Drugs and Poisons

Rasburicase (Elitek, Fasturtec) - 'Cause curing cancer can cause catastrophe

2007-08-15T20:03:00.000-04:00

recombinant form of urate oxidase (uricase), a peroxisomal enzyme that catalyzes the transformation of uric acid, a waste product of nucleic acid (purine) catabolism, into a more water soluble molecule called allantoin, thus facilitating the removal of uric acid by the kidneys

this enzyme is found throughout the five kingdoms, including in most animals, but the gene that encodes it in humans is no longer functional (likely due to a sudden significant mutational event)

used to treat hyperuricemia (abnormally high levels of uric acid in the blood), which can lead to kidney damage

gout (a variety of arthritis) is the result of low-level, long term hyperuricemia

hyperuricemia is usually due to either reduced removal of uric acid by the kidneys or increased production of uric acid due to things like a deficiency in HGPRT (Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome), eating too much purine-rich foods (meats, alcohol, legumes), and tumour lysis syndrome (TLS)

TLS refers to a bunch of metabolic problems that can occur when chemotherapy successfully kills a bunch of cancer cells

usually associated with hematologic cancers like lymphomas and leukemias

cells tend to concentrate certain ions within their cytoplasm, so when a whole whack of them are killed en masse, these ions are released into the blood, causing things like hyperkalemia and hyperphosphatemia (leading to hypocalcemia)

the degradation of all of the nucleic acid released from the destroyed cancer cells can lead to a rapid and impressively huge rise in uric acid, capable of precipitating acute renal failure

since it is produced using non-human cells, the immune system can mount an allergic reaction against it, and the development of antibodies that bind it all up can lead to a reduction in efficacy

- Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007 Mar 2;4(2):83-93. Review.
- Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: primary structure and evolutionary implications. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9412-6. [link]

Shiga Toxin - Two words: bloody diarrhea

2007-08-13T21:41:00.000-04:00

Today's post is compliments of Toaster, who knows a whole lot about bacterial toxins. Check out his website, Mad Scientist, Jr.

Background:
Bad-ass hexameric molecule produced by some strains of your friendly neighborhood bacteria, most notably Shigella dysenteriae (named after Kiyoshi Shiga, who discovered them in 1898: "Hmm...I wonder what this bloody diarrhea looks like under my microscope?") and Escherichia coli.

Structure:
Once again, hexameric (although this a picture of SLT-1, which warrants a discussion on nomenclature)

Nomenclature:
This terminological mess once confused me, I hope this will make it clearer for you. True Shiga toxin is made by S. dysenteriae, although several strains of E. Coli (collectively termed STEC, which includes EHEC, the stuff that was on spinach recently) also make very closely
related toxins. Shiga-like toxin 1 is made by STECs and differs from S. dysenteriae by only 1 amino acid, while Shiga-like toxin 2, also made by STECs, has ~60% sequence homology with Shiga-like toxin 1. However, most microbiologists refer to Shiga toxins interchangeably,
and may call any of the above Shiga toxins (abb. Stx), verotoxins, or verocytotoxins, leading to a lot of people being very often confused and frustrated, which I think that microbiologists secretly enjoy.

Back to Structure:
So, Shiga toxins are hexameric, with 6 distinct subunits: 5 B subunits and 1 A subunit per molecule. The whole thing is shaped like a big hook (A subunit) with a fan at one end (the B subunits).

Genetics:
From what I understand, Shiga toxin generally isn't encoded in the genome of E. Coli strains that produce it (I don't know about Shigella strains), but is instead encoded in the genome of a bacteriophage that infects most of the bacteria in a population of STECs. So when the
bacteriophage is induced from its happy little quiet lysogenic phase to the lytic phase it fills the bacteria up with Shiga toxins until the bacteria bursts like a sticky balloon of kidney death.

Pathophysiology:
Shiga toxin will mess you up. Seriously. Like, no joke. The LD50 for Shiga-like toxin 2, calculated upwards from animal studies, for a 60kg person would be approximately 3 milligrams. Luckily, true Shiga toxin and Shiga-like toxin 1 are about 400 times less toxic.

In any event, playing pretend is a good way to learn. So let's say you eat some undercooked beef that's been contaminated with poop. The STECs manage to colonize your digestive system and start sticking to your intestinal epithelia. At this point, bloody diarrhea begins. But
as the bacteria pop and release Shiga toxin everywhere, some of it is going to wind up in your bloodstream. And, like anything that gets into your bloodstream, it winds up pretty much everywhere in your body. But Shiga toxin affects mostly renal tissue, hepatic tissue, endothelial cells, and the central nervous system, where it can wreak cellular havoc.

It's best understood how Shiga toxin affects renal tissue, which is to say, it targets distal tubules and the glomerular thingies because these tissues express an abnormally large amount of globotriaosylceramide, a lipid also known as Gb3, which Shiga toxin binds to very strongly. This is highly unusual because lipids don't normally function as receptors. No one knows why this is or why it happens here. Nonetheless, it is the B subunits of the Shiga toxin that bind Gb3
(interestingly, Stx-B subunits have been found to be very potent adjuvants) and somehow (once again, no one knows) get the Shiga toxin into the cell, where the A subunit dissociates from the B subunits and binds to one of the subunits of the ribosomes, essentially shutting all protein synthesis down, which is very, very bad for your cells.

It has been hypothesized, but not conclusively determined, that Shiga toxin plays a role in the development of HUS. HUS is not good. It stands for hemolytic uremic syndrome and involves your red blood cells being transformed from their normal fat happy selves into ragged hunks
of cellular detritus. This condition is associated with infection with STECs (e.g., H7:O157) and usually only happens in those who are very young, old, or immunocompromised.

Then come the complications of Stx interaction with LPS, but that is an entirely different post.

- Palermo M et al. Pretreatment of mice with lipopolysaccharide (LPS) or IL-1beta exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol. 2000 Jan;119(1):77-83.
- Warnier M et al. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int. 2006 Dec;70(12):2085-91. Epub 2006 Oct 25.

Reader experiences: Demerol horror story

2007-08-12T23:15:00.000-04:00

Hey folks. Here's a story:

My experience with Demerol

When I was 14 years old, it was determined that I required a spinal fusion to correct a congenital birth defect with one of my vertebrae. (Congentical kyphosis, for those interested.) The operation itself went ok, with the possible exception that the instrumentation failed near the end of the surgery and they had to extend the fusion down one slot, resulting in only 2 vertebrae left to do my bending for me for the rest of my life. (The Xrays now, 20 years later, are not pretty. Not pretty at all.)

In any case, after the surgery, Demerol was selected as the pain killer of choice. After administration, about 10 minutes later, I basically had a low-grade heart attack. I had heart fibrillation, and they called in a heart specialist who managed to keep me alive for the short term, while I was off day-tripping some near-death light-at-the-end experience.

They determined that I had an extremely adverse reaction to the Demerol. As a result, they decided to eliminate all pain killers from my system for 48 hours, and then start me on straight morphine (mmmmm...smack...), since almost no one rejects the GOOD stuff. Now, my spine had been flayed open literally, metal clamps screwed down all over the place, and bone scraped from my hip to cover the instrumentation and start my body completing the fusion by itself. And staples to close it all up. With no pain killers.

48 hours.

My parents learned every single bad word I ever knew, and some I even made up. The ICU was in a children's hospital, and for some weird reason they had these recessed little panels right above each bed, with Biblical scenes of smurfs in them. (Seriously. I checked later. This is not the lack-of-smack talking.) I talked to Papa Smurf as he loaded the smurfs 2-by-2 on to the Ark. I warned him about flood plains, levees, and the force of water and riptides. I urged him to get a move-on or everyone was gonna' die. The nurses and my family had no idea what I was talking about. They assumed I had lost my mind.

I only remember a few things, one of which was this: I remember waking up, feeling like I had been in that bed for days and days and days. I looked over and a nurse was there, next to my bed. I asked her what day it was. She asked me what day I thought it was. (Grrrrrr...) The operation was on Sunday, so I thought I'd be conservative and say "Tuesday" even though it had to be Thursday at the earliest. She got this very sad look on her face and said "No, I'm sorry, it's been three minutes since the last time you woke up and asked me that very same question."

This pain would never, ever, ever, ever, ever end.

But, of course, it did, and they gave me morphine, and everything was coolio after that.

Not the best way to discover that Demerol will kill you...

- Trey

Sanguinarine - How toothpaste can cause cancer and mustard can cause swollen limbs

2007-08-11T14:20:00.000-04:00

quaternary benzophenanthridine glycoside alkaloid synthesized by plants belonging to the Papaveraceae, Fumariaceae, and Rutaceae families

quaternary compounds possess a permanent positive charge, making them exceedingly lousy at passing through fatty things like cell membranes
specific plants include Sanguinaria canadensis (Bloodroot), Chelidonium majus (Greater celandine), and Argemone mexicana (Mexican prickly poppy)

the seeds of Argemone mexicana look very much like mustard seeds, which can (and has) lead to the adulteration of foods cooked using mustard oil with sanguinarine

people consuming said foods this thing called epidemic dropsy, which features such exciting symptoms as your limbs swelling up (extremity swelling with pitting edema), anemia, heart failure, renal failure, and glaucoma

found in some mouthwashes and toothpastes since it kills bacteria (helping to reduce dental caries) and has antiinflammatory effects (apparently helping to reduce gingivitis)

Viadent, a toothpaste/mouthwash brand that contains sanguinarine, has been linked to oral leukoplakia

has been shown to induce apoptosis in certain cancer cell lines, possibly related to its ability to inhibit the activation of nuclear transcription factor NF-kB (which is involved in regulating cell growth and apoptosis and stuff) or promote the production of reactive oxygen species and/or mitochondrial membrane depolarization

- Allen CL, Loudon J, Mascarenhas AK. Sanguinaria-related leukoplakia: epidemiologic and clinicopathologic features of a recently described entity. Gen Dent. 2001 Nov-Dec;49(6):608-14.
- Chang MC et al. Induction of necrosis and apoptosis to KB cancer cells by sanguinarine is associated with reactive oxygen species production and mitochondrial membrane depolarization. Toxicol Appl Pharmacol. 2007 Jan 15;218(2):143-51. Epub 2006 Nov 1.

Reader experiences: More readers respond

2007-08-01T13:52:00.000-04:00

I am pleased to announce that my mouth no longer contains any wisdom teeth. I also just misspelled wisdom as widoom three times in a row, so the codeine is definitely working it's wonders on my brain. I better stop typing while I'm ahead, so here are a couple of stories that people have sent in for you to read. Thank you, people! Check out the first installment. Here we go:

Steve wrote in to say, "I think it's fair to say that they're [SSRIs] the best thing that's ever happened to me." Well, I've got to share the love for my antidepressant of choice, venlafaxine (a. k. a. Effexor), which is actually an SNRI (it affects norepinephrine as well as serotonin). Before, I was chronically depressed, rock-bottom self-esteem, apathetic, anxious, the whole shebang. Now -- well, I feel like things are going to turn out all right. Ordinary, everyday
hopefulness. Gooooo drugs!

- ap

P. S. Ironically, one of Effexor's most dangerous side effects is suicidal ideation -- which is why it's most definitely NOT recommended for kids and teens.

---

Your blog is sweet! Ok well I've had the privilege to experience a multitude of drug experiences but here's one from last night which involved our friend DXM (dextromethorphan HCL).

Ok so I was experiencing these very nasty coughing fits and decided it was worth it to bicycle in the rain to the grocery store before it closed to get some syrup. Being an impoverished university student I opted for the generic brand which contained 15 DXM/5mL plus some disgusting cherry flavors (read the labels kiddies, brand names are for suckers).

I drank approx 80 mL (240 mg DXM, much more than the recommended dosage) and the bad news was that it did absolutely nothing for my cough. However, I was treated to a wonderful state of opiated-semi-psychedelic-drunkenness, which was further complemented with some high-quality cannabis. This state lasted many hours and when I went to bed I was treated with some groovy shapes and funky colors behind the eyes, and a feeling I was leaving my body. Super-fun! Just don't tell your friends or they'll think you're huffing gas on the side too!

- Luke

---

Since you ask, I am reminded of one time I was in the hospital for kidney stones, which ended up being one of the longest sedative drug-binges of my life. It began as what I hoped was a quick visit for some hydrocodone to dull the relentless visceral groin pain, but ended up in a 3 day hospital stay and a lithotripsy. What follows is the truly amazing list of substances I was on, and my personal opinion of them.

In the ER, while hoping for Vicodin, they instead gave me an NSAID; I think it was dolobid, but I can't remember. I mentioned getting stomach upset from ibuprofen, so they gave it to me IV. That worked pretty well for a while, but left me a tad too alert to be entertained by hospital TV.

Once admitted, I asked for some better pain killers, and they decided to give me Dilaudid (hydromorphone). I doubt they gave me more than 1mg, but even that, I realized almost immediately, was much too much. Pretty soon the side effects were competing with kidney stone pain to see which could make me more miserable. As the drug hit in a matter of seconds, I first felt a wave of euphoria, but this was quickly followed by uncomfortable flushing and profuse sweating, with severe nausea. I should have lain down and stopped moving, but I was stubborn and talking to a friend, and so soon found myself vomiting into a trashcan. It was at this point that I asked for something for the nausea.

They gave me Zofran (ondansetron), a rather expensive drug that can only be given every 8 hours, apparently. It worked pretty well - for about 4 hours. After that time, I was left to fend off the opiate nausea myself. It was around this time that I really wanted some cannabis. Make whatever dumb stoner jokes you want, but nothing that I've tried or heard of works as well, or faster, at treating nausea that cannabinoids. It's way cheaper than Zofran, too. Given my hospitalized state however, it was not to be.

After the Dilaudid fiasco, they switched me to a 1mg/hour self-administered morphine pump. This worked out alright, but not great. It didn't control the pain as well as dilaudid, and performed worse and worse over time, not surprisingly. The nausea left me feeling useless and immobile, but fortunately I never vomited again.

The next day, I had my lithotripsy, and being a neuroscience major, I couldn't resist talking to the anesthesiologist about his pharmacological arsenal. As it turns out, the list of drug's he'd use was quite impressive:

chloral hydrate - for initial sedation. I'm not convinced about this one; I thought he mentioned it, but I'm not sure.

midazolam (Versed) - benzodiazepine for initial sedation, as well as retrograde amnesia. It worked very well in its latter role.

fentanyl - opioid for pain. I imagine it served its purpose effectively.

sevoflurane - one of the newer halogenated ethers. Be grateful they're not still using halothane, like I do on my rats.

Some other muscle relaxants he didn't name. The urologist probably used some local anesthetics for the procedure as well. He may have mentioned nitrous oxide as well, but I can't remember.

Despite the high risk of such a cocktail, I made it through ok, although I can't remember anything after lying down on the operating table until I was rolling towards recovery. I woke confused, thinking I was a child again, being pushed in a shopping cart down a grocery
store aisle. Aren't hallucinations fun?

The real bummer was that I hadn't had a bowel movement in three days, due to opioids and Zofran. This problem plagued me for a couple days after coming home as well. Still, I much prefer my suffering to that experienced by people in the past who had to have kidney stones surgically removed with no anesthesia but strong liquor!

- Aaron

Codeine

2007-07-31T00:36:00.000-04:00

Getting my wisdom teeth out tomorrow, folks. Should be fun.

This is a prime time for you, oh dedicated or happenstance reader, to write a guest post for this blog. So long as it is related to drugs and poisons I'm happy. Interesting drug/poison experiences (see the link above this post for details) would be especially awesome. Send 'em to [email protected]">[email protected] and be sure put something related to the site in your subject line, otherwise it might be doomed to a slow death in the Junk folder. Assuming I can operate a computer in a codeine-induced haze, this should be fun. Actually, if I'm high out of my mind, it'll be fun regardless. Whee! As always, I'll link back to your website, if you have one.

Cyclopamine - The Purple People Eater's mom must have had a taste for it

2007-07-29T23:21:00.000-04:00

steroidal alkaloid actualized by Veratrum californicum (corn lily or vetch weed), a plant native to the subalpine meadows of the western US
teratogenic, meaning that it causes congenital (birth) defects, specifically cyclopia

cyclopia (AKA cyclocephaly or synophthalmia) is severe facial defect that results from a type of holoprosencephaly (the failure of the forebrain to divide into distinct hemispheres) that messes up the development of the face such that the two orbits merge into a single cavity, containing one eye, in the middle of the face in place of a nose

gets its name from the Cyclopes of Greek mythology, a race of one-eyed giants that snacked on people
inhibits the Hedgehog (Hh) signaling pathway, which is involved in the regulation of prenatal development

is currently being investigated as a possible anticancer drug, since an overactive Hh pathway can produce many different varieties of cancer

the corn lily closely resembles hellebore, an herb reportedly used by some pregnant women as 'natural' means of treating morning sickness and cramps, which has on occasion led to them eating the wrong plant and having a deformed kid
jervine is a related (just add a ketone group) teratogenic alkaloid found in the corn lily that also causes cyclopia

Incardona JP et al. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development. 1998 Sep;125(18):3553-62.
http://hedgehog.sfsu.edu/overview.html

Verteporfin (Visudyne) - Lasers, free radicals, and fixing people's eyes

2007-07-25T21:28:00.000-04:00

macrocyclic porphin-derived photosensitizer used as part of ocular photodynamic therapy (PDT) for the treatment of ocular diseases that feature choroidal neovascularization (CNV), a major cause of vision loss

the choroid is a layer of the eye (between the sclera and the retina) that contains lots of blood vessels

CNV is the abnormal growth of blood vessels from the choroid toward the retina, where seeing takes place, and is associated with a number of eye diseases including age-related macular degeneration (AMD, deterioration of the central part of the retina), pathological myopia (abnormal changes in eye structure causing vision problems), and ocular histoplasmosis (a crazy-ass fungal infection of the eye)

administered intravenously, then once it reaches the choroidal circulation and begins hanging out in the aberrant vessels there, a nonthermal red laser light (wavelength of 693 nm, natch) is shone on the afflicted eye, resulting in the activation of the drug

as it is a highly conjugated molecule, it absorbs the light and, in the presence of oxygen , transfers its energy to oxygen atoms, producing radical oxygen species (ROS) like singlet oxygen and superoxide, which then go about and wreck havoc on the bad vessels both directly and via platelet activation with thrombosis and vessel occlusion

since it's modus operandi is to cause temporary photosensitization, patients have to avoid exposing their skin or eyes to direct sunlight or even very bright indoor light for 5 days after getting the drug, or else the drug will be activated where it shouldn't be and a severe reaction featuring things like blistering, burning, and swelling will develop at the sites of light exposure
PDT with verteporfin may also work on corneal neovascularization

Yoon KC et al. Photodynamic Therapy with Verteporfin for Corneal Neovascularization. Am J Ophthalmol. 2007 Jul 12; [Epub ahead of print]
http://www.drugs.com/cons/verteporfin.html

The pharm + tox lecture series: #3 - Absorption, putting the A in ADME

2007-07-23T22:15:00.000-04:00

When it comes to describing the journey that a drug takes through the body, pharmacologists like to employ a cute little acronym: ADME. It stands for Absorption, Distribution, Metabolism, and Elimination. I'll be covering the D, M, and E parts in future posts, but for now let's focus on the A.

Absorption refers to the passage of a drug from the external environment into your systemic circulation (bloodstream). In essence, how you get a drug into you. There are all sorts of interesting ways by which this can be accomplished. Allow me to describe a few.

Topical administration consists of applying a drug directly to the part of the body where you want it do stuff. The drug does not get into your systemic circulation, either because it is given in such a small amount or it specially formatted so that it won't pass into your blood in appreciable amounts. Examples include skin ointments and creams, eye drops, nose sprays, ear drops, vaginal suppositories, as well as drugs injected into body cavities (e.g. corticosteroids injected into joints to treat arthritis), the epidural space (e.g. an epidural), or the cerebrospinal fluid (intrathecal administration)

Percutaneous or transdermal administration consists of applying a lipid soluble drug to your skin with the intent that it will dissolve through your dermis into your systemic circulation. Nicotine (quit!), scopolamine (to prevent you from puking in moving vehicles) and birth control patches (which apparently make you fat) are primo examples. A similar route is via inhalation, with the drug passing through the lung epithelium instead of the skin. This tends to occur very rapidly. Things like general anaesthetics, medicinal marijuana, and asthma drugs (e.g. puffers) can be administered this way.

Enteral administration refers to giving a drug in such a manner that it enters your body at some point along your gastrointestinal (alimentary) tract. Sites include your oral mucosa (e.g. buccal or sublingual nitroglycerine drops), your stomach/intestines (referred to as the oral or p.o. route, any drug that you have to swallow), or your rectal mucosa (mmm, mmm, suppositories!).

Parenteral administration refers, quite literally, to giving a drug 'beside the gut'. In other words, injecting it somewhere with a needle so that it gets into your blood. The types of injections are fairly self-explanatory. Subcutaneous (s.c.) means under your skin, intramuscular (i.m.) means into a muscle, intravenous (i.v.) means into a vein (the medical world's usual target of choice), and intra-arterial (i.a.) means into an artery (used to direct anticancer drugs at high concentrations into tumours).

p-Phenylenediamine (p-PD) - When temporary tattoos go bad

2007-07-22T23:48:00.000-04:00

aromatic amine dye present in most hair dyes
added to henna paste to create "black henna", which is intended to make henna tattoos appear darker in order to create the classic black ink tattoo look

henna (Lawsonia alba/inermis) is a flowering plant that contains lawsone, a red-orange dye that likes to associate with protein, meaning that it will effectively dye protein-containing things like skin, hair, nails, leather, silk, etc.

the leaves of the plant, which contain the highest concentration of lawsone, are dried, ground into a powder, and then mixed with a weak acid (like lemon juice) to release the lawsone and create a paste, which is then applied to one's skin to produce a nifty tattoo

contact allergen, meaning that it causes allergic stuff to happen once you, er, come in contact with it

reactions are usually mild, consisting of things like pruritus (itching), dermatitis, erythema (redness), and edema (swelling)

reactions can be treated with topical steroids and oral antihistamines, but may result in altered skin pigmentation and even permanent scarring
also causes this thing called sensitization, which means that subsequent exposure to it or to other things containing similar aromatic amines (certain inks, dyes, and drugs) can cause a more severe reaction

is colourless in its fully reduced state, becoming coloured only as it becomes oxidized

it's the partially oxidized stuff that can cause allergic reactions, as neither the fully reduced nor fully oxidized forms appear to do much of anything

has been shown to be strongly mutagenic by the Ames test, able to induce DNA damage by the Comet assay and alter expression of proteins associated with cancer phenotype, suggesting it may cause cancer

the use of hair dyes has been weakly linked to bladder cancer, although similar studies have failed to find such an association

- Gulen F et al. Urticaria and angioneurotic edema due to the temporary henna tattoo. Minerva Pediatr. 2006 Dec;58(6):583-5.
- Huang YC et al. p-Phenylenediamine induced DNA damage in SV-40 immortalized human uroepithelial cells and expression of mutant p53 and COX-2 proteins. Toxicol Lett. 2007 Apr 25;170(2):116-23. Epub 2007 Mar 1.
- http://en.wikipedia.org/wiki/Henna
- http://en.wikipedia.org/wiki/P-Phenylenediamine

Varenicline (Chantix, Champix) - Because cigarettes are gross and expensive

2007-07-20T18:49:00.000-04:00

synthetic derivative of the alkaloid cytisine used to treat smoking (nicotine) addiction
partial agonist at neuronal nicotinic acetylcholine receptors, which means that it acts at the same places that nicotine does in the brain, but with less strength, thus reducing the rewarding effects of nicotine without precipitating withdrawal and hopefully making it easier for people to quit smoking

acts primarily at the α4β2 subtype of nicotinic receptors, which are found primarily in the central nervous system

side effects are primarily gastrointestinal in nature (NVD, natch) and not severe, although it is has also been reported to cause crazy dreams and insomnia
at doses that have been shown to reduce nicotine intake in lab animals, has also been shown to reduce ethanol (the stuff in beer that makes everything nicer) intake in three different animal models for ethanol consumption, making it a prospective treatment for alcohol dependence (alcoholism) as well

about 85% of alcoholics smoke, and both nicotine and ethanol can produce reinforcing effects via nicotinic receptors

Steensland P et al. Varenicline, an {alpha}4{beta}2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A. 2007 Jul 11; [link]

Ajmaline - Mysteriously chilling out your heart

2007-07-18T23:22:00.000-04:00

monoterpenoid indole alkaloid manufactured by Rauvolfia serpentina (Indian snakeroot or sarpagandha), a tropical evergreen plant used traditionally in Indian medicine

is synthesized via a complex pathway involving an impressive number of long-named enzymes

the first step, common to the biosynthesis of most terpenoid indole alkaloids, is a condensation reaction that serves to combine the precursors tryptamine and secologanin into a super-molecule

Rauvolfia serpentina is also a natural source of reserpine, an antipsychotic and antihypertensive drug that blocks the release of monoamine neurotransmitters

class Ia antiarrhythmic drug used to treat abnormal heart rhythms such as ventricular tachycardia
also used to screen for individuals afflicted with Brugada syndrome, a genetic disease that predisposes one to dying suddenly and terribly due to unanticipated ventricular fibrillation, which can lead to cardiac arrest or sudden cardiac death

involves having some sort of mutation in a gene encoding an ion channel or ion channel modulator found in cardiac muscle cells

its mechanism of action remains poorly understood, although it has been shown to block voltage-gated sodium and potassium channels in skeletal muscle, suggesting it has a similar action on cardiac (heart) muscle, ultimately acting to depress the electrical activity of the heart so as to abolish arrythmias
named by its discovers after Hakim Ajmal Khan, a famous Indian physician and nationalist who, arguably appropriately, died of heart problems

- Friedrich O et al. NA+- and K+-channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres. Br J Pharmacol. 2007 May;151(1):82-93. Epub 2007 Mar 12.
- Isharwal S, Gupta S. Rustom Jal Vakil: his contributions to cardiology.
Tex Heart Inst J. 2006;33(2):161-70. [link]
- Ruppert M et al. Functional expression of an ajmaline pathway-specific esterase from Rauvolfia in a novel plant-virus expression system. Planta. 2005 Nov;222(5):888-98. Epub 2005 Aug 18.
- http://en.wikipedia.org/wiki/Brugada_syndrome

(with thanks to Jim for the suggestion!)

Mitragynine - Speedballing for lazy people

2007-07-17T22:37:00.000-04:00

the principal alkaloid situated in the leaves of Mitragyna speciosa Korth (Kratom, Biak-Biak), a rubiaceous tropical tree that is native to Southeast Asia

people have been known to chew fresh leaves to acquire a numbing and stimulating effect, enabling them to fight fatigue and increase their tolerance to harsh working conditions

acts like morphine via mu opioid receptors to produce analgesia, although the potency of this effect is only about one-fourth that of morphine, making it akin to less potent opioid analgesics such as codeine (Tylenol 3s, baby!) or methadone
also produces a cocaine-like stimulating effect, likely due to it possessing a similar structure to yohimbine, an alpha2-adrenergic receptor antagonist that has stimulant activity and is best known for its alleged ability to treat erectile dysfunction (not an ad, I promise!)
changing a carbon double bond to a single bond and adding a hydroxyl group gives you 7-hydroxymitragynine, which is also found in the aforementioned plant, albeit in fairly small amounts, but is significantly more potent than morphine and so is likely primarily responsible for the analgesic effects of the plant

Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo). 2004 Aug;52(8):916-28. Review.
http://en.wikipedia.org/wiki/Kratom

The pharm + tox lecture series: #2 - Drugs, medications, and poisons (Oh my!)

2007-07-16T22:14:00.000-04:00

The name of this site is a misnomer. Sad but true. You see, technically, poisons ARE drugs, so it's pretty silly to make a distinction between them ('Drugs and Poisons'). It's a shame, but at least I wasn't writing a textbook or something.

The definition of a drug is shrouded in caliginous gloom. Actually, it's not that bad (I just wanted to use the word caliginous), but it certainly isn't clear-cut. The key feature of a drug is that it alters in some way the function(s) of an organism when introduced into an organism's body. In a broad sense, food can be considered a drug.

It can get tricky. Estrogen naturally produced in people's gonads is not a drug, but it becomes one once it is packaged into birth control pills.

Anyway, way back in the sixteenth century, this Swiss fellow named Paracelsus (oh for the days of one-word names) introduced an intriguing concept: All drugs are poisons. Any drug, regardless of how benign it may seem, when given in a sufficiently high enough dose, will cause harm to a person. Poisons refer to drugs that are recognized for their ability to cause disease, while medications are drugs that usually treat disease.

In conclusion, I should have named this site 'Medications and Poisons', but 'Drugs and Poisons' sounded too cool to pass up. The end.

Cerium (Ce) - Stealing calcium's place in the physiological spotlight

2007-07-12T23:47:00.000-04:00

a paradoxically relatively common (more so than lead!) rare earth metal

rare earth metals, also known as lanthanides or lanthanoids, are the elements found in the first row of that cute little two-row structure situated at the bottom of the periodic table

the trivalent form of this metal resembles (divalent) calcium in size and things it likes to bind to, enabling it to mess with calcium-dependent physiological processes like the clotting of blood, the contraction of muscles, and the release of neurotransmitters.

lanthanides were considered for development into anticoagulants prior to the dawn of the age of heparin

cerium salts, particularly cerium(III) oxalate, were used roughly between 1850 and 1950 to stop people from puking, but no one knows exactly how they do this nor how effective they really are (there are no good papers on it)
cerium salts are also capable of both inhibiting the growth of and actively killing bacteria, and the recognition of this ability in the late nineteenth century lead to their use as topical antiseptics (they had fun names like "dymal", "ceolat", and "ceriform"), a use which continues to this day (typically cerium nitrate as an adjunct to an antiseptic silver compound)

the salts also modulate the immune system in such a manner as to help burn victims resist sepsis (likely by inactivating burn toxins and other such endogenous immunosuppressive agents)

perhaps most interestingly, a solution of cerium(III) iodide called "introcid" was injected into cancer patients during the genesis of cancer chemotherapy and was found to shrink tumours more effectively than other iodine compounds, suggesting that it was the cerium and not the iodine that did something

cesium(III) complexes are reportedly being developed as cancer drugs, and are particularly exciting because they appear to take out multi-drug-resistant varieties of cancer just as easily as sensitive varieties

since calcium is involved in the control of cell proliferation, the development of cancer cells, and angiogenesis, all components of tumour development, it is possible that cerium works as an anticancer agent because it can screw with these processes

Jakupec MA, Unfried P, Keppler BK. Pharmacological properties of cerium compounds. Rev Physiol Biochem Pharmacol. 2005;153:101-11. Review.

Carbon tetrachloride - The sweet, sweet smell of hepatotoxicity

2007-07-11T21:30:00.000-04:00

saccharine-smelling (akin to the scent of a dry cleaner's) synthetic halomethane widely used in the early 20th century to extinguish fires, help cool things down (it is a good refrigerant), and dry clean clothing

was replaced by tetrachloroethylene in the 1940s because it was making people tremendously ill

currently used to make other refrigerants

much like the infamous chlorofluorocarbons (CFCs), it is really good at annihilating the ozone layer

used as an insecticide in the good old US of A up until the 1970s, at which point it was finally banned
when subjected to high temperatures, it can form the toxic gas phosgene
if you get a lot of it in you somehow, it'll wreck havoc on your liver, kidneys, and central nervous system

the liver is particularly sensitive, likely reflecting the presence of a tonne of xenobiotic-metabolizing enzymes such as CYP2E1 that are capable of changing a whole bunch of it into highly reactive free radical intermediates

has been shown to cause cancer in lab animals when either swallowed or inhaled

Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33(2):105-36. Review.
http://en.wikipedia.org/wiki/Carbon_tetrachloride
http://www.atsdr.cdc.gov/tfacts30.html

Xenon (Xe) - The cool-sounding knock-out drug of the future

2007-07-10T20:45:00.000-04:00

a noble gas that is heavier than air, possesses neither colour nor odour, and has revolutionized lighting

xenon flash lamps helped make electronic flash, strobe lights (ugh), and very high speed photography possible

makes good fuel for an ion thruster, a type of spacecraft propulsion that is best known to nerds everywhere as the thing that powers TIE fighters

just for the record, star wars > star trek

can be used to induce general anaesthesia, although it isn't used very often because it costs a heck of a lot to manufacture since it is so rare in the atmosphere
is actually one of the best anaesthetic agents out there, so once we come up with a cheaper way of acquiring it expect it to find it on a surgical floor near you!
it isn't yet understood how it knocks you out, but scientists have come up with two pretty good ideas:

it blocks glutamate receptors, glutamate being the main excitatory brain signaling chemical (neurotransmitter)

this is neat because most inhalational anaesthetics do their thing by stimulating GABA receptors, GABA being the main inhibitory neurotransmitter in the brain

it messes with the levels of calcium ion (Ca2+) in neurons, leading to changes in the release of neurotransmitters because Ca2+ plays an important role in many second messenger systems

is essentially inert in the body (its outer shell is full, so no need for other molecule's electrons), so it won't cause problems by forming covalent bonds with proteins and DNA, one of the issues with certain halogenated ether anaesthetics (see: halothane and liver toxicity)
it somehow provides protection against ischemia-reperfusion injury to the cardiovascular and nervous systems that can occur during big surgeries
like sulfur hexafloride, lowers the pitch of your voice when inhaled, due to it lowering the resonant frequencies of the vocal tract

Preckel B et al. Molecular mechanisms transducing the anesthetic, analgesic, and organ-protective actions of xenon. Anesthesiology. 2006 Jul;105(1):187-97. Review.
http://en.wikipedia.org/wiki/Xenon

The pharm + tox lecture series: #1 - Pharmacy vs. pharmacology (plus toxicology!)

2007-07-09T19:15:00.000-04:00

After much thought and careful inaction, I've decided to broaden the content of this site. On an approximately once-a-week basis, I'm going to drone incessantly on about pharmacology and toxicology, the scientific disciplines concerned with, quite appropriately, drugs and poisons.

First off, I need to stress to you a distinction of the utmost concern: pharmacology IS NOT pharmacy. Pharmacologists are not responsible for dispensing drugs at your local Walgreens or Shoppers Drug Mart. Although I've only recently finished up my pharmacology degree, I've already become intimately acquainted with the pain and suffering associated with trying to explain to just about everybody who asks what I've gone to school for that I do not, in fact, plan on opening up my own pharmacy any time soon.

Now that I've got that out of my system, let me break it down for you:

Pharmacology is the science concerned with (a) the fate of drugs in the body after you take/are given them and (b) the actions of drugs on the body. The branch of pharmacology concerned with (a) is called pharmacokinetics, while that concerned with (b) is called pharmacodynamics. Other branches include pharmacovigilance, pharmacoepidemiology, pharmacogenomics, pharmacoeconomics, clinical pharmacology, and agricultural pharmacology.

Pharmacy is a health profession concerned with the preparation and proper use of drugs. A pharmacist attempts to optimize the use of drugs to help make people better, while a pharmacologist attempts to understand how drugs actually work.

Toxicology is the science concerned with the adverse effects that chemicals have on living things, particularly people. It includes the detection and treatment of poisonings.

The rundown: Ten popular drugs in ten awe-inspiring sentences

2007-07-08T22:30:00.000-04:00

Okay, look. I usually try to post about fairy obscure compounds, since the internet is teeming with about a zillion drug/medicine sites (not to mention the dreaded Wikipedia) that will give you a much more comprehensive rundown on any popular drug out there. Sure, it won't be nearly as snarky or silly as it would be here, but it essentially renders me obsolete.

That said, it's awfully tempting to post about popular drugs, since that means more Google searches coming my way. I'm all about having a hip blog on the Internet, folks. So I've given in. I surfed on over to Forbes.com for 'The World's Ten Best-Selling Drugs (of 2006)' and wrote this post.

Ten drugs, ten sentences. Pure D & P stylings.

Lipitor (atorvastatin) is given to older people to slow the inevitable progression of cardiovascular disease by lowering their cholesterol levels.
Plavix (clopidogrel) inhibits platelet aggregation, thus making it less likely that blood clots will bung up your arteries and kill you if you have some sort of vascular disease.
Nexium (esomeprazole) deals with heartburn, peptic ulcers, and other stomach ailments by knocking stomach acid production out of commission.
Seretide/Advair is a two-drug formulation of fluticasone (makes things less inflamed) and salmeterol (opens up the airways) used to deal with asthma and COPD.
Zocor (simvastatin) is essentially a less popular and yet equally exciting version of atorvastatin.
Norvasc (amlodipine) is but one of the oodles of drugs that relieve angina and lower blood pressure by opening up arteries.
Zyprexa (olanzapine) renders crazy people not crazy by stimulating or blocking an array of different receptors in the brain.
Risperdal (risperidone) is just like olanzapine, only with a lousier name.
Prevacid (lansoprazole) is akin in chemical structure and action to esomeprazole.
Effexor (venlafaxine) helps depressed and anxious people to brighten up and chill out.

Chlorothalonil (CHT, Daconil) - Eat it, barnacles!

2007-07-06T14:56:00.000-04:00

broad-spectrum fungicide employed to vanquish fungi that ruin such things as vegetables, lawns, and cranberries (it is added to the beds)
also used as a biocide in combination with copper (which inhibits the growth of living things) to kill marine organisms that cause biofouling (growth on submerged surfaces) on ships and boats

it is mixed in with the paint that is applied to hulls, such that it is released throughout the lifetime of the paint

like a lot of chemicals, very high doses of it can kill, but is actually considered to be only moderately toxic in the acute sense due to its ability to cause severe eye and skin irritation
studies done in rats have found that chronic exposure through food result in chronic renal (kidney) toxicity and increased risk of developing tumours

is potentially biotransformed in the liver to a toxic glutathione conjugate (i.e. glutathione is added on to the compound to facilitate its elimination from the body) that is removed by the kidneys and expelled in the urine, which would expose them to high levels of the stuff and thus cause damage to DNA and/or protein in kidney cells

can be classified as any of the following: chlorinated benzonitrile, chloronitrile, organochloride, or aromatic halogen

- Konstantinou IK, Albanis TA. Worldwide occurrence and effects of antifouling paint booster biocides in the aquatic environment: a review. Environ Int. 2004 Apr;30(2):235-48. Review.
- Rosner E, Klos C, Dekant W. Biotransformation of the fungicide chlorthalonil by glutathione conjugation. Fundam Appl Toxicol. 1996 Oct;33(2):229-34.
- http://extoxnet.orst.edu/pips/chloroth.htm

Dantron (1,8-dihydroxyanthroquinone, danthron, chrysazin) - Poop, red urine, and cancer

2007-07-05T22:24:00.000-04:00

stimulant laxative banned in the USA because Americans think it causes cancer, restricted to use in palliative care in the UK because Britons think it might possibly cause cancer, and widely used in a bunch of other countries that apparently either think it to be safe or else don't really care that much

a stimulant laxative is something that makes you poop by stimulating peristalsis, and represents the most severe type of laxative you can get, generally only being used in extreme not-being-able-to-poo situations

has been shown to cause liver cancer in mice and colon cancer in rats, suggesting that it probably does something bad to people

a derivative of anthraquinone, an excitingly symmetrical structure of carbon and oxygen that is used to make dyes, speed the production of wood pulp, and make seeds taste nasty so that birds won't eat them

similar poop-inducing derivatives of anthraquinone can be found in a number of plants that have seen use as laxatives (aloe, senna, rhubarb, cascara sagrada, etc.)

found naturally in several species of plants and insects, including the ever-popular elm-leaf beetle (Pyrrhalta luteola)
turns your pee red
has been shown to reduce neuronal injury induced by a number of bad things, including beta-amyloid (25-35), which has a role in Alzheimer's disease
also used as an antioxidant in synthetic lubricants and as a fungicide to obliterate powdery mildew

- Kwon YS et al. Danthron inhibits the neurotoxicity induced by various compounds causing oxidative damages including beta-amyloid (25-35) in primary cortical cultures. Biol Pharm Bull. 2004 May;27(5):723-6.
- Danthron (1,8-dihydroxyanthraquinone). Report on carcinogens : carcinogen profiles / U.S. Dept. of Health and Human Services, Public Health Service, National Toxicology Program. 2002;10:76-7.
- http://en.wikipedia.org/wiki/Anthraquinone
- http://en.wikipedia.org/wiki/Dantron

Bromoacetone - Don't mess with exotic red alga seaweed!

2007-07-04T23:33:00.000-04:00

violent lachrymator (think tear gas and pepper spray) that can be easily synthesized in a laboratory (mix a little bromine with a little acetone, natch)
also present naturally in a certain species of red alga seaweed (Asparagopsis taxiformis) apparently found only in the ocean waters surrounding Hawaii (sounds like it should be a quest item in some sort of adventure book or something)

the seaweed is called limu kohu (supreme seaweed) by native Hawaiians and is apparently considered so supreme because of its enticing aroma and flavour

employed as a chemical weapon during World War I by both sides and has also seen use as a riot control agent, but this has been discontinued due to its relatively high toxicity compared to newer agents
as bromine serves as a good leaving group, bromoacetone can be used as a reagent in organic synthesis reactions, including those by which drugs are produced
rapidly turns purple upon exposure to light or water

Hazardous Substances Data Bank - Bromoacetone
http://en.wikipedia.org/wiki/Bromoacetone

Q & A #3 - Cannabis and cancer, tasteless poisons, and getting high

2007-07-03T23:26:00.000-04:00

It's been a while since I've done one of these questions and answers sessions, but I seem to recall people enjoying them and I'm beginning to feel that familiar old research itch coming on. It's either that or all the blackfly bites I got this past long weekend (yay Canada!) decided to make their presence known simultaneously. To recap: I monitor the crazy things that people type into search engines that bring them to this site, pick out the most intriguing questions that people searched for, and then attempt to answer them with my trademark wit and dry humour. Check out the first and second installments of this exciting feature for more Q & A goodness. Onward!

Is THC carcinogenic?

Tetrahydrocannabinol, better known by it's acronym THC, is the primary compound in cannabis that is responsible for getting you high. THC on its own is not carcinogenic. In fact, it's pain-killing, anti-puking, and appetite-promoting (see: the munchies) properties make it an effective adjuvant to cancer chemotheraphy, and it may actually possess anticancer effects. The important thing to realize here is that while THC on its own is groovy, other compounds found in cannabis may cause cancer, and cannabis smoke definitely contains a number of carcinogens.

What organs are affected by MDMA?

MDMA, better known to the world as Ecstasy, obviously has effects on the brain. As these include modulation of the autonomic nervous system, all of the organs that it innervates are indirectly affected by the drug. These include the heart (speeds up), eyes (pupils dilate), and numerous glands (dry mouth, sweating). One of the fun things about MDMA is its propensity to kill people who fail to adequately hydrate themselves while under its effects. It is thought at MDMA can screw with the part of your brain that is responsible for regulating your body temperature, potentially resulting in hyperpyrexia (crazy high fever), rhabdomyolysis (destruction of skeletal muscle) and multi-organ failure. Obviously, in this case, all of your organs are affected, and not in a good way. MDMA has also been reported to cause liver damage independent of this hyperpyrexia business.

What are some tasteless poisons?

I've got to wonder why a person needs to know this. I mean, sure, maybe they are doing a research project for school or writing a novel or something. But what if they are planning on doing somebody in? How would I ever know? Ok, deep breath. There are, after all, about a hundred other sites on the internet that will answer this question, and I'm curious what the answer is. Here we go. There are plenty of poisons that have no taste. To name a few:

carbon monoxide
heavy metals, including antimony, arsenic, lead, mercury, and thalium
bacterial, shellfish, and mushroom toxins
ricin, nicotine, and likely other plant alkaloids
rat poisons (got to fool the rats, yo)

Does testosterone destroy cartilage?

I sure hope not, 'cause I'm sure going to be in trouble otherwise. Y'know, because I'm a, err, tough manly man. Testosterone is an anabolic steroid, which means that it promotes the synthesis of macromolecules like protein. It has a role in the maintenance of muscle mass and bone density in adult life. Thus, I can't see why it would destroy cartilage. However, a study published in 2005 reported an association between higher blood testosterone levels and an increased rate of cartilage loss, so there you go.

Does 'X' get you high?

I get a tonne of these ones. Might I refer to you the mighty Erowid. They will know.

http://en.wikipedia.org/wiki/Health_issues_and_the_effects_of_cannabis#Cancer_risk

Hall AP, Henry JA. Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth. 2006 Jun;96(6):678-85.

Hanna F et al. Factors influencing longitudinal change in knee cartilage volume measured from magnetic resonance imaging in healthy men. Ann Rheum Dis. 2005 Jul;64(7):1038-42. Epub 2005 Jan 7.

Disulfur decafluoride - Even awesome gas can't make Leno funny

2007-06-29T14:41:00.001-04:00

The above is a video of Jay Leno (I'm a Letterman guy myself) and some dude playing with a gas called sulfur hexafluoride. It has no colour or odour and is neither toxic nor flammable. It's also denser than air, which means you can pour it into containers and float things on top of it and stuff. While this is, admittedly, pretty nifty, it also appears to have little to do with D&P. Fret not, oh reader, for if you pass high-voltage electricity through this impressively innocuous gas, it can decompose to produce disulfur decafluoride, a highly toxic phosgene-like pulmonary agent. A potential chemical weapon. Since sulfur hexafluoride is used as an insulator in electrical things like switchgear and transformers, it potentially poses a risk to lineworkers and electricians.

http://en.wikipedia.org/wiki/Sulfur_hexafluoride
http://en.wikipedia.org/wiki/Disulfur_decafluoride

Monocrotaline (MCT) - The lung-killer

2007-06-28T15:10:00.000-04:00

pneumotoxic macrocyclic pyrrolizidine alkaloid churned out by a number of exciting plants
causes a pulmonary vascular syndrome, which essentially means that a bunch of things go wrong with the blood supply to your lungs, including:

proliferative pulmonary vasculitis (spreading inflammation of the wall of blood vessels in the lung)

pulmonary hypertension

cor pulmonale with right ventricular hypertrophy

used to intentionally produce pulmonary hypertension in animals in order to create an experimental model for investigating the pathophysiology of pulmonary hypertension and the development of pharmacological means of treating it
has been hypothesized that it is biotransformed in the liver to a feisty little reactive metabolite that then travels via the blood to the lungs where it starts messing with endothelial cells, altering their function to cause detrimental structural changes in pulmonary blood vessels (particularly the arteries)
its selectivity for the lung likely has something to do with the way it is biotransformed by the liver and the manner in which blood circulates through the lungs (vs. any other part of the body)

Tanino Y. [Monocrotaline-induced pulmonary hypertension in animals] Nippon Rinsho. 2001 Jun;59(6):1076-80. Review. Japanese.
Wilson DW et al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5-6):307-25. Review.