have since been developed in an attempt to increase the range of bacteria that it can fight and improve its pharmacokinetics (essentially, its ability to get to the site of infection at a high enough concentration to do its thing) and safety. Further research in the realm of microbe-produced antibiotics has yielded a slew of other beta-lactam ring-containing classes of drugs. These include cephalosporins (original compound is produced by fungi of the genus Acremonium), cephamycins (produced by bacteria of the genus Streptomyces), cephabacins (produced by several bacteria of the family Xanthomonadaceae), carbapenems (based on thienamycin, a product of the bacterium Streptomyces cattleya), nocardicins (produced by the bacterium Nocardia uniformis), and monobactams (produced by the bacteria Chromobacterium violaceum).

The monobactams are neat because a) only one of them (aztreonam) has actually been developed into a commercially available drug and b) their beta-lactam ring is not fused to another ring, as it is in all of the other classes except the nocardicins. The natural synthesizer of aztreonam (Azactam), Chromobacterium violaceum, is a Gram-negative rod-shaped bacteria found in water and soil all over the world that occasionally infects humans. When grown in culture, it produces distinctive smooth metallic dark violet colonies, reflecting the production of a pigment called violacein, which is capable of killing amoebae and trypanosomes. C. violaceum also produces other antibiotics, including aerocyanidine and aerocavin. Unlike the penicillins, aztreonam is lousy at binding to and destroying gram-positive and anaerobic bacteria. However, it has good activity against most aerobic gram-negative bacteria, including those belonging to the genus Pseudomonas. In the clinic, aztreonam must be injected. An inhaled form has been developed (based on the use of an ultrasonic nebulizer to render a solution of the drug airborne as a mist) and is currently in trials.

- Aoki H, Sakai H, Kohsaka M, Konomi T, Hosoda J. Nocardicin A, a new monocyclic beta-lactam antibiotic. I. Discovery, isolation and characterization. J Antibiot (Tokyo). 1976 May;29(5):492-500.
- Durán N, Menck CF. Chromobacterium violaceum: a review of pharmacological and industiral perspectives. Crit Rev Microbiol. 2001;27(3):201-22. Review.
- Hellinger WC, Brewer NS. Carbapenems and monobactams: imipenem, meropenem, and aztreonam. Mayo Clin Proc. 1999 Apr;74(4):420-34. Review.
- Ono H, Nozaki Y, Katayama N, Okazaki H. Cephabacins, new cephem antibiotics of bacterial origin. I. Discovery and taxonomy of the producing organisms and fermentation. J Antibiot (Tokyo). 1984 Dec;37(12):1528-35.

Mupirocin

2008-05-13T13:49:00.008-04:00

Pseudomonas fluorescens is a common nonpathogenic Gram-negative bacteria found in poop, soil, and water that gets its name from the fact that it secretes a fluorescent siderophore (iron-binding compound) called pyoverdin (fluorescein). Cultures of it glow under black light, making it the raver's bacterium of choice. P. fluorescens also produces an epoxide antibiotic, originally named pseudomonic acid A but commonly called mupirocin (trade names Bactroban or Centany), that is good at inhibiting the growth of and outright killing (at higher concentrations) Gram-positive bacteria, particularly staphylococci and streptococci.

Mupirocin is typically formulated as a topical cream, ointment, or spray used to treat infections of the skin (e.g. boils, impetigo, the likely consequence of not bothering to clean a dirty scrape on your knee, etc.). It can only be used topically (i.e. applied to the surface of the body) because it is rapidly and extensively broken down once it gets into the blood and interstitial fluid. Notably, it is capable of killing methicillin-resistant Staphylococcus aureus (MRSA), and has been used to treat nasal carriers of this bacterium in addition to those infected with it. Although resistance to mupirocin is more or less inevitable, limiting its use could prolong its usefulness until resistant bacteria become widespread.

The ability of mupirocin to extirpate bacteria that are resistant to other antibiotics is due to its novel mechanism of action, which involves the inhibition of the enzyme isoleucyl-tRNA synthetase, which is responsible for attaching the amino acid isoleucine to its corresponding transfer RNA . Bacteria need this amino acid to make proteins. Most antibiotics mess with either the bacterial cell wall or the synthesis of bacterial DNA or proteins, so hitting the bacteria at the amino acid level is something different.

- Parenti MA, Hatfield SM, Leyden JJ. Mupirocin: a topical antibiotic with a unique structure and mechanism of action. Clin Pharm. 1987 Oct;6(10):761-70. Review.

Puerarin - Good for hearts and hangovers

2008-05-06T00:44:00.006-04:00

Kudzu (Pueraria lobata) is a fast-growing and incredibly resilient invasive climbing vine that was introduced to North America from its native habitat in East Asia. This plant is an intense sonofabitch, being capable of growing at a rate of up to 30 centimetres (inches) per day. It has been known to smother forests with its growth, and is taking over the American south as we speak. The purple flowers of the plant are used to make a scrumptious jelly, and the leaves and roots can be eaten.

Kudzu produces a number of isoflavones, organic compounds with rings and stuff that are typically strong antioxidants (may reduce tissue damage by free radicals, which are produced as a part of normal metabolic activity) and capable of mimicking the effects of estrogen in mammals (phytoestrogens).

Puerarin is the most concentrated isoflavone found in kudzu. This makes it the major active ingredient in Ge-gen, a traditional Chinese medicine made from kudzu root. Ge-gen is used traditionally to treat fever, pain, diabetes, measles, diarrhea, and cardiovascular diseases including coronary artery disease, arrhythmia and hypertension. It also has been employed as a means of relieving drunkenness and hangover after a long night on the town.

Interestingly, puerarin is capable of selectively suppressing alcohol intake in animal models of excessive drinking (rats and monkeys), suggesting that it may have application as a drug therapy for alcoholism (anticraving agent). It is thought to reduce alcohol absorption by inhibiting the movement of alcohol across gut membranes, thus reducing blood alcohol levels.

- Rezvani AH, Overstreet DH, Perfumi M, Massi M. Plant derivatives in the treatment of alcohol dependency. Pharmacol Biochem Behav. 2003 Jun;75(3):593-606.
- Zhang SY, Chen G, Wei PF, Huang XS, Dai Y, Shen YJ, Chen SL, Sun-Chi CA, Xu HX. The effect of puerarin on serum nitric oxide concentration and myocardial eNOS expression in rats with myocardial infarction. J Asian Nat Prod Res. 2008 Apr;10(4):323-8.

Drugs of the future: CBLB502

2008-04-23T17:42:00.001-04:00

A chunk of Salmonella flagellum has been shown to protect mice and rhesus monkeys from the toxic effects of ionizing radiation. The drug binds to Toll-like receptor 5 (TLR5) and turns on the nuclear factor-κB signaling pathway, which leads to the induction of factors that protect cells (apoptosis inhibitors and reactive oxygen species scavengers) and promote tissue regeneration (cytokines). The activation of this pathway also results in the inhibition of the p53 tumour suppressor pathway, which is one of the means by which cancer cells are able to resist the effects of radiation. Incidentally, things like cytokines and amifostine are also radioprotective, but CBLB502 appears to be the best of 'em.

Flagellin, the principal protein component of bacterial flagella, is the only thing that we know of that binds to and activates TLR5. The drug was synthesized based on the structure of flagellin made by Salmonella enterica serovar Dublin, a human pathogen found in raw cow milk.

A single injection of CBLB502 was able to protect mice from the normally lethal whole-body gamma-radiation doses of 10 and 13 Gy, and increased their survival by almost a week after a dose of 17 Gy.

If this is legit, it could mean safer cancer radiotherapy and better protection in radiation emergencies.

Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, Kurnasov OV, Fort FL, Osterman AL, Didonato JA, Feinstein E, Gudkov AV. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008 Apr 11;320(5873):226-30.

Lobeline - Cure for meth and heroin addiction?

2008-04-10T17:10:00.008-04:00

Matthias de L'Obel (1538-1616) was a French physician and botanist. He devised and published a system of plant classification, and served as the personal physician to William the Silent and James I. The plant genus Lobelia is named for him.

A number of Lobelia species, including Lobelia inflata (Indian tobacco) and Lobelia tupa (Devil's tobacco), produce a piperidine alkaloid called lobeline. Lobeline is a nicotine-like stimulant, which explains why L. inflata is used by Native Americans and others in the know as a substitute for regular tobacco.

Lobeline, like nicotine, enjoys long walks, romantic candlelit dinners, and binding to nicotinic acetylcholine receptors in the brain. However, it is apparently less active than nicotine at these receptors and so can actually diminish the effects of the drug. This antagonism is the basis for the use of lobeline as a treatment to help people quit smoking, although its effectiveness is still very much up for debate.

Lobeline has been shown to decrease methamphetamine self-administration in rats, while not being self-administered itself. This suggests that it could be used as a treatment for meth addiction and is unlikely to be abused on its own (unlike nicotine). The decrease in meth self-administration is thought to be due the ability of lobeline to screw around with the storage and release of dopamine by acting on the protein transporters such as VMAT2 that responsible for these processes. Dopamine release in the corpus striatum (a part of the brain) is responsible for the rewarding and reinforcing effects of methamphetamine.

Lobeline has also been shown to be capable of blocking mu opioid receptors, which are what morphine binds to in order to produce its effects. So potentially it can do a world of good for both amphetamine and opioid addiction.

- Miller DK et al. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. Drug Alcohol Depend. 2007 Jul 10;89(2-3):282-91.
- Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. Eur J Pharmacol. 2007 Sep 24;571(1):33-8. Epub 2007 Jun 13.

Sildenafil (Viagra) - Get on up

2008-04-05T19:21:00.004-04:00

Ah, sildenafil. What more is there to say? It has saved marriages. Broken up marriages. Provided fodder for terrible comedians. Made spam just that much more intolerable.
It works as follows. You swallow a pill, which breaks down in your stomach and intestine, releasing molecules of sildenafil that are absorbed into your bloodstream and transported throughout your body. When these molecules encounter an enzyme called PDE5, they inhibit its ability to break down a signal molecule called cGMP. If you're a dude, PDE5 is found in your corpus cavernosum, which is the spongy region of expandable erectile tissue found along the length of your willy. It's responsible for getting you up, so to speak. In the corpus cavernosum, cGMP controls blood flow. By inhibiting PDE5, sildenafil causes cGMP to accumulate, resulting in the expansion of penile blood vessels due to the relaxation of smooth muscle in vessel walls mediated by the accumulated cGMP. This leads to an increase in blood flow to the penis, resulting in a boner.

In individuals with normal erectile function, cGMP is increased by the release of nitric oxide (NO) from nerves in the corpus cavernosum when you get horny or during REM sleep. NO is a gas that can bind to and stimulate guanylate cyclase, an enzyme that produces cGMP.

Fun side effects of sildenafil include sneezing, priapism (perma-boner, one which stays up for longer than four hours), photophobia (you become very sensitive to light), and weird visual changes (blurring, everything develops a bluish tinge to it, loss of peripheral vision).

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
- http://en.wikipedia.org/wiki/Sildenafil

Heads up: Sweet Onion A.V. Club drug article

2008-03-31T11:53:00.001-04:00

Dig this fine article on fictional drugs.

Caffeine - Drink coffee to breathe easier

2008-03-30T18:57:00.003-04:00

Caffeine is a methylxanthine stimulant found in coffee that makes morning lectures somewhat more tolerable. Methylxanthines are methylated derivatives of xanthine. Animals produce xanthine as an intermediate in the breakdown of purines (e.g. guanine or adenine, the purine bases found in DNA and RNA) to uric acid, the stuff that causes gout and is excreted in urine. Other methylxanthines include theophylline (found in tea) and theobromine (found in cocoa, and thus in chocolate).

At the biochemical level, caffeine inhibits an enzyme called phosphodiesterase (the same target of Viagra!) and blocks the action of adenosine. These actions wake you up (and produce nervousness and insomnia at high doses), get your heart pumping (increase heart rate and increase the force of heart contraction), cause vasodilatation (except in the brain), and make you have to pee (by increasing how much urine your kidney makes).

Caffeine is used to diagnose people who have a genetic predisposition to malignant hyperthermia, a condition invoked by general anaesthesia that causes your muscles to intensely contract, producing tonnes of heat such that you run an exceptionally high fever and the enzymes in your body begin to stop working and you die very quickly. Incidentally, this terrifying condition is also a side effect of ecstasy (MDMA) use and can be treated with a drug called dantrolene.

Back in the day, caffeine was used to treat asthma, since it causes bronchodilation (relaxes the smooth muscle of the airways, causing them to expand) and so can help to reverse the constriction that occurs during an asthma attack.

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.

Drugs, drugs, everywhere: Throat lozenges edition

2008-03-11T23:41:00.003-04:00

Hey everyone. My wonderful and ever patient girlfriend is fighting a nasty cold right now, and has taken to using throat lozenges made by Strepsils to make her sore throat less sore. I got my hands on the lozenge box and discovered that they contain not one, but two active ingredients. Hokey doodle! Each lozenge of Strepsils extra Black Cherry contains 2.4 mg of hexylresorcinol and 4 mg of menthol.

Menthol is a cyclic terpene alcohol that makes plants belonging to the genera Mentha (the mints) smell and taste the wonderful way that they do. It is able to produce a cooling sensation by stimulating a receptor found in skin and mucous membranes called TRPM8 that usually responds to cool temperatures (i.e. 8-28 degrees Celsius). At concentrations of 1% of less, menthol depresses skin sensory receptors, resulting a local anaesthetic effect. At concentrations between 1.25 and 16%, it actually stimulates sensory receptors, countering the effects of any irritants. In either case, topical pain relief (including relief from a sore throat) is achieved. At concentrations above 30%, menthol actually can induce cold pain. Menthol also somehow kills bacteria and fungi, making it a reasonably good antiseptic.

Hexylresorcinol (also called 4-hexylresorcinol) has a long history of use as a drug and ingredient in cosmetics. It works as an antiseptic, and can therefore be found in soaps, skin cleaners, and throat lozenges. Back in the day, before the development of more selective agents, hexylresorcinol was widely used as an antihelmintic. Meaning you could potentially use throat lozenges to get rid of parasitic worms if they were growing inside of you. Awesome. Hexylresorcinol can also be used to prevent shrimp black spot (melanosis), an unappealing surface discoloration of shrimp caused by the enzymatic production of pigmented compounds, as well as the browning and decay of fresh-cut mangoes and apples. It accomplishes these tasks by inhibiting enzymes called polyphenol oxidases.

Strepsils is probably named for Streptococcus, a genus of bacteria that includes a number of species capable of causing sore throats. They've been making it since 1958, so I guess it must do something. That said, if you've got friggin' Strep throat, you want prescription antibiotics and not some OTC throat lozenges. Trust me on this one.

Incidentally, the fine folks at Wikipedia have informed me that cough drops are not the same things as throat lozenges. You see, cough drops are designed to reduce coughing, while throat lozenges are designed to sooth a sore throat.

- Frankos VH, Schmitt DF, Haws LC, McEvily AJ, Iyengar R, Miller SA, Munro IC, Clydesdale FM, Forbes AL, Sauer RM. Generally recognized as safe (GRAS) evaluation of 4-hexylresorcinol for use as a processing aid for prevention of melanosis in shrimp. Regul Toxicol Pharmacol. 1991 Oct;14(2):202-12.
- Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol. 2007 Nov;57(5):873-8. Epub 2007 May 10. Review.

Book Review: Interim Report of the Commission of Inquiry into the Non-Medical Use of Drugs

2008-03-05T19:52:00.006-05:00

Way back in the spring of 1969, amid Apollo launches and Lennon/Ono bed-ins, the Canadian government appointed a commission to look into the recreational use of drugs by its citizens. The Commission of Inquiry into the Non-Medical Use of Drugs, also known as the Le Dain Commission as it was chaired by Gerald Le Dain, was completed in 1972. FYI, Mr. Le Dain was a lawyer and World War II vet who after the completion of the commission went on to become a judge and eventually work his way up to sitting on the Supreme Court of Canada for four years. Fancy.

An interim report, consisting of 557 pages + appendices, was released in 1970. I found a copy in a used bookstore this afternoon, amidst a thousand terrible guides to herbal medicine. It is set in what appears to be Courier typeface, with wonderfully extravagant leading and tracking. Based on a quick skim through, the report appears to be comprehensive, readable, insightful, and perhaps most importantly, impartial.

Barbiturates, alcohol, minor tranquilizers (e.g. benzodiazepines such as Valium), amphetamines, LSD, cannabis, opiate narcotics, and volatile solvents (inhalants) are all reviewed in terms of their medical uses, pharmacokinetics, psychological and physiological effects, potential for dependence, and interactions with other recreational drugs. A brief but informative history of the medical and recreational use of the drugs is given at the beginning of their individual sections.

A chapter on the frequency and patterns of recreational drug use in Canada reveals the following wonderful tidbits:

Regina, Saskatchewan was a hotbed of marijuana and LSD use among high school and university students in the late 1960s in comparison to the rest of Canada
LSD use increased rapidly in Canada during periods when marijuana was in short supply
Between 1951 and 1965, the estimated number of Canadian alcoholics increased by over 60%, while the rate of convictions for drunkenness remained virtually stable
Street samples of marijuana from the time were frequently found to be alfalfa, marjoram, or parsley
Nail polish remover and plastic glue were the most popular solvents to get high off of in 1969

The interim report also contains a chapter on Canadian drug policy at the time, which is followed up with a series of interim recommendations on the appropriate social response (research, education, law, treatment and supportive services, prescribing controls) to recreational drug use. Solid stuff, to be sure.

Incidentally, as part of the commission, hearings were held during which testimony was heard from a bunch of people, including John Lennon and Yoko Ono.

The final report of the commission recommended that marijuana be legalized and controlled in a manner similar to alcohol in terms of possession, production, and distribution. This made it big with the stoner crowd, but it ended up being largely ignored by the government.

To close, here is an amusing excerpt from a discussion of the illicit drug market in a bygone age lacking the massive Canadian suburban hydroponic grow-ops we have today:

One pound of marijuana, for example, is worth $10 in Mexico, about $50 in parts of California, and $100 by the time it reaches distributors in Canada. If this same pound of marijuana is divided into ounces, these ounces (or 'lids') are likely worth $10 in California, $15 apiece in New York, and $20 to $25 to their owner in Canada. Further subdivisions into 'nickel' ($5) or 'dime' ($10) lots (generally called 'bags') are worth exactly that - and no more.

You can order a copy of the interim report through AbeBooks.

Streptomyces - Genus of plenty (of drugs)

2008-02-29T01:25:00.007-05:00

Okay. Actinomycetes are a group (phyla, actually) of Gram-positive bacteria that like hanging out in soil and water (as decomposers of organic materials) and plants and animals (some are pathogenic, while others do the whole symbiotic thing). The Actinomycetes get their name from the fact that some of them form branching filaments that look kind of like the branching hyphae (collectively referred to as a mycelium) formed by fungi. In an effort to lessen confusion, Actinomycetes are now commonly referred to as Actinobacteria.

Actinobacteria are neat because they tend to produce cool secondary metabolites, many of which have been successfully isolated and turned into useful drugs and other organic chemicals. In particular, an appreciable number of Actinobacteria produce antibiotics, which they use to compete with fungi and other bacteria for resources (and because they are totally badass). The genus Streptomyces (not to be confused with Streptococcus!) is a particularly fruitful source of these compounds, a number of which have been developed as antifungals, antibiotics (antibacterials), and chemotherapeutic (anticancer) drugs. Sit tight, here we go with the lists.

Streptomyces-derived antifungals tend to be macrolide polyenes (large ring structure with lots of conjugated carbon-carbon double bonds), and include such illustrious members as: nystatin (the first Actinobacteria-sourced human antifungal, made by S. noursei), amphotericin B (made by S. nodosus, originally isolated from a sample of Venezuelan soil), and natamycin (made by S. natalensis, insert not-a-mycin joke here).

There are a friggin’ tonne of Streptomyces-derived antibiotics used specifically as antibacterial agents. To begin with, a good number of the aminoglycosides (a class of antibiotics that possess cyclohexyl rings substituted with amine groups and linked together by glycosidic bonds) are the work of this genus. These include: streptomycin (S. griseus), neomycin (S. fradiae), and kanamycin (S. kanamyceticus).

Other antibacterial antibiotics of note include: erythromycin (a macrolide that often subs for penicillin when people be allergic to it, made by S. erythraea), tetracycline (a longstanding acne drug that makes you light-sensitive, made by S. rimosus), chloramphenicol (cheap, effective, but can cause aplastic anemia, made by S. venezuelae), vancomycin (a relatively ginormous glycopeptide that can turn people red, made by S. orientalis), and thienamycin (made by S. cattleya, modified by us to make imipenem, the first carbapenem beta-lactam antibiotic). Whew!

Here is where it gets really cool. A number of the antibiotics produced by Streptomyces have proven to be too toxic for use as antibiotics in humans, but because of their toxicity towards cells (specifically dividing cells) they have been reinvented as chemotherapy drugs. We’re talking drugs like: actinomycin-D (the original), bleomycin (glycopeptide made by S. verticullus), mitomycin (aziridine made by S. lavendulae), and plicamycin (made by S. plicatus). Plus we have the anthracyclines daunorubicin and doxorubicin (S. peucetius), and migrastatin (macrolide, under investigation, made by S. platensis).

Whoo-wee! As you may have noticed, drugs isolated from species of Streptomyces tend to have the suffix -mycin, although there are lots of exceptions. And that's that.

- Birnbaum J, Kahan FM, Kropp H, MacDonald JS (1985). Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin. Am. J. Med. 78 (6A): 3-21.
- http://en.wikipedia.org/wiki/Actinobacteria
- http://en.wikipedia.org/wiki/Streptomyces

Osmium tetroxide - Oxidizer...of death!

2008-02-21T20:31:00.001-05:00

Osmium (Os) is one of those elements situated smack dab in the middle of the periodic table and thus destined to be ignored by pretty much everyone. Let's show it a little love, shall we? A couple of choice facts about osmium: it is a member of the platinum family of transition metals, is incredibly dense (22.61 g/cm³ - gold is only 19.3 g/cm³ and lead a measly 11.34 g/cm³), has a very high melting point (3033 ºC - iron melts at 1538 ºC), and gets its name from the Greek osme (meaning odour). To explain that last bit, when solid osmium is heated above 100 C, it readily reacts with oxygen in the air to form osmium tetroxide, which apparently stinks like ozone or chlorine (i.e. very acrid). This reaction occurs slowly at room temperature with powdered osmium.

Osmium tetroxide is a wonderful combination of highly volatile (evaporates quite readily) and highly toxic. Solids generally don't appreciably sublime (convert directly into a gas) at room temperature, but osmium tetroxide is special. Its high toxicity is the result of it being: (A) an extremely powerful oxidizing agent, meaning that it loves to react with (and so damage) living tissues, and (B) relatively small and water soluble, such that it easily penetrates skin and mucous membranes.

Exposure to even low concentrations of osmium tetroxide vapour can cause severe irritation of the skin, eyes, and respiratory tract. This can mean fun things like dermatitis and ulceration, blindness (it can stain the cornea of the eye), and pulmonary edema. Chronic exposure to the vapour can lead to the accumulation of osmium in the liver and kidney with damage to these organs.

The whole oxidizing living tissues things makes osmium tetroxide useful to researchers as a means of fixing biological samples in place, since the oxidation of macromolecules such as lipids leads to their atoms becoming cross-linked. It is also used by researchers to stain biological things in order to image them using transmission electron microscopy. Osmium nuclei are nice and dense, and so are good at scattering electrons.

- Makarovsky I, Markel G, Hoffman A, Schein O, Finkelstien A, Brosh-Nissimov T, Tashma Z, Dushnitsky T, Eisenkraft A. Osmium tetroxide: a new kind of weapon. Isr Med Assoc J. 2007 Oct;9(10):750-2. Review.
- Smith IC, Carson BL, Ferguson TL. Osmium: an appraisal of environmental exposure. Environ Health Perspect. 1974 Aug;8:201-13.

Cyclopropane - The little ring that can knock you out cold

2008-02-19T00:29:00.004-05:00

Like it's acyclic cousin, cyclopropane is a colourless gas with a notable smell and taste that is both inflammable and potentially explosive and typically stored in metal cylinders as a liquid under pressure.

Cyclopropane is the simplest possible cyclic hydrocarbon, consisting of just three carbon atoms bonded together at 60 degree angles to one another, plus a bunch of hydrogen atoms. Since carbon bonds are normally (and ideally) positioned at a 109.5 degree angle to one another, the bonds in cyclopropane are weakened by angle strain, making the gas more reactive than any other cyclic or acyclic alkane. Molecules of cyclopropane really like to break down to form linear acyclic compounds, and this decomposition can be explosive. Such an explosion can be even more powerful if the gas is mixed with oxygen. Sufficient volumes of pure liquified cyclopropane will self-detonate. The liquid has to be shipped in containers filled with metal or glass wool to improve its stability in order to prevent explosions.

Cyclopropane was first investigated as a potential anaesthetic agent in the early 1930s. Doctors liked it because unlike the other anaesthetic gases/vapours available at the time, it was non-irritating to the respiratory tract, did not significantly depress respiration, heart function or blood pressure, was highly potent (meaning that it could be diluted way down with oxygen), was not appreciably metabolized in the body, and possessed a relatively wide margin of safety between therapeutic and toxic concentrations.

The propensity for cyclopropane to burn/explode and occasionally produce arrhythmias, particularly ventricular tachycardia, led to it being replaced by halothane and it's brethren in the 1950s and 60s (in the Western world).

- Goodman and Gillman
- http://en.wikipedia.org/wiki/Cyclopropane

Toxalbumins - Peas and beans gone bad

2008-01-29T22:45:00.004-05:00

Toxalbumins are protein phytotoxins (toxins produced by plants) capable of inhibiting protein synthesis, which is kind of a really bad thing to have happen to you. They are technically a type of ribosome-inactivating protein (RIP, a most suitable acronym), but more on that later.

Abrin is a toxalbumin made by Abrus precatorius (Rosary Pea, Crab's Eyes, Jequirity), a vine that produces pea-sized bright red with a black splotch seeds that are used as beads and to make rattles. These seeds, although chock full of abrin, have a hard water-resistant coat, meaning that if you ingest them they are only toxic if they are chewed or broken.

Ricin is a toxalbumin present in the seeds (beans, although not true beans) and other parts of Ricinus communis (Castor Bean). It is by far one of the easiest chemical warfare agents to obtain, since the plant grows all over the place (it's a common weed in North America) and the extraction of the toxin is relatively simple.

Viscumin and phoratoxin are toxalbumins produced by species belonging to the genera Viscum and Phoradendron, respectively. Both are mistletoes, those wonderful Christmas plants that enable public displays of affection and parasitize trees. Apparently mistletoe evolved independently five times, meaning that there are five different families of it. Viscum album (European mistletoe) is featured in Greek and Celtic mythologies and was the original Christmastime decoration, while Phoradendron serotinum (Eastern Mistletoe) is the main species grown and used by those in North America during the season of giving.

Other toxalbumins include: crepitin (aka hurin), found in the seeds of Hura crepitans (Sandbox tree), a tropical evergreen tree that produces numerous pointed spines on its trunk and pumpkin-like fruits that explode with considerable kaboom on drying; curcin (aka jatrophin), found in the seeds of species of the genus Jatropha, a New World shrub; momordin, found in the seeds and outer rind of the fruit produced by species of the genus Momordica; and robin and phasin, present in the bark, leaves, and seeds of Robinia pseudoacacia (Black Locust), a tree native to the United States with pretty little white flowers.

As I mentioned previously, toxalbumins are toxic because they inhibit protein synthesis. They accomplish this in a neat way. Each one is a dimer made up of two subunits, simply designated A and B. To spice things up, I will refer to them Albert and Betty. Albert is the actual toxin, while Betty is a lectin (carbohydrate-binding protein) that helps get him inside cells by binding to the cell membrane. Many plants produce Albert, but without Betty, he's just a harmless old fart. Once inside a cell, Albert is able to selectively catalyze the cleavage of an N-glycosidic bond in the 28S ribosomal RNA that is a crucial part of eukaryotic ribosomes, the things inside cells that make proteins, thus inhibiting their formation and essentially shutting down the cell. A single molecule of one of these toxalbumins is capable of inactivating thousands of ribosomes. Ribo oh no! Since people are generally exposed to these things via ingestion, their first site of action tends to be the rapidly proliferating cells of the intestinal wall.

Poisoning proceeds as follows. First there is a latent period, in which nothing appears to be happening. In actuality, the toxin is hard at work, shutting down ribosomes. Then things start to happen. Time to get out your catastrophic health insurance card and head to the hospital. A little nausea, some vomiting and diarrhea. Some victims develop ulcerative lesions throughout their GI tract. The gastric mucosa starts to hemorrhage. Total disruption of intestinal function leads to massive fluid and electrolyte loss, and death soon follows.

- Lampe KF and McCann MA. AMA Handbook of Poisonous and Injurious Plants. American Medical Association, Chicago, 1985.
- Hui A, Marraffa JM, Stork CM. A rare ingestion of the Black Locust tree. J Toxicol Clin Toxicol. 2004;42(1):93-5.
- The pretty pictures were taken by deadmike, M Kuhn, and Randy Read.

Cerberin - To hell and back again

2008-01-27T22:29:00.000-05:00

Deep in the coastal salt swamps of south India, there grows a species of tree. This tree, though taxonomically classified in Latin as Cerbera odollam, is known by most as the Suicide tree [1].

Plants belonging to the genus Cerbera are wonderfully toxic. They get their name from Cerberus, the hellhound of Hades in Greek mythology. The primary toxin responsible for the toxicity of Cerbera species is cerberin, a digoxin-like cardiac glycoside that is capable of royally messing up your heart [1]. Now, digoxin is a useful drug. It can be used to treat a whole lot of heart problems, including atrial fibrillation/flutter. Problem is, you give too much of it, and suddenly it starts causing things like ventricular fibrillation and heart block. Things that are fatal.

Cerberin has a couple of properties that make it an attractive poison. It is difficult to detect the toxin in dead people without real fancy (and expensive) chromatography and spectrometry, and the taste of the plant can be hidden with the use of potent spices [1].

[1] Gaillard Y, Krishnamoorthy A, Bevalot F. (2004). Cerbera odollam: a 'suicide tree' and cause of death in the state of Kerala, India. J Ethnopharmacol. 95(2-3):123-126.