Puerarin - Good for hearts and hangovers

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.

Sildenafil (Viagra) - Get on up

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

Mesna (Mesnex, Uromitexan) - Terminator of thiols

• also called sodium 2-mercaptoethanesulfonate, but mesna sounds way cooler
• given during cancer chemotherapy involving oxazaphosphorine drugs like ifosfamide and cyclophosphamide to prevent damage to the bladder and kidneys, which can result in hemorrhagic cystitis
• it is thought that mesna is able to bind up toxic metabolites of the cancer drugs that have been filtered out by the kidneys
• hemorrhagic cystitis is inflammation of the linings of the bladder and kidneys resulting in bleeding, which can present as blood in the urine (haematuria)
• contains a thiol (sulfhydryl) group, which enables it to release thiol-containing compounds that have become bound to proteins via disulfide bonds by exchanging itself with the compound
• increased release of these thiol-containing compounds from proteins leads to their increased excretion and lowered blood levels
• thiols affected include cysteine and homocysteine
• homocysteine is produced by the breakdown of methionine, another amino acid
• an elevated level of homocysteine in the blood has been positively associated with atherosclerosis
• also reduces oxidative damage induced by reperfusion following ischemia in the kidneys and intestine
• if you are starting a new job, drug testing can be a source of major anxiety
  
• screening for drugs by means of a urine or hair drug test is a standard procedure carried out in medical laboratories all over the world
• testing for drugs can be scary if you are on prescription medications, so consider some ADHD alternatives to drug therapy
  

- Urquhart BL, Freeman DJ, Spence JD, House AA. Mesna as a nonvitamin intervention to lower plasma total homocysteine concentration: implications for assessment of the homocysteine theory of atherosclerosis. J Clin Pharmacol. 2007 Aug;47(8):991-7. Epub 2007 Jul 5.
- Ypsilantis P, Lambropoulou M, Tentes I, Kortsaris A, Papadopoulos N, Simopoulos C. Mesna protects intestinal mucosa from ischemia/reperfusion injury. J Surg Res. 2006 Aug;134(2):278-84. Epub 2006 Feb 28.
- http://en.wikipedia.org/wiki/Mesna

Drotrecogin alfa (Xigris) - For when things get really bad

• recombinant form of human activated protein C (APC)
• APC is a serine protease (a type of protein-cleaving enzyme) that is capable of suppressing inflammation (by inhibiting a number of pro-inflammatory substances and events), blocking coagulation (by cleaving apart Factors Va and VIIIa to block thrombin formation), and restoring normal fibrinolysis (the physiological busting of clots)
• recombinant protein drugs like drotrecogin alfa are produced by inserting the gene that encodes them into a bunch of fast-growing cells, growing the cells in a culture, and then harvesting all of the protein that the cells have produced
• used to reduce the number of people that bite the dust after developing severe sepsis, which is essentially sepsis (a whole-body inflammatory response to a severe infection) with acute organ dysfunction due to widespread coagulation (dysfunction of the circulatory system)
• since it inhibits blood coagulation, it is important to watch for bleeding problems
• like most recombinant protein drugs, it is very, very, very expensive
  

- http://en.wikipedia.org/wiki/Drotrecogin_alpha
- http://www.emedicine.com/EMERG/topic533.htm
- http://www.kcom.edu/faculty/chamberlain/website/lectures/lecture/sepsis.htm

Lanthanum (La) - The hidden binder of phosphate

• rare earth element (atomic number 57) named after the Greek word lanthano, meaning to lie hidden, in reference to the fact that the dude who discovered it found it 'hiding' in a sample of another rare earth element, cerium
• lanthanum carbonate (Fosrenol) is a phosphate binder, which is a drug used to curtail the gastrointestinal absorption of phosphate from ingested food
• phosphate binders are an important pharmacological means of alleviating hyperphosphatemia (excessively high blood phosphate levels) in people with chronic renal failure, who are unable to remove phosphate from their body because their kidneys aren't working properly
• hyperphosphatemia can promote the breakdown of bone, potentially leading to bone deformation, pain, and increased susceptibility to fractures
• lanthanum carbonate is also used, in an industrial setting, to produce lanthanum strontium manganite, used to make solid oxide fuel cells
• since it is so good at binding up phosphate, lanthanum is commonly found in pool products intended to remove phosphates, a source of nourishment for algae, from pool water
  
• a number of rare earth chlorides, including lanthanum chloride, are capable of inhibiting the clotting of blood
• has been reported to modulate neurotransmitter systems, including the potentiation of receptors for inhibitory GABA and glycine receptors (which suggests that lanthanum may depress brain function)
  

- Albaaj F, Hutchison AJ. Lanthanum carbonate (Fosrenol): a novel agent for the treatment of hyperphosphataemia in renal failure and dialysis patients. Int J Clin Pract. 2005 Sep;59(9):1091-6. Review.
- Chang CW, Qu B, Hong Z, Gao GD. Potentiation of inhibitory amino acid receptors-mediated responses by lanthanum in rat sacral dorsal commissural neurons. Neurotoxicol Teratol. 2006 Nov-Dec;28(6):657-63. Epub 2006 Aug 30.
- http://en.wikipedia.org/wiki/Lanthanum

Cantharidin - Spanish fly and blister beetles

• vesicant (blistering agent) synthesized by over 1500 species of beetles (members of the order Coleoptera)
• these beetles, affectionately known as 'blister beetles', come in an array of pretty colours, don't bite or sting, and are found all over the world
• male beetles produce and utilize cantharidin as a defence mechanism to avoid being eaten and stuff, while female beetles receive it from males for the same reason that female humans receive a nice dinner and jewelry from males: in hopes of getting laid
• contact with catharidin or the beetle itself produces a vesiculobullous (features both vesicles and bullae) skin disease that manifests within hours of exposure
• apparently blowing a beetle off rather than brushing it off will reduce the severity of a resulting skin reaction
• absorbed into the lipid (fat) component of skin cell membranes, where it activates neutral serine proteases, which are enzymes that go about breaking down other proteins, leading to degeneration of desmosomes, which help to anchor cells together
• the ultimate result is blistering within the layers of the epidermis, which usually heals without scarring
• has been shown to be a vasoconstrictor and positive inotrope in cardiac tissue in vitro, suggesting that less toxic derivatives might make good heart drugs
• has been employed historically as an aphrodisiac and an abortifacient
• is the primary active ingredient in Spanish fly, a purported aphrodisiac made by grinding up a bunch of dried out blister beetles
• whole dried beetles, called mylabris, are utilized in Chinese traditional medicine to treat a whole bunch of things
• its so-called aphrodisiac effects are likely related to its ability to produce skin irritation, which can provide extended stimulation of the necessary, uh, tissues to produce arousal
• cantharidin also irritates the genital tract, mimicking arousal
• employed as a 0.7% solution (applied topically) to treat warts and molluscum contagiosum (both of which are viral skin infections that are gross, can easily spread, and can be sexually transmitted)
• unsurprisingly, cases of poisoning are generally due to the ingestion for aphrodisiac purposes as opposed to topical administration for medical purposes and can feature such severe symptoms as coagulopathy, seizures, renal failure, and death
• for more information about terminology, it can be helpful to consult an online medical dictionary or other Internet resources such as legitimate library or medical reference sites
• the Internet also can be used to locate a doctor or purchase diabetes supplies
  

- Moed L, Shwayder TA, Chang MW. Cantharidin revisited: a blistering defense of an ancient medicine. Arch Dermatol. 2001 Oct;137(10):1357-60. Review.

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

• 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 rasburicase 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
• if you have medical questions, there are a variety of Internet resources such as library or medical reference sites available for free
• the Internet also can be used to find a doctor or select the right acne treatment for you
  

- 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]

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

• 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
• verteporfin is a highly conjugated molecule, which enables it to effectively absorb light and, if in the presence of oxygen, transfer the radiant 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 being dosed with verteporfin, 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

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

• 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]

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

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 than I can even begin to hope to accomplish. Sure, it won't be nearly as snarky or silly as it would be here, but it essentially renders me obsolete. Boo.

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 styling.

1. Lipitor (atorvastatin) is given to older people to slow the inevitable progression of cardiovascular disease (aka the death march) by lowering their cholesterol levels.
2. 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.
3. Nexium (esomeprazole) deals with heartburn, peptic ulcers, and other stomach ailments by knocking stomach acid production out of commission.
4. 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.
5. Zocor (simvastatin) is essentially a less popular and yet equally exciting version of atorvastatin.
6. Norvasc (amlodipine) is but one of the oodles of drugs that relieve angina and lower blood pressure by opening up arteries.
7. Zyprexa (olanzapine) makes crazy people not be crazy by stimulating or blocking an array of different receptors in the brain including those for dopamine and serotonin.
8. Risperdal (risperidone) is basically just like olanzapine, only with a lousier name.
   
9. Prevacid (lansoprazole) is akin in chemical structure and action to esomeprazole.
10. Effexor (venlafaxine) helps depressed and anxious people to brighten up and chill the heck out.

Drugs that turn your pee funny colours

Personal experiences with these medications are welcomed in the comments section. The colour of the drug indicates the colour it turns urine.

Metronidazole
Used to treat a variety of infections caused by protozoans or anaerobic bacteria as well as the skin condition rosacea. It kills the little buggers by selectively disrupting their ability to synthesize nucleic acid.

Phenytoin
An anticonvulsant that I blogged about previously.

Rifampicin
An RNA polymerase-inhibiting, liver cell-killing antibiotic.

Pyrvinium (Vanquin)
Used to kill pinworms. May also turn your poo red.

Phenazopyridine
A specialized analgesic that acts specifically on the urinary tract, enabling its use to ease pain and discomfort associated with infection (i.e. UTI), surgery, or injury of/to said body part. Taking this drug may cause your pee to turn dark orange, red, or brown. As a special bonus, it may also cause a yellowing of your skin and/or eyes.

Propofol
A short-acting general anaesthetic that has to be emulsified with egg phospholipid and soya oil before it can be injected. Green pigmentation of the liver and hair have also been reported. Also associated with pink and white urine.

Methocarbamol (Robaxin)
A muscle relaxant that may cause your pee to turn black, blue, or green.

Methylene blue
A dye used to treat methemoglobinemia and cyanide poisoning. Has also been used successfully in the past to treat malaria, and is currently attracting a fair deal of interest for this application since it's cheap as hell. Taking this drug will cause your pee to turn green (small doses) or deep blue (larger doses).


Gillett MJ, Burnett JR. Medications and green urine. Intern Med J. 2006 Jan;36(1):64-6.
http://urology.stanford.edu/articles/abnormal_urine.html

Thiabendazole (Mintezol, TBZ)

Hey there. Let me break it down for you, nice and easy like:

KILLS

• fungi (molds and spots and rots and blights) that spoil fruits and vegetables
• messes up cell division, protein synthesis, and cellular respiration
• sprayed on crops and used as a food preservative
• parasitic worms that cause disease in livestock and humans
• human diseases it is used to treat include strongyloidiasis, cutaneous larva migrans (aka creeping eruption...totally icky), visceral larva migrans (aka toxocariasis), and trichinellosis
• messes up cellular respiration (citric acid cycle) by inhibiting some enzyme
  

SAVES

• people poisoned with metals (lead, mercury, antimony)
• it is a chelating agent that can bind said metals and facilitate their excretion from the body, thus limiting their toxicity

http://extoxnet.orst.edu/pips/thiabend.htm
http://en.wikipedia.org/wiki/Thiabendazole

Carbonic anhydrase inhibitors - Fixing pretty much everything

• class of drugs that inhibit (wait for it...) carbonic anhydrase (CA), an enzyme with a variety of functions specific to different parts of the body, enabling it to be used to treat a number of seemingly unrelated diseases
• include acetazolamide (Diamox), methazolamide (Neptazane), topiramate (Topamax) and zonisamide (Zonegran)
• are structurally related to sulfonamide antibiotics ('sulfa drugs'), from which they were developed
• carbonic anhydrase inhibitors, thiazide diuretics and sulfonylurea antidiabetic drugs were all developed from sulfonamide antibiotics, after it was noticed that, in addition to killing bacteria, the antibiotics produced 'side effects' including diuresis, metabolic acidosis, and increased insulin secretion from the pancreas
• things that these drugs can fix:
• glaucoma - decrease the formation of aqueous humour, which reduces intraocular pressure
• idiopathic (benign) intracranial hypertension - decrease the formation of cerebrospinal fluid (CSF), which reduces intracranial pressure
• hypertension, congestive heart failure, cirrhosis with ascites - increase urine production (diuresis) so that you lose more fluid than normal, lowering blood volume and thus blood pressure (since PV=nRT, natch)
• note: CA inhibitors are rarely used as diuretic agents since there are lots of other drugs capable of doing the same thing, only better
• hyperkalemic periodic paralysis - increase urinary potassium excretion
• note: can lead to mild hypokalemia (too little potassium in the blood) that can cause fun side effects like numbness and parageusia (things tastes weird)
  
• mild altitude (mountain) sickness - increase urinary bicarbonate excretion, which increases the plasma concentration of hydrogen ion and thus relieves the effects of respiratory alkalosis that occur at high altitudes (the reduced availability of oxygen at higher altitudes stimulates respiratory centres in the brain resulting in increased ventilation, decreasing the plasma concentration of carbon dioxide and thus hydrogen ion)
• cystinuria and hyperuricosuria - increase urinary bicarbonate excretion, alkalinizing urine so as to maintain acidic substances such as cystine and uric acid, which would normally precipitate out and form stones, in solution
• epilepsy and migraine - increase cerebral blood flow and raise carbon dioxide levels in the brain, also block sodium channels and glutamate receptors and/or enhance GABA activity
  

Masereel B et al. Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. J Med Chem. 2002 Jan 17;45(2):312-20.

Anti-Gerasone

If only. R.I.P. Mr. Vonnegut.

Bremelanotide (PT-141)

• synthetic peptide analog of alpha-melanocyte stimulating hormone (α-MSH) that is currently being developed as a treatment for sexual dysfunction, specifically erectile dysfunction and sexual arousal disorder (cue a spike in my search traffic, hooray for sexy keywords!)
• α-MSH is a peptide hormone that acts via melanocortin receptors to do interesting things like turn you on and cause your skin to produce more melanin (pigment)
• has been shown to cause a rapid dose-dependent increase in erectile activity in dudes and increase sexual arousal in both the ladies and the gents
  
• derived from melanotan-II (MT-II), a cyclic lactam analog of α-MSH that is being developed as a sunless tanning agent (it was during studies with this compound as a tanning agent that it's ability to cause erections was discovered, much the same way that Viagra was discovered, leading to the development of bremelanotide)
  
• stimulates certain neurons in rat brain (specifically: hypothalamus) that are responsible for signaling erections (induces and facilitates erections) and increases activity in brain regions associated with sexual responses
• doesn't appear to affect the vasculature of the genitals (like Viagra and co.) but instead appears to act directly on brain to increase sexual desire
  

- Diamond LE et al. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006 Jul;3(4):628-38.
- Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003 Jun;994:96-102.

Nitisinone (Orfadin)

• used to treat hereditary tyrosinaemia type 1 (HT-1), a rare genetic disease caused by a deficiency in fumarylacetoacetase (FAH), an enzyme involved in the metabolism of tyrosine
• tyrosine is my very favourite amino acid, since the body uses it to make a number of important biological molecules including thyroid hormones, melanin, and catecholamines
• tyrosine metabolism consists of a series of steps, with FAH being in charge of the last one
• FAH deficiency causes the buildup of tyrosine metabolites produced by prior metabolic steps, several of which happen to be toxic to cells
• since FAH is highly expressed in liver cells, HT-1 usually presents as liver failure or chronic liver disease
• does its thing by inhibiting 4-hydroxyphenyl pyruvate dehydrogenase (HPPD), an enzyme with an annoyingly long name that is responsible for an early step in tyrosine metabolism (upstream of FAH), thus preventing toxic tyrosine metabolite production
• initially developed as a maize herbicide
• is a derivative of leptospermone, a natural compound present in the roots of bottlebrush (Callistemon citrinus), a shrub native to Australia that kinda resembles one of those things that you clean your toilet with if you aren’t a typical male university student sharing an apartment with two other typical male university students (yes, we are gross)
• HPPD is also present in plants, where it has a role in the synthesis of plastoquinone from tyrosine
• plastoquinone is a cofactor required for the biosynthesis of carotenoids, which in turn are required for photosynthesis (making food from sunlight) and the prevention of chlorophyll (the stuff that makes plants green) destruction
• weeds sprayed with mesotrione, another derivative of leptospermone that is used expressly as a herbicide, acquire a bleached appearance due to the destruction of chlorophyll prior to biting the dust
• maize is tolerant because it is able to rapidly break down leptospermone-like compounds

Callisto: a very successful maize herbicide inspired by allelochemistry
McKiernan PJ. Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs. 2006;66(6):743-50.

Coprine - Why you sometimes don't want to pair a wine with a mushroom dish

• a rare amino acid (derivative of glutamic acid, natch) present in several edible species of mushroom belonging to the genus Coprinus ("inky caps") including the common ink cap (Coprinus atramentarius), a lawn mushroom that is, most unexpectedly, fairly common
• is thought that it or one of it's metabolites (cyclopropanone hydrate) inhibits the enzyme aldehyde dehydrogenase (ALDH)
• alcohol (ethanol) is primarily metabolized in the body by the enzyme alcohol dehydrogenase (ADH) into acetaldehyde, a fairly toxic substance that is responsible for many of the symptoms of a hangover
• acetaldehyde is then further metabolized by ALDH into not nearly as toxic acetic acid, the stuff in vinegar that makes it taste and smell the delightful way that it does
• inhibition of ALDH results in the accumulation of acetaldehyde when alcohol is consumed, essentially giving you an insta-hangover
  
• gettin' smashed or even just having a single drink up to 72 hours after eating mushrooms containing coprine will cause acetaldehyde poisoning, symptoms of which include flushing, nausea and vomiting, headache, and palpitations
• symptoms usually only last 2-4 hours but may last up to 2 days (yay!)
• the same reaction is seen in individuals who: (a) are taking disulfiram (Antabuse), an anti-drinking drug used in the treatment of alcohol dependence (alcoholism) that inhibits ALDH or (b) possess a super effective form of ADH and/or a crappy form of ALDH due to variation in the genes that encode these enzymes (these people are often of East Asian descent)
• has no known toxic effects on its own - is only poisonous when ingested prior to alcohol consumption, and even then it is the metabolized alcohol that is causing the problems

Berger KJ, Guss DA. Mycotoxins revisited: Part II. J Emerg Med. 2005 Feb;28(2):175-83.

Clomifene (Clomid, Serophene, Milophene)

• what "fertility pills" are usually made of
• used to treat female infertility due to anovulation (lack of ovulation)
• doesn't work if infertility is caused by the dude (defective or lack of spermies) or woman's infertility is caused by ovarian dysfunction
• inhibits the negative feedback action of estrogen in the anterior pituitary gland, resulting in increased release of follicle-stimulating hormone (FSH) - this leads to a higher rate of ovulation and hence increased potential for pregnancy
• can actually cause multiple ovulation, increasing the risk of multiple births
  
• sometimes four or five ova are released and fertilized - say hello to the local news crew, quintuplets!
• actually is a mixture of two geometric isomers, enclomifene and zuclomifene
• used (abused?) by some male bodybuilders to block the estrogen-like effects (e.g. man titties!) produced by anabolic steroids and restore the body's natural production of testosterone (which is lost with steroid use)
  

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

Darbepoetin alfa (Aranesp)

• synthetic form of recombinant human erythropoietin (epoetin)
• erythropoietin is an glycoprotein (protein with a bunch of sugars attached to it) hormone produced mostly by the kidney that stimulates erythropoiesis (production of red blood cells by the bone marrow)
• epoetin and darbepoetin are manufactured using recombinant DNA technology:
  

1. a gene encoding the protein/drug is inserted into a bunch of mammalian cells (usually Chinese Hamster Ovary cells)
   
2. cells that begin to produce the drug are isolated and cultured in a bioreactor (placed in a controlled artificial environment and permitted to multiply)
   
3. cultures of cells are processed to harvest the drug (see why they call it molecular farming?)
   

• the gene encoding epoetin is identical to that which is found in humans, but the gene encoding darbepoetin has been tinkered with such that darbepoetin contains more sialic acid (a type of sugar) groups than epoetin - this modification increases its half-life three-fold and enhances its activity relative to epoetin
• used to correct anemia (reduction in the amount of circulating red blood cells) associated with chronic kidney disease and cancer chemotherapy - these feature damage to the kidneys and bone marrow, respectively, which blunts the normal response of the body to anemia (increased release of erythropoietin from the kidney leading to increased red blood cell synthesis in the bone marrow)
• has been abused by a number of athletes in endurance sports, particularly during the 2002 winter Olympics, as a variety of blood doping - increasing the number of red blood cells in order to enable the blood to carry more oxygen and thus enhance athletic performance
• since it contains no components of human blood, may be okayed for use by those crazy Jehovah's Witnesses as a possible alternative to blood transfusion
• excessive use can cause polycythemia (too many red blood cells to the point that they begin to significantly thicken the blood) - the heart has to work harder to pump the blood, increasing the risk of heart failure and other cardiovascular problems
  

Joy MS. Darbepoetin alfa: a novel erythropoiesis-stimulating protein. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1183-92.
http://en.wikipedia.org/wiki/Darbepoetin_alfa

Precious medicines: Platinum, gold, and silver as therapeutic agents

It's true. Precious metals are used as drugs. As a complete and utter pharmacology nerd, I happen to think that this is awesome. Let me tell you some things.


Platinum

Platinum-containing compounds represent an important class of anticancer / antitumour / antineoplastic agents, the prototype of which is cisplatin (Platinol). Cisplatin was first synthesized in 1844, but it was not until 1965 that it's ability to inhibit cell division was discovered. Like the discovery of penicillin, it was made totally by accident.

A dude named Barnett Rosenberg was delivering electric current to cultures of bacteria as part of a series of experiments that he was doing. Rosenberg made the observation that the ability of the bacteria to multiply was inhibited in these cultures. It was soon realized that the inhibition of bacterial growth was due to the presence of platinum coordination complexes, among them cisplatin, in the cultures. These complexes were being generated by the platinum electrodes that were being used to deliver the electrical currents. After further investigation, cisplatin was found to possess anticancer activity in a number of different animal tumour models. It was first approved for human use in Canada in 1978, and is now employed worldwide against a number of different cancers, including: germ cell, ovary, bladder, cervix, head and neck, esophageal, gastric, prostate, lung (NSC), and neuroblastoma.

Platinum-containing anticancer drugs are alkylating agents, meaning that they react with the nitrogenous bases in DNA strands to cause the formation of cross-linkages within and between strands. It is thought that the resulting DNA adducts mess up cellular repair mechanisms, with the accumulating genetic damage activating apoptosis (controlled cell death) preferentially in fast growing cells such as cancer cells. As a result of their high level and broad spectrum of activity (effectiveness against a variety of different types of cancer), platinum-containing drugs based on cisplatin continue to be developed for use in the treatment of cancer.


Gold

Gold has a long and sordid (well, maybe not so sordid) history of being used medicinally in most cultures around the world. The Chinese used it as early as 2500 BCE. There are records dating back to 500 BCE of gold salts being used to treat leprosy. Indian physicians used various preparations containing gold as antiepileptic agents.

In the late 19th century, gold cyanide compounds were shown to kill Mycobacterium tuberculosis (the bacteria responsible for most causes tuberculosis) in test tubes but were found to be too toxic to use in people. Over the course of the 20th century, organogold drugs have been used (albeit often unsuccessfully) to treat a wide variety of autoimmune diseases, kala-azar, tuberculosis, and malaria. Gold-chloroquinone drugs are currently being developed to combat malaria.

Gold drugs have been shown to have anti-tumour, anti-HIV, anti-microbial, and anti-fungal activities. However, the primary therapeutic application for gold in today's world is in the treatment of rheumatoid arthritis. This is an incurable chronic inflammatory autoimmune condition that progressively destroys the articular cartilage that lines the surfaces of bones where they meet in joints. Since cartilage is necessary for joints to work, this disease can lead to the loss of joint function (i.e. the bones at the affected joint(s) fuse together). It is estimated that 1-2% of all people everywhere have this form of arthritis, and we still don't understand exactly what causes it. Rheumatoid arthritis is routinely treated with gold drugs, which have anti-inflammatory and other properties that help to combat the disease. In most cases, monovalent organogold salt formulations are injected into the joints. The use of gold drugs in this application is called chrysotherapy, and has been in use for over 70 years. The major side effect of these drugs is dermatitis. In the exciting and ever-so-controversial world of alternative medicine, gold needles are used by many acupuncturists in patients with rheumatoid arthritis.


Silver

Silver has long been employed as an antiseptic. The ancient Phoenicians used silver bottles to store their beverages to prevent them from spoiling. Alexander the Great reportedly would only drink from silver vessels. My homeboys Hippocrates (the dude who invented how to be a good doctor) and Paracelsus (hero to toxicologists everywhere) both noted the healing effects of silver in their writings. Once bacteria were discovered, silver was recognized to be effective at knocking them off. This lead to silver being used as an antimicrobial agent, which remains its primary therapeutic application to date. Silver is toxic to many bacteria, viruses, algae, and fungi. Yet it does not appear to pose a significant threat to human cells or humans as a whole. This selective toxicity makes silver a great antimicrobial agent, although we still don't understand the mechanism behind it.

K. S. F. Crede, a German obstetrician, is credited with introducing (in 1884) the practice of applying eye drops containing silver nitrate to the eyes of newly-born children to prevent them from becoming infected with gonorrhea (yeah, that STD we all know and love). Early on in the twentieth century, a surgeon by the name of William S. Halstead figured out that silver foil bandages for wounds helped to prevent the development of infection. These bandages, as well as topical creams containing silver salts, were used during World War I. With the development of systemically-acting sulfa drugs and penicillin, and the spread of their use worldwide following World War II, the use of silver as a general antimicrobial agent fell out of favour. It remains a mainstay in the treatment of burns, traumatic wounds, and diabetic ulcers. Ointments containing silver sulfadiazine (Silvazine and Flamazine) were the treatment of choice for controlling bacterial infections in patients with serious burns up until the late 1990s, at which point bandages containing slow-release silver compounds became popular. A 10% solution of silver nitrate has recently been show to be an effective treatment for warts.

Although silver, as noted previously, is essentially non-toxic to humans, it can cause a rare permanently disfiguring condition called argyria. Silver is absorbed into the blood and deposited in tissues, such that the skin, eyes, and mucous membranes acquire a grey to blue-black colouring.


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

Eisler R. Chrysotherapy: a synoptic review. Inflamm Res. 2003 Dec;52(12):487-501.

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

Lebwohl D, Canetta R. Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. Eur J Cancer. 1998 Sep;34(10):1522-34.

Silver S, Phung le T, Silver G. Silver as biocides in burn and wound dressings and bacterial resistance to silver compounds. J Ind Microbiol Biotechnol. 2006 Jul;33(7):627-34. Epub 2006 May 25.