Khellin - Toothpicks, kidney stones, and mast cells

• chromone brought into existence by Ammi visnaga, a herbaceous plant native to the Middle East that is also affectionately known as toothpickweed since it's pedicels apparently make good toothpicks (hooray!)
  
• relaxer of smooth muscle
  
• used historically to treat pain caused by kidney stones since it relaxes ureteral smooth muscle in order to facilitate the rather uncomfortable movement of stones into the bladder
• relaxes the vascular smooth muscle found in coronary arteries, resulting in improved coronary blood flow, making it a possible treatment for angina pectoris and coronary heart disease
• used to treat asthma since it has antispasmodic activity with respect to bronchial smooth muscle
  
• cromoglicate (cromolyn, cromoglycate) and nedocromil (Tilade) are synthetic khellin analogues that have neat names and do cool stuff like prevent the release of pro-inflammatory mediators such as histamine from mast cells, making them effective drugs for treating asthma
  

Cockcroft DW. Pharmacologic therapy for asthma: overview and historical perspective. J Clin Pharmacol. 1999 Mar;39(3):216-22.
http://www.ibiblio.org/pfaf/cgi-bin/arr_html?Ammi+visnaga

Manganese - Strengthening steel and weakening brains

• metal used to strengthen steel
  
• much cooler than magnesium (seriously, it even sounds better...try saying it out loud...manganese...mmmmanganeeeeeese)
• an essential trace nutrient required by all living organisms (functions as a cofactor for a number of enzymes including superoxide dismutase)
• present in extremely large quantities in manganese nodules on the ocean floor (there was a big commotion in the 70s about mining these little bastards but it has since been deemed too expensive a proposition)
• dilute solutions of potassium permanganate, a manganese salt, are employed as a topical treatment for canker sores (which, unlike cold sores, are not transmittable) mild dyshidrosis, and fungal infections affecting the hands or feet
• permanganate has also been used by clandestine drug manufacturers in Eastern Europe to synthesize methcathinone, an amphetamine-like stimulant, from pseudoephedrine (often found in cold medications)
• this process results in the production of a mixture known as "ephedrone" that contains methcathinone as well as manganese (as a byproduct), and so is capable of causing manganese poisoning
  
• exposure to this metal (e.g. miners, smelters, and welders) has been linked to three distinct forms of neurotoxicity:

1. "manganism" featuring dramatic symptoms resembling idiopathic Parkinson's disease (IPD) but unlike IPD not being responsive to dopamine replacement and featuring early personality changes
2. subtle neuropsychological abnormalities (exposed workers exhibited poorer performance on neurophysiological tests compared to unexposed workers)
3. actual IPD that is responsive to dopamine replacement
   

- Martin CJ. Manganese neurotoxicity: connecting the dots along the continuum of dysfunction. Neurotoxicology. 2006 May;27(3):347-9.
- Sanotsky Y et al. Manganic encephalopathy due to "ephedrone" abuse. Mov Disord. 2007 Jun 12; [Epub ahead of print]
- http://en.wikipedia.org/wiki/Manganese

Cephalosporins - Behold the age of actual chalk lectures!

The Chem Blog has a neat little post and video up on cephalosporins, which are a class of antibiotics that share their mechanism of action with penicillins, monobactams, and carbapenems. Check it.

The discount drugs cards are strategies that offer discounts on all major drugs i.e. diazepam. These plans may be formed by a state government, membership organizations. A few of these cards are free for many prescription drugs, but some others have a monthly or yearly fee.

Capsaicin - A cause of and a cure for pain

• the main compound in chili peppers (genus Capsicum) that makes them so gosh darn spicy
• the hottest chili in the world is the Naga Jolokia (I know you were wondering)
• is one of six natural capsaicinoids found in chili peppers, all of which produce a wonderful burning sensation when they come in contact with mucous membranes
• the burning sensation it produces is due to it activating vanilloid receptor subtype 1 (TRPV1), a type of ionotropic receptor found on neurons called C-fibres that carry pain signals (particularly those associated with excessive heat or abrasive damage, in other words, things that produce a burning sensation) to the brain
• does not actually cause tissue damage, instead produces the sensation of it by hijacking the neural pathway by which the sensation is transmitted to the brain
• has been used to treat peripheral pain (pain not originating in the brain or spinal cord) associated with conditions including rheumatoid arthritis, diabetic neuropathy, and postherpetic neuralgia (pain occurring after a bout with shingles)
• topical preparations (ointments, creams) have been used for minor inflammatory joint and muscle pain
• can also be used to treat perennial nonallergic rhinitis (PNAR), which is essentially hay fever only the afflicted individual has no known sensitivities to specific allergens (e.g. pollen)
• in all of these applications, the administration of capsaicin initially worsens the condition being treated due to the stimulation of C-fibres, but with repeated administration is thought that the C-fibres get overstimulated such that they become depleted of the neurotransmitters and neuropeptides (e.g. substance P) that mediate their actions, leading to the loss of pain sensation and neurogenic (neuron-sourced) inflammation/reduced nasal hyperreactivity (congestion and runny nose)
  
• a typical treatment regime involves first the application of a topical anaesthetic followed by capsaicin in order to avoid the burning sensation it produces
• is neat because it represents an analgesic that is neither an NSAID nor an opioid and one that acts directly and selectively on pain transmitting neurons
• currently under investigation as a possible treatment for diabetes and cancer
• has been claimed to have antigenotoxic and anticarcinogenic effects by some researchers, yet has been reported to be a tumour promoter and carcinogen by others (the jury is still very much out on this one)
• is bioactivated by CYP2E1 (a drug-metabolizing enzyme) to reactive species that are capable of binding to the enzyme and potentially to DNA, which would be expected to cause mutations that could lead to the development of cancer
  

- Greiner AN, Meltzer EO. Pharmacologic rationale for treating allergic and nonallergic rhinitis. J Allergy Clin Immunol. 2006 Nov;118(5):985-98.
- Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides. 2004 Dec;38(6):377-84.
- Zhou S et al. Herbal bioactivation: the good, the bad and the ugly. Life Sci. 2004 Jan 9;74(8):935-68.
- http://en.wikipedia.org/wiki/Capsaicin

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

Rosiglitazone (Avandia) - Hooray for heart attacks!

I read the news today, oh boy. First rofecoxib (Vioxx), now this. A paper has been published in a prestigious scientific journal claiming that being on rosiglitazone, a drug used to treat diabetes, considerably increases one's risk of having a heart attack. Awesome. Diabetics rejoice.

This is the second strike against this drug. A study released earlier this year by the manufacturer reported that female diabetics taking rosiglitazone had an increased incidence of limb fractures compared to those on other antidiabetic medications. So it may soften up bones by promoting osteoporosis or something.

Rosiglitazone is a member of the thiazolidinedione (TZD) class of antidiabetic drugs, which are employed to treat type 2 (insulin-independent, adult onset) diabetes mellitus. TZDs bind to peroxisome proliferator-activated receptors (PPARs), a group of nuclear (intracellular) receptors that control the expression of a bunch of genes (i.e. function as transcription factors) and are normally activated by fatty acids and eicosanoids (e.g. prostaglandins). In particular, the activation of PPARγ results in a number of significant physiological effects. These include:

• reduced insulin resistance (take that, diabetes!) due to the re-sensitization of adipose (fat) tissue to insulin, resulting in improved glucose utilization and lowered blood glucose levels
• altered differentiation of adipocytes (fat cells) such that they are smaller and more responsive to insulin
• decreased levels of leptin, a hormone released from fat cells that signals the brain that you have had enough to eat, resulting in the munchies
• decreased levels of certain interleukins, which modulate the immune system, producing an anti-inflammatory effect
• increased levels of adiponectin, a hormone that controls insulin and blood glucose levels
  

TZDs are often used in combination with other classes of antidiabetic drugs such as sulfonylurea derivatives and biguanides. Troglitazone, another TZD, was withdrawn from the market due to it being linked to drug-induced hepatitis (inflammation of the liver). So there's been some problems with these compounds.

Interestingly, rosiglitazone is currently under investigation as a possible treatment for Alzheimer's disease, specifically for those afflicted individuals who possess the ApoE4 allele of the ApoE gene. This gene encodes Apolipoprotein E (APOE), an apoprotein that has important roles in lipoprotein metabolism, cardiovascular disease, Alzheimer's disease, regulation of the immune system, and cognition. ApoE4 encodes a dysfunctional form of APOE that somehow increases one's susceptibility to Alzheimer's disease.

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

Gyromitrin - Choose your mushrooms wisely

• toxic hydrazine derivative found primarily in the cup fungi (mushrooms) Gyromitra esculenta, Gyromitra fastigiata, Gyromitra ambigua and Helvella lacunosa
• these species are referred to as false morels, since they resemble in their appearance the true morels, which are yummy non-poisonous mushrooms belonging to the genus Morchella
• both types of morels appear very early on in the springtime, so the rogue mushroom picker should exercise caution in his/her pickings (see also: lots and lots of other poisonous mushrooms)
  
• volatile and water soluble, such that mushrooms containing it can usually be rendered safely edible by cuttin' 'em up into wee pieces and then boiling or pan-frying the bejesus of of 'em (releasing the toxin into the water or air, so cooks beware!)
• metabolized (by hydrolysis) in the body first to methyl-N-formylhydrazine (MFH) and then on to something called monomethylhydrazine (MMH)
• MMH is structurally similar to isoniazid (an antituberculous drug) and can be used as a friggin' rocket fuel (propellant, specifically) in bipropellant rocket engines (hydrazine, the parent form of MMH, is also a rocket fuel)
• MFH is also way toxic, being capable of causing hemolysis, seizures, and liver necrosis (widespread cell death), which can lead to liver and kidney failure
  
• MMH can cause seizures (often to the point of status epilepticus) by inhibiting the formation of GABA, the primary inhibitory neurotransmitter in the brain (less GABA means an increased propensity for the brain to become overexcited and throw a seizure)
• it inhibits GABA formation by reacting with and so depleting pyridoxal-5-phosphate, which is the active form of vitamin B6 and a required coenzyme for the synthesis of GABA from glutamate by the enzyme glutamic acid decarboxylase (GAD)
• can treat gyromitrin poisoning (at least the seizures) with pyridoxine (another form of vitamin B6) to antagonize it's GABA-related effects
  
• MMH-induced seizures are resistant to benzos (just like seizures caused by isoniazid overdose)
• has been shown to be carcinogenic in lab animals (even in very small doses) but there are no reports of it causing cancer in humans
  

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

Bacitracin - Healing blisters on my feet since 1983

• antibiotic consisting of a mixture of similarly-structured cyclic polypeptides produced by a particular strain (Tracy-I) of Bacillus subtilis, a spore-forming soil bacterium
• it gets its name from the fact that this particular strain of bacterium was first isolated and cultured in the 1940s from damaged tissue and dirt removed from an open (compound) fracture sustained by a little girl named Margaret Tracy (Bacillus + Tracy = Bacitracin)
• the drug was subsequently discovered by Balbina A. Johnson (a bacteriologist) and Frank L. Meleney (a surgeon)
  
• broad spectrum of action (kills lots of different bacteria, especially Gram-positive ones)
• royally screws up bacterial cell wall formation by binding to and inactivating the lipid carrier required to transport cell wall components (peptidoglycan monomers), which are synthesized intracellularly, outside the bacterial cell membrane where the wall is formed
• hinders the synthesis of sterols (e.g. cholesterol) in mammalian cells, which most commonly manifests itself as nephrotoxicity (kidney toxicity) if administered systemically (e.g. intravenously) in people
• is now primarily used as a topical antibiotic (e.g. skin ointments like Polysporin that are specially formulated so as to prevent absorption of the drug beyond the site of application)
• often combined with other antibiotics like neomycin and/or polymyxins in order to increase potency and decrease the potential for the development of drug resistance
• can cause allergic contact dermatitis (ACD) and, rarely, anaphylactic shock (which can potentially kill you)
  

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
- Jacob SE, James WD. From road rash to top allergen in a flash: bacitracin. Dermatol Surg. 2004 Apr;30(4 Pt 1):521-4.
- http://en.wikipedia.org/wiki/Bacitracin

Harmine - MAOI and possible inspiration behind In-A-Gadda-Da-Vida

• β-carboline alkaloid found in several species of plants belongings to the families Malpighiaceae and Zygophyllacae AND in butterflies of the family Nymphalidae (how trippy is that? psychedelic butterflies...IRON BUTTERFLY FOR TEH WIN!)
• plants known and exploited for their harmine content include Banisteriopsis caapi (a vine found in South America) and Peganum harmala (Harmal/Syrian Rue, found in the Middle East)
• reversibly inhibits monoamine oxidase (MAO), an enzyme in the brain that breaks down monoamines, resulting in increased levels of these compounds in the brain (and stimulation of the central nervous system)
• monoamines include neurotransmitters (serotonin, dopamine, norepinephrine), hormones (melatonin), and hallucinogenic drugs (tryptamines such as DMT and psilocybin)
• MAO inhibitors (MAOIs) have been used to treat depression since they inhibit the breakdown of serotonin and norepinephrine, two neurotransmitters that have a role in the pathophysiology of clinical depression, suggesting that harmine may have antidepressant effects
• like synthetic MAOIs, harmine can inhibit the breakdown of tyramine, which can lead to a hypertensive emergency
• plants containing harmine are often used in combination with plants containing DMT (see: yage/ayahuasca) or other tryptamine hallucinogens in order to increase their potency/duration of action (since their breakdown is inhibited by the harmine)
• harmine is generally used in this manner, although there are reports of it having hallucinogenic effects on its own
• was/is also known as banisterine in the late 1920s, when it was used to treat postencephalitic parkinsonism (it was the first MAOI to be used in parkinsonism)
  

Sanchez-Ramos JR. Banisterine and Parkinson's disease. Clin Neuropharmacol. 1991 Oct;14(5):391-402.
http://en.wikipedia.org/wiki/Harmine

L-Asparaginase (Elspar) - Sounds like an asparagus-based cream cheese spread

• anticancer drug used in combination with other such drugs to treat certain leukemias, particularly childhood acute lymphoblastic leukemia (ALL)
• is an enzyme derived from bacteria that breaks down L-asparagine, a non-essential amino acid that certain leukemic cells are incapable of making enough of for themselves
• these cells don't have enough L-asparagine synthetase, the enzyme required to, you know, synthesize the stuff
  
• these cells are vulnerable to a decrease in the extracellular supply of L-asparagine, which is exactly what the drug causes - since proteins are made up of amino acids, the cells experience inhibition of protein synthesis resulting in their utter and total destruction
  
• resistance appears as increased expression of the gene encoding L-asparagine synthetase, which enables the cells to synthesize enough L-asparagine on their own (boo!)
• hypersensitivity (allergic) reactions are common since it is a bacterial enzyme and so a foreign protein that the immune system takes issue with
  
• some normal cells are also vulnerable to a decrease in the extracellular supply of L-asparagine and so experience inhibition of protein synthesis following administration of the drug - this can lead to, among other things, decreased production of anticoagulant and thrombolytic factors (normally required to prevent the formation of blood clots or bust them apart, respectively) and possible thrombosis (clotting) of major vessels (the result being things like deep vein thrombosis, heart attack, and stroke)

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

White phosphorus - Matches, phossy jaw, and suicide by firework ingestion

• an artificial allotrope made up of molecules consisting of four atoms of phosphorus
• is actually yellow, which is why it is also called yellow phosphorus (mind boggling)
• is flammable and pyrophoric (self-igniting) when it comes in contact with air, with combustion producing a distinctive garlic smell
• first produced on a commercial scale during the industrial revolution (i.e. 19th century) for use in making matches
• during this time, chronic low-level intoxication was most common, occuring via inhalation of air contaminated with particles of the stuff and via the skin (dermal contact)
• chronic exposure to white phosphorus can cause a characteristic necrosis affecting the bones of the jaw ("phossy jaw"), which was commonly seen in match workers at the time
• matches are now made with red phosphorus, which is less flammable and toxic, and workers wear protective clothing and masks and stuff, so phossy jaw isn't really seen anymore
• currently most cases of intoxication are via self-induced (e.g. life isn't worth living anymore) ingestion of fireworks (!) and certain pesticides (organophosphates)
  
• this remains an important health problem in certain parts of the world as such poisonings are associated with a significant mortality (about 23% to 73% depending largely on the size of the ingested dose)
• following ingestion, concentrates primarily in the liver but also in the brain, striated muscle, and the kidneys where it causes damage to these sites - see liver damage, renal failure, arrhythmias, seizures, coma - death usually due to liver failure or cardiovascular collapse
• may also be toxic to bone marrow
• the poop of people who ingest white phosphorus can give off white smoke if it contains enought phosphorus, this is awesomely referred to as "smoking stool syndrome"

Tafur AJ et al. Bone marrow toxicity after yellow phosphorus ingestion. Emerg Med J. 2004 Mar;21(2):259-60.
http://en.wikipedia.org/wiki/Phosphorus
http://www.emedicine.com/EMERG/topic918.htm