Chloral hydrate (Aquachloral, Somnos, Noctec)

(surfing gossip sites to avoid studying anatomy)..."Oh look, Mel Gibson went nutso again, turns out that Anna Nicole Smith overdosed on chloral hydrate, and Lindsay Lohan has a...WAIT, HOLD THE PHONE! A drug in the news (okay, admittedly the entertainment 'news') is a blog post in the making. Let's do this thing.

• oral sedative (calms you down) and hypnotic (puts you to sleep)
• one of the first synthetic drugs (made in a lab in 1832) and definitely the first synthetic CNS depressant
  
• rapidly converted by hepatocytes (liver cells) and erythrocytes (red blood cells) into trichloroethanol, the active form of the drug
• widely used up until the middle of the 20th century, after which it found limited use as a sedative, having been largely displaced by the barbiturates and benzodiazepines
• since the 1990s it has been used primarily in pediatrics to sedate children prior to minor surgery as part of dental or diagnostic procedures (I have no idea how Ms. Smith got her hands on it)
  
• moderately addictive (does this sound inviting or what? I'm all like, I can totally handle something that is only moderately addictive)
  
• serious toxic effects of overdose include cardiac arrhythmias (your heart beat goes all bad drummer on you) cardiac and respiratory depression (heart slows down, breathing slows, both eventually stop), and convulsions (or, as I like to call them, the jumpities)
  
• is genotoxic and potentially carcinogenic
  
• is soluble in alcohol, enabling its use as the active ingredient in a Mickey Finn
• the first date rape drug (besides alcohol, other favourites include: GHB, flunitrazepam, and ketamine)
  

- Salmon AG, Kizer KW, Zeise L, Jackson RJ, Smith MT. Potential carcinogenicity of chloral hydrate--a review. J Toxicol Clin Toxicol. 1995;33(2):115-21.
- Sing K, Erickson T, Amitai Y, Hryhorczuk D. Chloral hydrate toxicity from oral and intravenous administration. J Toxicol Clin Toxicol. 1996;34(1):101-6.
- http://en.wikipedia.org/wiki/Chloral_hydrate

Podophyllotoxin (Podofilox)

• non-alkaloid lignan toxin present in podophyllin, resin produced by the rhizomes of plants belonging to the genus Podophyllum, for which it and the aforementioned resin are named, as well as a number of other genera that I don't feel like listing since I'm pretty sure most of you don't care that much and I really, really want to avoiding bogging down my posts with boring information and hideously long-winded sentences
• plants containing lignans are commonly found in traditional medicine, making them interesting starting points for the development of new drugs
• the genus Podophyllum includes Podophyllum peltatum (American Mayapple), a perennial herb native to eastern North America that grows in colonies
  
• is used as a topic antiviral agent in the treatment of condyloma acuminatum (genital warts!) caused by human papilloma virus as well as other types of warts found on one's naughty bits
• has also been used in the treatment of psoriasis vulgaris and rheumatoid arthritis
• kills cancer cells but was found to be too toxic in mice in preclinical trials, the step in drug development when compounds are evaluated in animals before trying them out in humans
• inhibits the polymerization of tubulin -> prevents the formation of microtubules -> arrests the cell cycle in metaphase -> inhibits the growth of tumours
• etoposide, teniposide, and etopophos are anticancer drugs derived from podophyllotoxin that permanently inactivate DNA topoisomerase II, resulting in DNA strand breaks (i.e. damage) that eventually lead to cell death, but have no effects on the polymerization of tubulin
  

Gordaliza M et al. Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon. 2004 Sep 15;44(4):441-59.
http://en.wikipedia.org/wiki/Podophyllotoxin

Itchy, itchy, itchy: Antifungals and the treatment of yeast infections

Being a dude, I thank my lucky stars on a daily basis that I am not prone to fungus-type infestations of my nether regions. Let's hear it for external genitalia! A woman's special area, like many other parts of the human body, is inhabited by both bacteria and fungi. These microbes are usually just chilling out, growing slowly and not bringing any attention to themselves. A yeast infection occurs when Candida albicans, a yeast (which is a type of fungus), is given the opportunity to take over downstairs due to a change in the local environment, which can be caused by a number of things including antibiotics, pregnancy, and a weakened immune system. Candida sets up shop in the most holy of holies, and before you know it, you've got vaginal candidiasis (a yeast infection)! And just so you know, I plan to see how long I can go in this post without mentioning the actual anatomical terms for 'womanly bits'. I consider this to be an exercise in puritan restraint. And euphemisms are fun!

Similar infections can be caused by bacteria, so it's important to establish that a prospective yeast infection is indeed due to yeast, otherwise antifungal drugs aren't gonna work and actually can increase the development of antifungal-resistant strains of yeast. It's akin to the contribution that extensive unnecessary antibiotic use has made to the evolution of antibiotic-resistant bacteria. On the other hand, it's a lot easier to just hit up the drug store than to book and drop by for an appointment with a doctor. I make no recommendations. IANAD. Anyway, since we're talking about a localized fungal infection, yeast infections generally don't cause systemic effects like fever, chills, nausea, or vomiting. Instead there is lots of itching. And soreness. And discharge.

Common antifungals on the market include butoconazole (Mycelex), clotrimazole (Canesten), miconazole (Monistat 3 or 7), and tioconazole (Vagistat, Monistat 1). If these don't work, they bring out the big guns: fluconazole (Diflucan), terconazole (Terazol), and ketoconazole. The more astute of you will have noted that all of the drugs that I mentioned have similar names, as they share the suffix -azole. Indeed, they all belong to the class of topical azole antifungals, so named for the presence a particular nitrogen-containing ring in their chemical structure. Any of the antifungals available OTC (i.e. you can buy them without a prescription) will effectively treat the majority of yeast infections, it's just that drug companies have a tendency to keep on modifying a drug in order to optimize it and/or try and sell you an ever-so-slightly 'improved' version that will make them more money. Friggin' big pharma.

Anyway, azole antifungals inhibit the fungal cytochrome P450 enzyme lanosterol 14-α-demethylase, which is responsible for the production of ergosterol, a steroid needed by Candida and certain other fungi to make their cell walls. The lack of this steroid causes changes in the fungal cell wall that modify the fluidity of the fungal cell membrane and activity of membrane bound enzymes, resulting in the inhibition of fungal growth and replication. The enzyme that is targeted by azole antifungals is similar to one that is found in humans, such that these agents can mess with steroid synthesis, potentially decreasing the levels of steroid hormones such as testosterone and cortisol. So there you go.

Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
http://www.msu.edu/user/eisthen/yeast/index.html

Gadolinium

• a malleable and ductile rare earth metal named after Johan Gadolin, a Finnish scientist who discovered the best named element of all time, yttrium
• apparently discovering one element means you get another one named after you, what the deal?
• is strongly magnetic at room temperature and demonstrates a magnetocaloric effect (which means, of course, magnetic refrigerators!)
• motexafin gadolinium is a novel anticancer agent that enhances the ability of radiation therapy to kill cancer cells
• consists of a gadolinium cation contained in the centre of a large heterocyclic organic ring, much like a porphyrin ring
• several mechanisms of action, including acting selectively on cancer cells to deplete their stores of metabolites that they need to repair the oxidative damage caused by irradiation
• is currently being studied for use alone or in conjunction with radiation therapy in a number of different cancers, including those of the brain, lungs, kidneys, and pancreas
• solutions of organic gadolinium complexes or gadolinium salts are used as contrast agents to enhance diagnostic imaging (mainly MRI but also X-rays)
• contrast agents are injected into the body to increase the visibility of tissues
• agents containing gadolinium have recently been linked to nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD), a rare and potentially fatal disease
• occurs in patients with kidney disease and likely involves a number of factors including decreased kidney function, inflammation, and exposure to gadolinium
• presents primarily in the extremities (arms and legs) as firm, erythematous (red), and indurated (hardened) plaques of the skin associated with subcutaneous edema (swelling) - thickening of skin restricts joint movement
• other organs including the lungs, heart, liver, and kidneys may be involved, such that organ damage can occur and potentially progress to death
• currently no effective treatment
  

- Richards GM, Mehta MP. Motexafin gadolinium in the treatment of brain metastases. Expert Opin Pharmacother. 2007 Feb;8(3):351-9.
- Sadowski EA et al. Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation. Radiology. 2007 Jan 31; [Epub ahead of print]
- http://en.wikipedia.org/wiki/Gadolinium

Benzylpiperazine (BZP)

• methamphetamine-like stimulant that has recently been the subject of much investigation in New Zealand (where it is legal and used as a party drug)
• effects include euphoria, enhanced sensory perception (whoa, this glo stick won't stop blinking out coded messages and this trance music tastes like the ocean!), hyperactivity, and stereotypy (constant repetition of certain meaningless gestures or movements, often seen in schizophrenics)
  
• repeated use leads to sensitization (less drug required to produce same effect) and cross-sensitization to crystal meth in rats
• less potent and probably less addictive than crystal meth (but potentially addictive nonetheless!)
• several contributing mechanisms of action, with the net result being the enhancement of the effects of serotonin, dopamine, and norepinephrine (all monoamine neurotransmitters) in the brain
  
• was originally designed in a lab to be an anthelmintic (works against parasitic worms) agent, to be used to expel wormies (particularly roundworms and pinworms, I don't recommend clicking those links!) from farm animals, on the basis of its structure resembling a group of compounds that are capable of paralyzing parasites (detaching them from the intestinal wall and thus permitting them to be pooped out)
• was found to be not very good at de-worming and, being a stimulant, caused restlessness and anorexia in animals, so it was scrapped
• tested in the early 1970s as a potential antidepressant, stopped when people realized it had amphetamine-like properties that probably were making things worse (especially if anxiety was a comorbidity with the depression, nothing like being hyperactive and anxious at the same time!)
• can cause serious toxicity in some people, as there have been reports of seizures that can progress to status epilepticus as well as severe respiratory and metabolic acidosis
  

- Brennan K et al. Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA). Drug Alcohol Depend. 2006 Nov 22; [Epub ahead of print]
- Gee P et al. Toxic effects of BZP-based herbal party pills in humans: a prospective study in Christchurch, New Zealand. N Z Med J. 2005 Dec 16;118(1227):U1784.
- http://en.wikipedia.org/wiki/Benzylpiperazine

Flunitrazepam (Rohypnol, roofies)

• fast-acting and powerful sedative/hypnotic drug used primarily to treat insomnia and settle people down prior to giving them general anaesthesia
• is a benzodiazepine, meaning that it acts on GABA-A receptors, which are prevalent throughout the brain, to enhance the flow of chloride ions into neurons, resulting in a generalized depression of neural activity that results in sedation (feeling dopey) progressing to hypnosis (sleep)
• is about 7-10 times more potent than diazepam (Valium), the archetypal benzodiazepine
• all benzos also work as anxiolytic and anticonvulsant agents, as well as skeletal muscle relaxants
• widely used recreationally to enhance the effects of alcohol and other drugs, although some people get high off of it alone (mechanism is unknown) or use it as a 'downer' to deal with the side effects of stimulants ('uppers')
• has been used as a date rape drug and to facilitate robberies (it causes anterograde amnesia in addition to sedation, so the victim often remembers nothing) and may precipitate violent behaviour in certain people
• long-term use can result in psychological and physical dependence (i.e. you can get addicted to it)
  

Druid H, Holmgren P, Ahlner J. Flunitrazepam: an evaluation of use, abuse and toxicity. Forensic Sci Int. 2001 Nov 1;122(2-3):136-41.
http://en.wikipedia.org/wiki/Flunitrazepam

Sodium fluoroacetate

• much cooler name: Compound 1080
• naturally occurring poison found in a number of plants from around the world
• converted in the body to to fluorocitrate, which disrupts the citric acid cycle, thus impairing cellular respiration
  
• this is very bad
• since it messes up an essential component of metabolism, there is no known antidote and few people survive significant ingestion of this substance
• a single teaspoon can potentially kill dozens of people
  
• discovered by the Germans during World War II
• they were looking for new chemical warfare agents
• highly potent (0.1 g can theoretically kill a man) but requires ingestion or injection to be effective, so not quite what they were looking for (inhalation is where it's at!)
  
• independently discovered by the Americans during the war and was introduced as a rodenticide (kills...rodents) in the US in 1946
• currently is used by farmers and the US government to kill various crop- and livestock-eating mammals
• delivered via livestock protection collars placed on sheep or goats, which are punctured by coyotes as they go for the throat
  
• is also highly toxic to birds and insects

- Proudfoot AT, Bradberry SM, Vale JA. Sodium fluoroacetate poisoning. Toxicol Rev. 2006;25(4):213-9.
- http://en.wikipedia.org/wiki/Sodium_fluoroacetate
- http://texnat.tamu.edu/publications/B-1664/p6.htm

Myristicin and Elemicin

• found in nutmeg and mace, two common spices that are produced from the seed and aril, respectively, of Myristica fragrans, a nice lookin' tree with green leaves that is native to tropical southeast Asia and Australasia
• are responsible for the psychedelic action of these spices
• about 1-2 teaspoons of spice can really mess you up: euphoria, visual hallucinations, psychosis, and feelings of impending doom and unreality PLUS impressively potent nausea, vomiting, and tremors (and lots of other stuff)
  
• nutmeg was at one point used therapeutically at doses of nine teaspoonfuls daily to control diarrhea associated with thyroid cancer
• makes sense since both compounds structurally resemble mescaline
• apparently myristicin is a moderately effective antibacterial agent, which would potentially make it a useful natural preservative
  

Narasimhan B, Dhake AS. Antibacterial principles from Myristica fragrans seeds. J Med Food. 2006 Fall;9(3):395-9.

Oseltamivir (Tamiflu)

Ladies and gents, I have acquired for my own personal use a flu bug. Posts will resume when I can get out of bed. Cheers.

Update: I can eat solid food once again! Yes!

Thank you for all your kind words, readers!

Some factoids about our good friend oseltamivir:

• used to fix people with the flu (the flu being an infection with the influenza virus, not a bacterial gastroenteritis, natch)
• used in those who: (a) aint none too good at fighting infections (babies, kids, old folks, etc.) or (b) are infected with crazy deadly strains of the influenza virus
• works against both Influenzavirus A (the one that keeps on mutating and causing all these pandemic scares) and Influenzavirus B (the one that pretty much just keeps to itself, oh, and makes people wonderfully miserable during that special time in the winter)
• inhibits neuraminidase, a viral enzyme that the bugs need to escape from cells after they infect and multiply like crazy inside them
• given the current limited supplies of this drug, it could be potentially given along with probenecid, a drug that inhibits the elimination of oseltamivir from the body via the kidneys (urine), in order to stretch supplies
• probenecid was used in this manner to deal with a limited supply of penicillin during the Second World War
• recently reported to have caused a number of Japanese kids to go nuts (hallucinations and delirium)
• got myself ten boxes of this bad boy in the fallout shelter out back fer when the Bird Flu drops its mighty payload of retribution on the world's populace

http://en.wikipedia.org/wiki/Oseltamivir

Dehydroepiandrosterone (DHEA)

• steroid hormone made primarily by the adrenal gland that is also used as a drug
  
• the adrenal gland can be thought of as a pair of triangular-shaped lemons (work with me, people) that sit on top of the kidneys - the rind (cortex) produces steroid hormones and the pulp (medulla) produces catecholamines (e.g. adrenaline)
• used by the body to make both androgens (e.g. testosterone) and estrogens (male and female sex hormones, respectively)
• cheating athletes, take note:
• in women, taking DHEA as a drug increases testosterone in women, leading to insulin resistance, acne, and masculinizing effects (kinda turns you into a dude - baldness, facial hair and increased body hair, lowering of voice, etc.)
• taking DHEA as a drug has not been shown to enhance gains in muscle size or strength produced with strength training alone and thus has little or no benefit for use in athletics
• classified as an anabolic steroid in 2004 in the US of A, making it a controlled substance
• previously was sold legally as a nutritional supplement in health food stores
• currently is sold illegally as a nutritional supplement in health food stores
  
• has been used successfully to treat adrenal insufficiency (adrenal glands not making enough cortisol, an essential steroid hormone released in response to stress), depression, induction of labour, and systemic lupus erythematosus (SLE or lupus)
• SLE is a chronic disease in which the immune system attacks the body in a nonspecific manner to cause inflammation and tissue damage
• presumably DHEA, like the glucocorticoids, suppresses the immune system and reduces inflammation, thus relieving the symptoms of SLE
• because it alters hormone levels in the body, taking DHEA as a drug may increase risk of certain hormone-sensitive cancers (e.g. prostate, breast, ovarian)
  

http://www.mayoclinic.com/health/dhea/NS_patient-dhea
Brown GA, Vukovich M, King DS. Testosterone prohormone supplements. Med Sci Sports Exerc. 2006 Aug;38(8):1451-61.