Dichloroacetate - Miracle brain cancer drug or overhyped disappointment?

I've realized that blogging about topical drug or poison news is kinda fun, so here's another actual blog post. CBC News has reported that Health Canada (the Canadian FDA) just approved a phase 2 clinical trial (testing a drug in a small number of sick people to see if it helps them get better) to see if a compound called dichloroacetate (dichloroacetic acid, DCA) can help people with glioblastoma multiforme, an incurable variety of brain cancer that typically knocks people off within a year of diagnosis.

DCA is a relatively simple chemical; It's essentially just vinegar (acetic acid) with a couple of chlorine atoms taking the place of hydrogen atoms. It is currently a generic (off patent) drug used to treat lactic acidosis, a potentially serious condition associated with a number of things including certain inherited mitochondrial diseases (e.g. MELAS), hypoglycemia (low blood sugar, a recurring issue with diabetes mellitus), severe malaria, and anything that results in a prolonged period of reduced systemic oxygen availability (shock, ischemic heart disease, anemia, etc.). By indirectly up-regulating the pyruvate dehydrogenase complex (PCD), a group of three enzymes that convert pyruvate (pyruvic acid) into acetyl-CoA, in the mitochondria of cells, DCA reduces the amount of pyruvate that would otherwise be converted into lactate (lactic acid) in the cytoplasm. As lactate is a fermentation product, it can accumulate in the body under anaerobic (no oxygen) conditions and produce a variety of metabolic acidosis.

By boosting aerobic (oxygen-dependent) cellular respiration, DCA reportedly attenuates the oxygen-independent pathway of energy production preferred by cancer cells, causing tumors to shrink. The compound has been shown to shrink tumors in rats and kill human cells in vitro (in laboratory cell cultures).

The CBC article states that DCA does not affect normal cells, such that its side effects, if any, would be considerably less terrible than those for 'typical' anticancer drugs (e.g. nausea and fatigue). Given that DCA has been used to treat lactic acidosis for a while now without any particularly serious adverse effects showing up, this is probably true. Interestingly, DCA is a confirmed animal carcinogen, having been shown to increase the incidence of liver cancers in mice. There is insufficient human data to say whether or not it can cause cancer in people. DCA has also been found to have neurotoxic effects in lab animals, but reports of such effects in humans are sparse and controversial.

In any event, the Wikipedia article on DCA makes a good point, which is that the overwhelming majority of new drugs never make it to a pharmacy's shelves. DCA is neat because scientists, small Albertan towns, and private citizens, not big pharmaceutical companies, are paying for its development, but ultimately the chances of it becoming the miracle drug the media is making it out to be are depressingly slim.

If you are addicted to opiate painkillers like Percocet, drug treatment options are available that have been shown to be effective. One variety of drug rehab involves suboxone treatment, where a drug is given to help you detoxify.

- Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. 2003 Jul;43(7):683-91. Review.
- http://www.depmed.ualberta.ca/dca/
- Hazardous Substances Data Bank (HSDB) record for Dichloroacetic Acid [no permanent link available]


Apparently coffee and Tylenol don't mix

Just heard via the CBC (the Canadian equivalent of the BBC) web site about a recent study that found that caffeine, the stuff in coffee that perks you up in the morning, apparently promotes the conversion of acetaminophen (paracetamol, Tylenol) into a super toxic liver poison.

Now, as I understand it, acetaminophen is metabolized via several pathways in your liver (the primary site of drug metabolism), most of which end with the addition of a water-soluble group (e.g. sulfate or glucuronide conjugation) that leads to the removal of the drug via kidneys in the urine. However, if these pathways are overwhelmed (e.g. you eat an entire bottle of Tylenol, including or excluding the container), acetaminophen is shunted to another pathway, catalyzed by an enzyme called CYP 2E1, which converts it to a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a real sonofabitch; It is highly reactive and so is able to bind non-specifically to liver cells and cause significant liver damage, potentially leading to liver failure (and death). A small amount of NAPQI is produced even when you take a normal dose of acetaminophen, but your body is able to handle it without problems.

The authors of the study found that caffeine was able to bind to a related enzyme called CYP 3A4 and act in such a way as to enhance the ability of this enzyme to convert acetaminophen into NAPQI. I have to confess at this point that I'm a wee bit confused by the relevance of this finding, since my understanding is that acetaminophen is not appreciably metabolized by CYP 3A4, even in the event of an overdose.

Furthermore, the investigators used doses of acetaminophen and caffeine that far exceed the levels of typical daily consumption of these drugs by most people, so even if CYP 3A4 does indeed convert acetaminophen into a toxic metabolite and caffeine enhances this process, it is likely only relevant to a small group of people: Those who take too much Tylenol on a regular basis AND consume coffee like a marathon runner consumes water.

In any event, liver damage is an insidious thing, since you can damage a large part of the organ before any symptoms of the destruction show up. It's possible that people who drink a tonne of coffee and pop Tylenol on a regular basis are doing damage to their liver, and that this damage is accumulating over time, leading to possible problems down the road. Now for a little public service bit. Alcohol (ethanol) definitely enhances the ability of CYP 2E1 to convert acetaminophen into NAPQI, so doing shots of tequila while popping Tylenol for a headache is a terrible idea. Respect your liver, people.

Drug screening can refer to the drug tests that employers and hospitals perform on people, as well as to finding out information on drugs, such as their potential to be metabolized by the liver into toxic derivatives. If you are starting a new job, having to undergo a drug screening can be a source of major anxiety. Screening often is carried out by urine or hair drug testing, which are established methods. A number of resources on hair drug testing are available.


(1-3)-beta-D-glucan - How moulds can make you ill

  • major component of the cell wall of fungi, also found in some bacteria and plants
  • a glucan is a type of polysaccharide made up soley of a bunch of D-glucose molecules linked together in a particular manner
  • thought to be responsible for annoying respiratory symptoms in people exposed to indoor mould infestations (when suspended as a bioaerosol)
  • experimental data is not conclusive, but a positive association between exposure to (1-3)-beta-D-glucan and both general (fatigue and headache) and respiratory (nose and throat irritation and cough) symptoms has been found in a wide variety of workplaces
  • is considered to be the fungal equivalent of bacterial endotoxin (i.e. lipopolysaccharide), a toxic fat-sugar hybrid molecule found in the outer membrane of gram-negative bacteria that can set off the immune system and the coagulation cascade, leading to terrible things like fever, disseminated intravascular coagulation (whee, excessive bleeding!), shock, and even death
  • has been used as a biological marker for the diagnosis of invasive fungal infection
  • there are many ways to get drug treatment for drug and alcohol abuse but one of the best ways for drug rehabilitation is through treatment centers
Iossifova YY et al. House dust (1-3)-beta-D-glucan and wheezing in infants. Allergy. 2007 May;62(5):504-13.


The pharm + tox lecture series: #3 - Distribution, putting the D in ADME

To recap: Pharmacologists use a cute little acronym, ADME, to describe the path that a drug takes through the body: Absorption into the bloodstream, Distribution to the tissues, Metabolism in some of those tissues to produce metabolites, and finally Elimination in body wastes like urine and poop.

Heh. I said poop.

Today is distribution day. Well, make that more like absorption and distribution day. Allow me to explain.

Most routes of administration involve the delivery of a drug into the body at a site removed from the bloodstream. Hence the drug must pass across cell membranes (including those of the cells that make up the walls of blood vessels) to reach the systemic circulation (i.e. the bloodstream). Once it gets there, it must again pass through cell membranes to exit the blood and enter tissues (and organs, which are a specialized collection of tissues), this being the process of distribution.

All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: intravascular (blood plasma found within blood vessels), interstitial/tissue (fluid surrounding cells), and intracellular (fluid within cells, i.e. cytosol). The distribution of a drug into these compartments is dictated by it's physical and chemical properties. I'm gonna discuss a couple of these.

Relative solubility is the solubility of a drug in lipid, which is the primary component of cell membranes, relative to it's solubility in water, the primary component of body fluids. This can be measured by mixing a known amount of drug with equal parts oil and water, and then determining the ratio of the drug concentration in the oil to that in the water (this can be accomplished easily using a radiolabeled drug). This ratio is called the partition coefficient (Po/w) and can be used to determine where a drug likes to go in the body. Any drug with a Po/w greater than 1 is generally going to be capable of rapidly passing (diffusing) through cell membranes with relative ease, and so will likely be found throughout all three fluid compartments. Drugs with low Po/w values (meaning that they are fairly water-soluble) are often unable to appreciably enter the intracellular fluid compartment and require more time to distribute throughout the rest of the body.

The size of a drug also dictates where it can go in the body. Most drugs have molecular weights between 250 and 450 Da. Antibodies and other recombinant proteins and peptides like ADH or insulin range into the thousands of daltons (insulin is about 6000 Da). Tiny drugs (150-200 Da) with low Po/w values (meaning that they are quite soluble in water) like caffeine, furosemide, and ephedrine are able to passively diffuse through cell membranes via water channels called aquaporins. Drugs over 200 Da with low Po/w values cannot passively cross membranes and so require specialized protein-based transmembrane transport systems. Their distribution throughout the compartments of the body tends to be slower. Drugs under a thousand daltons with high Po/w values are able to simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.


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.


Reader experiences - Pain edition

Two new stories for y'all:

I just finished reading William Gibson's new novel "Spook Country", and one of the main characters is addicted to anti-anxiety drugs, specifically Ativan (lorazepam) and Rize (clotiazepam). He seems to like Rize better. It's not available in the U.S. apparently due to some adverse effects. There's an interesting theme there: unusual drugs in famous literature.

I only have one quasi-interesting personal drug story: I once had a serious toothache and the dentist gave me a prescription for a narcotic painkiller -- don't remember the precise one any more. I also suffered from migraine-type headaches at that time. While the painkiller was effective for the toothache pain, it wasn't effective for the headache pain. I had to use Excedrin for that. All pains are not pharmacologically alike.

- Dean


I had a perianal abscess which started to hurt so damn much I went to the ER at 5 in the morning. Filled out the charts and wrote in big capital letters all over the "Current medications" and at the top : NO DEMEROL -- TAKING AN MAOI (Explanation!).

Lucky for me the the head of colorectal happened to be in the hospital (This was San Francisco and he'd been called in for the removal of a 'foreign rectal body' -- never found out what it was, but the guy had to go to surgery to get it out; but I digress....). He and the green resident show
up, and like a good tutor asked the resident for his opinions. Seeing how much pain I was in, and believe me, it hurt, he recommended -- wait for it -- some Demerol.

I literally screamed at the guy, "Can't you read the charts! I'm taking an MAOI!!!" He shut up, the old guy glared at him, and they gave me some morphine instead. Talk about a miracle drug! They ended up draining the abscess, and that hurt, but I didn't care. Cleared up just fine.

The whole ER episode ended up costing like $1100 or something. It flared up again on a trip to India a few years later. Had that one lanced at a grand total of 2000 rupees, which was about $45 at the time.

I liked the Indian guy better. He asked, can you stand a little pain? I said sure, if you can stand a little scream. So he sprayed some ethyl chloride (do they still use that anymore?) on the damn thing and lanced it. In and out in 15 minutes...

Finally had a fistulotomy, or I'd have more stories to tell. :p

- Jim


Book Review: Laughing Gas, Viagra, and Lipitor by Jie Jack Li

I am filled with jealous rage. Well, maybe not rage, but certainly jealousy. I happened upon this book in the pharmacology section of the Gerstein Science Information Centre, which is the big old health science library at the University of Toronto. It's sort of like this blog, but appreciably better in every possibly way. First of all, it's written by an established science author who manages to humanize the easily dry subject of drug development. It has nice pictures. There are actual paragraphs. It's chapters were very likely not written with haste only hours prior to publication. The stories of how a whole slew of drugs came into being are recounted in a wonderfully succinct yet personable manner, with every effort made to provide the necessary chemistry and pharmacology in order for the reader to better grasp the material. Li doesn't shy away from big science words, so a background in chemistry or medicine or a related field is probably necessary to ensure complete enjoyability. I appreciated the fact that a large number of drugs were covered, as opposed to the one drug per chapter approach I have seen in similar books. A sterling read that, having been published only last year (2006), is nearly up to date with all the goings-on in the pharmacological world.


Pamabrom - For that extra special time of the month

  • mild diuretic consisting of a 1:1 mixture of 2-amino-2-methyl-1-propanol and 8-bromotheophylline
    • 8-bromotheophylline is a methylxanthine, meaning that it is structurally similar to things like caffeine and theobromine (found in chocolate), and like these compounds it is a diuretic, mild stimulant, and bronchodilator
    • 8-bromotheophylline also inhibits alkaline phosphatase, resulting in elevated levels of phosphate and potentially messing with bone metabolism (excessive bone breakdown is a bad thing)
    • 2-amino-2-methyl-1-propanol (AMP) can be used to create a phosphorylating buffer solution, so I'm guessing that it functions to limit the inhibition of alkaline phosphatase by 8-bromotheophylline
  • often found in combination with acetaminophen (paracetamol) in drugs sold for relief of the wondrous symptoms associated with menstruation (things like pelvic pain, headache, and bloating, just in case you wondering) or for just plain old back/head/muscle pain
    • acetaminophen, being an analgesic, helps alleviate pain (by inhibiting the synthesis of pain-inducing molecules called prostaglandins), while pamabrom, being a diuretic, allegedly helps reduce bloating
    • there isn't a whole lot of data to suggest that either acetaminophen or pamabrom actually do much of anything for menstrual discomfort, but autosuggestion is a powerful thing
  • has been reported to be the cause of drug hypersensitivity reactions, including a serum sickness-like reaction (SSLR, featuring fever, rash, and joint pain) and a fixed drug reaction (a single lonely perioral red 'n raised skin lesion)
- Nedorost S et al. Fixed drug eruption from pamabrom. Cleve Clin J Med. 1991 Jan-Feb;58(1):33-4.
- Oner P et al. Evaluation of the effect of low-dose oral theophylline therapy on some bone turnover markers and serum prolidase I activity in mild asthmatics. Pharmacol Res. 1999 Aug;40(2):189-93.
- Swanson JK, English JC 3rd. Serum sickness-like reaction to Pamabrom. J Drugs Dermatol. 2006 Mar;5(3):284-6.
- http://en.wikipedia.org/wiki/Pamabrom
- http://www.aafp.org/afp/20031101/1781.html


How war promotes drug development

One of the beautiful incongruities of human existence is how our best ideas (and the technological advances they bring about) are usually the result of our need to be better at fighting wars. Nuclear reactors and nuclear bombs. Radar and microwave ovens. V-2 rockets and spaceflight. Early warning systems and the Internet. The list goes on. An impressive number of common drugs can thank armed conflict for their existence. These can be loosely divided into two categories: 1) those used to help fix injured soldiers (antibiotics, painkillers, etc.) and 2) those used to enhance the performance of combatants (stimulants and sleeping pills). Here are a few of the cool ones:


Only a couple of years prior to the Second World War, even a small laceration could mean a death sentence if it became infected. With no check on their growth other than an often weakened immune system, bacteria could multiply like crazy, and soon it enough it was morgue time. Penicillin (along with the sulfa drugs) helped change things. Although Fleming discovered penicillin in 1928, he was unable to come up with a way to mass-produce it. It was not until 1941 that Pfizer got on board and, within a year, came up with a novel fermentation method that could churn out penicillin like Catholics churn out babies. The American government, recognizing that penicillin was better than the sulfa drugs (safer and more potent), ordered all of the big American pharmaceutical companies to start producing a poopload of penicillin. When soldiers got themselves non-fatally shot or blown up on the beaches of Normandy in the summer of '44, penicillin was there to help their wounds from becoming infected. It should be noted that the sulfa drugs also made a huge, and arguably greater contribution, to fighting infections during WWII, but had been developed in the previous decade under peaceful conditions.


Given their aspirations for taking over the world, the higher ups in Nazi Germany realized that they needed to reduce their dependence on foreign resources until such a time as those resources became their own. This led to a boom in artificial substance research, yielding, among other things, synthetic rubber and synthetic oil. And methadone. As morphine was an exclusive export of the somniferous poppy fields of central Asia, within the sphere of influence of the Allies, efforts were made to find a synthetic opioid that could be manufactured at home. This led to the development of Hoechst 10820, better known as methadone, during the war. Initially investigated as a spasmolytic agent, methadone was put on the fast track for development after it's painkilling properties were discovered. Methadone is neat because it doesn't resemble anything found in opium (like morphine) but still is able to act at opioid receptors to produce analgesia. Sadly for all those injured German soldiers, it ended up setting on the shelf until after the war, possibly because the Germans got their doses all wrong and figured it was too toxic. Because it possesses an appreciably longer half-life than opioids that are typically abused (morphine, heroin, oxycodone, etc.), methadone is ideal for a one-a-day dosing in the treatment of opioid dependence. In related news, although morphine itself wasn't anything new at the time of WWII, the Squibb syrette was. A single dose of morphine (sufficient to deaden pain without risking an OD) in a toothpaste tube with a needle. This nifty method of drug containment meant that medics could easily give morphine on the battlefield, helping those injured avoid having to suffer until could be transported to a medical facility.


Mustard gas, a chemical warfare agent that has been employed by armies around the world to kill and disfigure, is responsible for the birth of modern cancer chemotherapy. As I've written about in a previous post, in Italy during WWII a stockpile of the gas was blown up, exposing people in a village nearby. Doctors treating the villagers noticed that they had decreased white cell counts, suggesting that the mustard gas had selectively destroyed them. Since Hodgkin's lymphoma (a type of cancer) was known to originate in lymphocytes (a type of white cell), researchers decided to see if they could use the gas to treat it. They could, and this led to the development of mechlorethamine (Mustargen), an analogue of mustard gas, and a class of drugs known as the nitrogen mustards that ushered in the era of treating cancers directly with drugs.

There is no doubt that those who abuse alcohol and are in need of treatment can find help at California drug detox centers. With all the alcohol rehabilitation success with different people, bipolar treatment centers and other types of treatment programs have been introduced.

- http://home.att.net/~steinert/wwii.htm
- http://www.ampainsoc.org/pub/bulletin/sep00/upda1.htm