Heads up: Sweet Onion A.V. Club drug article

Dig this fine article on fictional drugs.

This just in: Red Bull and vodka is a bad idea

The online news media is reporting that students who drink energy drink cocktails are more likely to mess themselves up than people who just drink regular old booze. Given the things that people manage to do when trashed exclusively on the sauce, this is some unfortunate news.

Some researchers in the States (Wake Forest University in North Carolina) carried out a web-based survey of 4,721 students. About a quarter of those who took the survey reported mixing an energy drink with their booze within the past 30 days. These special folks were found to be more likely to injure themselves, require medical assistance (read: alcohol poisoning), or get raped/rape someone. Party time!

Energy drinks generally contain high levels of some sort of stimulant. Usually it's a methyxanthine, like caffeine or theobromine. Other ingredients of pharmacological interest include natural products, which are often either herbs such as ginseng or ginkgo or royal jelly that are usually present in insufficient levels to actually produce any sort of medicinal effect, or else are just plants that contain caffeine (e.g. guarana) so as to disguise its presence in the product.

One big problem with energy drink cocktails is that the effects of the stimulant(s) in the energy drink masks feelings of drunkenness, so you don't feel as loaded as you actually are. This can lead to you do stupid things. Additionally, both methylxanthines (caffeine) and alcohol are diuretics. Dosing yourself with both drugs can lead to intensive dehydration, potentially causing cardiovascular problems such as hypotension and tachycardia. Not to mention the worst hangover known to man.

The goal of drug rehabilitation centers is to help individuals achieve and maintain abstinence from drugs and alcohol through a drug treatment program. With California drug rehab, people find a sense of self worth and begin to learn to manage the stresses of an active life without drug and alcohol abuse.

Ferreira SE et al. Effects of energy drink ingestion on alcohol intoxication. Alcohol Clin Exp Res. 2006 Apr;30(4):598-605.

Aspirin: The keep 'em in the kitchen drug

An analysis of data from clinical trials evaluating the effect of aspirin on preventing heart attacks suggests that the drug has sexist tendencies. Science be rocking the discrimination lately, eh?

Apparently aspirin is less effective at preventing non-fatal heart attacks in women relative to men. It has been suggested that this gender difference reflects a greater prevalence of aspirin resistance in women. Aspirin resistance refers to the reduced ability of aspirin to thin the blood (i.e. prevent the aggregation of platelets, which can lead to blood clot formation) in some unlucky people.

The less effective in the ladies thing might also have something to do with the fact that women who develop heart disease are typically older and have progressed further along with the disease at the time of diagnosis. The coronary vessels (the blood vessels that supply the heart muscle) are typically smaller in women compared to men, which might also have something to do with it.

The Internet is a great place to find cheap prescription drugs such as Viagra, which has more uses than you might think. Cheap phentermine and other appetite suppressants can help keep you looking and feeling great.

Tuesday Threefer: Phthalates, statins, and maraviroc

A couple of notes on three news articles that recently came to my attention:

California has passed a law that limits the levels of phthalates, a group of chemicals that are added to plastics to make 'em all bendy and soft-like, in products intended for kids under 3. The maximum concentration has been set at 0.1 percent. Governor Ah-nold, who in the humble opinion of this blogger was totally robbed of a Best Actor for the beautiful film that is Twins, said something about how important it was to prevent kids from being exposed to these chemicals. In that wonderful Austrian accent of his. In contrast to the views of the Californian legislature, my peeps at Health Canada claim that the levels of phthalates currently found in children's products do not represent a significant health risk. As is usually the case for sketchy chemicals like aspartame and saccharin, the scientific literature on phthalates is mixed. They have been shown to mess with reproduction and development in lab animals, and are suspected to be endocrine disruptors in humans. I'm betting that Schwarzenegger and some lawmakers just wanted to pat themselves on the back. And it's not really a ban, as everyone is saying, if they are just setting a limit. It's still in there!

A study by researchers at the Harvard School of Public Health (Public Health represent!) found that statins, a class of drugs given to lower the levels of bad cholesterol in your blood in order to slow the progression of cardiovascular disease, also slow the decline in lung function that occurs in the elderly and in smokers. Can't wait to see how the tobacco companies spin this one. Seriously, watch for it. Those bastards will take what they can get. Anyway, it all has something to do with the supposed ability of statins to reduce lung-based inflammation and smoking-induced injury while providing protection against oxidative damage. I love how they always hide the important science bits at the end of an article. The groups in the study were not randomized and a control group was not used, two important things that researchers usually try to do in order to strengthen their findings. Plus, let's remember here, it's just one paper. It's entirely possible that response papers contesting the findings are being written as I type (typed as I type?).

Finally, Health Canada has approved a new HIV drug. It's called maraviroc (Celsentri) and it's the first of a newfangled class of HIV-fighting drugs called CCR5 antagonists. CCR5 is a receptor found on T cells and a couple of other types of white blood cells that HIV uses as an entry point into the cells. By blocking the receptor, maraviroc prevents HIV from getting into T cells (No Stairway - Denied!), which means less cells getting infected. It's always great to get a new type of HIV drug on the market, since it represents another figurative gun in the arsenal of drugs used to fight HIV. Maraviroc is particularly crucial for people who have a variety of HIV that has become resistant to existing medications. Hooray for new drugs!

Appetite suppressants such as amphetamine and phentermine are drugs that act on your brain to prevent you from feeling hungry. A new appetite suppressant, a hormone called obestatin, was recently discovered and is currently in development. You have to be careful with amphetamine, because like a number of other drugs it can be addictive, and you don't want to end up in drug rehab. Make sure that you get educated on the risks associated with drug use.

- Heudorf U, Mersch-Sundermann V, Angerer J. Phthalates: Toxicology and exposure. Int J Hyg Environ Health. 2007 Oct;210(5):623-34.
- http://en.wikipedia.org/wiki/CCR5

Lipstick - A delightful combination of fryer oil and lead

Lead has allegedly been found in a number of popular brands (Cover Girl, L'Oréal and Christian Dior, to name a few) of red lipstick. An advocacy group went on a lipstick shopping spree (good times) and then shipped their purchases off to an independent lab for testing.

Now, if the analysis by the lab was done correctly, this is bad news. Lead is a toxic heavy metal that likes to hang around in people's bones and cause damage to all sorts of body systems: nervous (neurotoxicity and developmental delays in kids), cardiovascular (hypertension and anemia), gastrointestinal (abdominal pain, NVD, anorexia and weight loss), urinary (kidney damage), and reproductive (male infertility). To quote a friend: "Now we know why hot chicks are so dumb and skinny". Lead poisoning!

But let's take a closer look at this all. The Reuters article puts it like this:

The Campaign for Safe Cosmetics said tests on 33 brand-name red lipsticks by the Bodycote Testing Group in Santa Fe Spring, Calif., found 61 per cent had detectable lead levels of 0.03 to 0.65 parts per million (ppm).

Okay, first of all, 61 per cent works out to 20 of the 33 lipsticks having detectable levels of lead. Of these, only 11 had levels above the FDA's limit for lead in candy. That's right, in candy. The FDA hasn't set a specific limit for lipstick, and the assumption is made that a considerable portion of the wearer's lipstick (and thus the lead) is eventually ingested. I have no idea how reasonable an assumption this is. Lipstick wearers?

But there's more. The FDA's limit for lead in candy is specific to candy likely to be consumed frequently by small children. Lead poses a greater health risk to kids (relative to adults) because they absorb it more readily and are more susceptible to it's toxic effects. Lipstick use is generally (and hopefully) limited to teenagers and adults, who can tolerate greater levels of lead. It's really not as bad as it all sounds.

Incidentally, the FDA thinks the whole thing is a load of crap. They've said that they'll look into it, but brought up the fact that claims of lead in cosmetics pop up every once in a while but are never confirmed.

In case you were wondering, here are the worst ones they tested:

• L'Oreal Colour Riche "True Red" - 0.65 ppm
• L'Oreal Colour Riche "Classic Wine" - 0.58 ppm
• Cover Girl Incredifull Lipcolor "Maximum Red" - 0.56 ppm
• Dior Addict "Positive Red" - 0.21 ppm

A tyrosine kinase inhibitor for a Toronto maple leaf

Jason Blake, a top-notch hockey player currently playing for the Toronto Maple Leafs (suck it, Ottawa), has been diagnosed with chronic myelogenous leukemia (CML). CML is a hematological stem cell disorder (i.e. problem involving the cells in bone marrow from which mature blood cells develop) that involves uncontrolled proliferation (i.e. cancer) of myeloid cells (including all white blood cells except lymphocytes, and the precursors from which they are produced). CML is bad news because it means that the bone marrow is making tonnes of useless cancer cells while neglecting the production of useful blood cells, particularly white blood cells that are an important component of the immune system.

CML, if untreated, typically progresses through three phases. The initial chronic phase, which Blake is in right now, can last for months or even years and usually features either mild symptoms such as fatigue or else is asymptomatic. So for now Blake can keep on scoring goals (ahem, make that start scoring goals) for the most annoying team in the NHL. If drugs aren't given or don't work, the chronic phase eventually graduates to an accelerated phase, at which point things start going downhill as the cancer cells get better at dividing and avoiding apoptosis (staying alive). The final phase is called a blast crisis, at which point the leukemia is said to be acute (rapid proliferation of cancer cells and near-total shutdown of normal blood cell production). It's usually fatal. Thus the crisis bit.

CML, like a small number of cancers, is the result of a specific genetic defect. People with CML have an abnormally small chromosome called the Philadelphia chromosome in their myeloid cells. This chromosome, boringly named after the city in which it was discovered, is the result of a type of mutation called a chromosomal translocation, in which the long arms of chromosomes 9 and 22 break apart and trade places. This results in two genes, BCR and c-ABL, getting stuck together as a fusion gene.

Small digression time. Tyrosine kinases are a class of phosphorylating enzymes (proteins that catalyze reactions) that are involved in the regulation of cellular growth and differentiation. In other words, they can turn on and off the signal pathways that make cells divide like crazy and change from stem cells into mature cells.

Now, c-ABL encodes a tyrosine kinase. As a result, the BCR-ABL fusion gene also encodes a tyrosine kinase, albeit one that is completely wonkified (not a word). It is permanently set to turn on cell division and turn off the proper differentiation of stem cells into mature cells. This results in cancer, specifically CML.

Although it has not been stated explicitly, Blake is likely taking a rad new drug called imatinib (Gleevec, Glivec). Back in the day, when it was still under development, it was called STI-571. Anyway, imatinib is the first member of a brand spankin' new class of anticancer drugs, the tyrosine kinase inhibitors. Most anticancer drugs are cytotoxic agents intended to selectively kill enough cancer cells that your immune system can mop up the remainder. CML has proven to be tough to treat with typical anticancer drugs, which is why we have imatinib. Imatinib and other tyrosine kinase inhibitors are neat because their primary action is not to kill cancer cells, but rather to suppress their growth by selectively inhibiting the tyrosine kinases responsible for their existence. Imatinib is particularly good at shutting down BCR-Abl, making it a near-miracle drug for those with CML. So Blake should be good to go, now the Leafs just have to make it to the playoffs. Wish they had a miracle drug for that.

Remember that discount drugs can be easily found online, so don't delay on getting your hands on some Viagra, which can do more than you think, or cheap hoodia, to help you lose a couple of pounds by making you think that you are full when you're not.

- Hunter T. Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest. 2007 Aug;117(8):2036-43. Review.
- Koretzky GA. The legacy of the Philadelphia chromosome. J Clin Invest. 2007 Aug;117(8):2030-2. Review.
- http://en.wikipedia.org/wiki/Imatinib

Another COX-2 inhibitor bites the dust

Health Canada has banned the sale of lumiracoxib (Prexige), an anti-inflammatory drug used to treat osteoarthritis, after determining that it poses a significant risk to the livers of those taking it. It was banned in Australia in August (2007) after being linked to serious liver damage, including full out liver failure. As the FDA has not yet granted its approval, this drug is not for sale in the US (and now probably won't ever be), and I've just lost the interest of most of my readers. Stick with me, folks, it's almost over.

Now, lumiracoxib is a selective inhibitor of COX-2. Rofecoxib (Vioxx), another COX-2 selective inhibitor, was withdrawn from the market in 2004 after being linked to an entirely different problem, an increased risk of adverse cardiovascular events (i.e. heart attack and stroke). Lumiracoxib is structurally dissimilar to your standard COX-2 inhibitors, including rofecoxib, which might explain why it causes a different problem. It is known to be metabolized by the liver, so it's possible that certain liver enzymes are capable of transforming it into an extremely reactive metabolite that, unless detoxified by other enzymes, goes on a cell killing spree. Instant hepatitis. It could be that most people possess either too little of the activating enzyme(s) or just enough of the detoxifying enzyme(s) that they are not appreciably harmed by the drug. Please note that the above was pure, slightly educated speculation. In any event, it's off the market, so Canadians are good to go.

If your opiate addiction is ruining your life, treatment options such as methadone detox and suboxone detox can help. Suboxone treatment can get you on the road to recovery from dependence on painkillers.

- Rordorf CM, Choi L, Marshall P, Mangold JB. Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet. 2005;44(12):1247-66. Review.
- http://en.wikipedia.org/wiki/Lumiracoxib

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.

Drugs and Poisons On Teh Interwebs

The U.S. Army 'fesses up to having secretly dumped millions of pounds of chemical weapons (arsenic trichloride, hydrogen cyanide, lewisite, mustard gas, various nerve gases, phosgene, and white phosphorus) off the coast of America
GlaxoSmithKline announces plans to introduce five new cancer drugs (cervarix, pazopanib, promacta, rezonic and ofatumumab) by 2010

Snopes determines that some crazy photographs of a tonne of cash made from illegal drug sales are authentic

A Canadian high school student gets suspended for suggesting that marijuana is safer than alcohol

Tamiflu is still making Japanese people crazy

Drugs and Poisons On Teh Interwebs

Behavioral Ecology Blog - Where poison dart frogs get their poison (cool, kind of like these birds)

Instructables - DIY Kitty Crack (extraction of nepetalactone from catnip by steam distillation)

Overcompensating - Chinese Death Toothpaste (a great comic strip)

Passive-aggressive notes.com - roommate poison (guessing this was in jest, otherwise ouch!)

Los Angeles Times - A new drug may clear the haze of chemo (sweet)

MSNBC.com - Spider venom may yield virility (also sweet)

Is Britney Spears dating her drug counselor? (OMG! tell me more, useless media outlets!)

Anti-Gerasone

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