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June 10, 2010

Alfred Renyi famously said "A mathematician is a device for turning coffee into theorems." (actually Paul Erdos famously said it, but according to Wikipedia it's actually Renyi). I'd long believed (and thought the evidence showed) that caffeine improved concentration and hence productivity. Now Rogers et al. have come along and spoiled everything:
Caffeine, a widely consumed adenosine A1 and A2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.

Roughly speaking, this paper says that if you don't use caffeine, taking it won't make you more alert. If you do use it, it will make you more alert but only because you're less alert due to caffeine withdrawal and taking it brings you back up to normal.

What's most surprising here is the result that caffeine doesn't improve alertness in non-users. This contradicts previous work which shows an improvement in alertness from caffeine consumption by non-users. The authors propose one explanation for this might be that people are reporting low/no usage of caffeine when they are actually using it at higher levels (the 40 mg/day level cutoff here between low and moderate is actually quite low; coffee contains something like 100mg/cup.) So, when you force withdrawal and then dose with caffeine you get an improvement in alertness. This is partly borne out by their measurements of caffeine levels in "non-users" which are actually modestly high. However, this seems like it would benefit from more study.

However, it appears that once you are already a regular caffeine user, you do get some benefit from caffeine, in that it restores normal function. So, it's not crazy to take it once you're a user. However, it appears that you could get an equivalent benefit from just abstaining entirely and then (maybe) using caffeine when you needed to be alert (assuming you don't believe the non-user result). Of course if you're a user, you'll have to withdraw, which isn't a lot of fun.

One thing I should note is that the instrument this paper uses is a direct measure of (subjective) perceived alertness. The authors also had subjects do a variety of tasks that presumably required alertness. Those results don't appear in this paper, so it could be that they show improvement in non-users: i.e., they don't feel more alert when taking caffeine but they are more effective, which would make consumption worthwhile. I look forward to the publication of that data.

 

October 2, 2009

The Times has an interesting article about how life extension research is getting more respectable. Obviously, really good life extension/anti-aging therapies would be world-changing, but even modestly effective drugs would have a big impact (imagine the effect of having to pay another 5 years of Social Security and Medicare for half the senior citizens in the US).

I want to focus on a rather more trivial effect, though: age grouping in athletic events. Athletic performance is fairly strongly correlated to age, so many amateur sports provide awards in different age categories (typically 5 or 10 year brackets). Even one age bracket can make a real difference: for instance at last year's Ironman World Championship, the 5th place finisher in M35-39 would have won M40-44. Similarly, the 6th place finisher in M40-44 would have won M45-49. The gap between the first place in M35-39 and M45-49 is around 30 minutes (~5%), so if you had a medication which reduced your physiological age by 5-10 years, that would represent a huge advantage. The problem from a doping control perspective is that you can't really ban people from taking a drug which extends their lifespan by 5-10 years, but people on this drug (which certainly won't initially be everyone) are going to have a big advantage over their competitors, who aren't on the drug. It will be interesting to see how the doping control regime responds to this sort of development (assuming it actually happens).

 

June 30, 2009

The standard first-line opioid painkillers, Vicodin and Percocet, are actually both combination medications containing an opioid (hydrocodone for Vicodin and oxycodone for Percocet) with acetaminophen. The theoretical advantage here is supposed to be that you get better pain suppression with the combination than with either alone. The disadvantage here is that acetaminophen has a relatively narrow therapeutic index, and overdoses cause acute liver damage. [I suppose there's an argument that this is an advantage, since it makes it hard to get enough opioid to get high without risking liver damage.] According to Wikipedia, acetaminophen poisoning is the most common cause of acute liver failure [*].

Because of concerns over liver damage, the FDA's Advisory Panel has recommended eliminating them:

The two drugs combine a narcotic with acetaminophen, the ingredient found in popular over-the-counter products like Tylenol and Excedrin. High doses of acetaminophen are a leading cause of liver damage, and the panel noted that patients who take Percocet and Vicodin for long periods often need higher and higher doses to achieve the same effect.

Acetaminophen is combined with different narcotics in at least seven other prescription drugs, and all of these combination pills will be banned if the Food and Drug Administration heeds the advice of its experts. Vicodin and its generic equivalents alone are prescribed more than 100 million times a year in the United States.

Laureen Cassidy, a spokeswoman for Abbott Laboratories, which makes Vicodin, said, "The F.D.A. will make a final determination and Abbott will follow the agency's guidance."

The question I have is what will replace these meds in common use. There appear to be a number of combination hydrocodone formulations (with aspirin, ibuprofen, chlorpheniramine, ...), but with the first two you need to worry about allergies and chlorpheniramine doesn't have any painkilling effect so you just have to accept the unnecessary antihistamine side effects. I'm not sure if there are any hydrocodone-only formulations—I've never been prescribed one. While there are oxycodone-only formulations, doctors typically start with vicodin and then move up to percocet if that doesn't work, so it's not clear what this does to the front line. Moreover, as I said earlier, if you prescribe non-combination formulations you need to worry more about abuse, since there's nothing stopping the patient from just upping the dosage.

Obviously, preventing people from overdosing is an important consideration, but we also need to make sure we have a solution for pain that doesn't respond to OTC medications (NSAIDs and acetaminophen).

 

May 27, 2009

William Saletan has a confusing article in Slate about GW Pharma's new cannabis-based product, Sativex:
Sativex is a cannabinoid pharmaceutical product standardized in composition, formulation, and dose, administered by means of an appropriate delivery system, which has been, and continues to be, tested in properly controlled preclinical and clinical studies. Crude herbal cannabis in any form--including a crude extract or tincture--is none of those things.
So there. Sativex isn't pot. It's a carefully refined derivative: "Once the plants have matured, they are harvested and dried. GW then extracts the cannabinoids and other pharmacologically-active components ... [to] arrive at a pharmaceutical grade material." Patients are further expected to regulate their intake to separate pot's approved effects--relief of pain and spasms--from its unapproved effects:
By careful self-titration (dose adjustment), most patients are able to separate the thresholds for symptom relief and intoxication, the 'therapeutic window', so enabling them to obtain symptom relief without experiencing a 'high'.

...

Every feat of re-engineering challenges our moral and legal assumptions. In the case of Sativex, two positions are under attack: the left's lazy tolerance of recreational marijuana in the guise of legalizing medical marijuana and the right's opposition to medical marijuana on the grounds that it's just a pretext. By refining, isolating, and standardizing pot's medicinal effects, pharmaceutical companies are showing us how to separate the two uses. Are you for symptom relief or getting stoned? That used to be a fuzzy question. Now it's concrete: Do you want the reefer or the spray?

As far as I can tell from the above, the story is that Sativex does get you high if you take enough; it's just that they're packaged it in a such a way that it's easy to take a small enough dose that it relieves whatever symptoms you allegedly have without getting you high. On the other hand, if you take a higher dose, presumably you do get high. But of course, the same thing is true of pharmaceutical opioids as well, and people abuse them. To the extent to which we have deterred such abuse it's because we have found opioids which provide pain relief with less euphoria and/or we've adulterated them so it's unsafe to take enough to get really high (e.g., the acetaminophen in vicodin). And of course we still have plenty of abuse of high-end opioids like demerol. I don't see any evidence that either of these has happened with Sativex.

Maybe I'm missing something, but I don't see how this usefully divides the world between people who are in favor of getting high and people who are in favor of symptom relief. On the contrary, Sativex seems like a new cool way to get high without the inconvenience of lighters, coughing, smelling like smoke, etc. I'm sure there are some people who like the ritual of actually smoking pot, but I suspect most would be perfectly happy to skip that and just get high. How exactly does being able to buy the active ingredients at Walgreens discourage use by stoners?

 

May 8, 2009

I'll be the latest person to pile on Mike Galanos's piece in CNN about how Plan B shouldn't be available OTC to 17 year olds:
Think of a 17-year-old girl. Most of the time she's a high school senior, still living at home with Mom and Dad. She still needs her parents in the tough times. But they will be cut out of a traumatic situation. All thanks to U.S. District Judge Edward Korman. Korman stated in his order, "The record shows that FDA officials and staff both agreed that 17-year-olds can use Plan B safely without a prescription."

Now keep in mind birth control pills require a doctor's prescription, but a drug that is more powerful doesn't? The effective ingredient in Plan B is the synthetic progestin levonorgestrel and this is also found in daily oral contraceptives. Some forms of birth control that require a prescription have levonorgestrel, while Plan B has significantly more of the synthetic hormone. Do we really want our daughters putting something like this in their bodies without a doctor? I still want Mom and Dad in on this.

This is bogus on a number of levels.

First, oral contraceptives arguably should be sold OTC (Grimes summarizes the debate here). The only real arguments for requiring a prescription are (1) that it forces women to get seen by their doctors, which is otherwise good, but sort of paternalistic and (2) that compliance isn't as good if you get them in a non-medical setting. As for the "more powerful" argument, that doesn't follow at all. There's a difference between occasional and acute usage. If I have a bad muscle sprain and need to take 2400 mg/day of ibuprofen, even for a few days, I think nothing of it, but I would see a doctor before settling into a regime of 1200 mg/day for the rest of my life. Third, pregnancy really is pretty bad for you and there is plenty of evidence that emergency contraception is safe, so it's not really like you need a doctor to make these tradeoffs for you. Finally, what the heck do mom and dad have to do with this medical argument? Unless they're doctors, they're no more qualified than the woman/girl to have an opinion.

Some argue that a girl can get an abortion without parental notification in some states, so why not Plan B? But just because those states got it wrong by leaving parents out of the loop doesn't mean others should follow suit. And the larger point is, society must help parents, not undermine their rights by keeping them in the dark on their child's life-changing decision.

Here's some perspective for you: In most states, minors can't get a tattoo, body piercings or go to a tanning salon without a parent's permission, but we are going to leave them alone to take Plan B.

I suppose there's legitimate room for discussion about whether or not we should have parental notification laws for abortion, but this just ignores the very real issues with them. To state the obvious: many kids (especially girls) have sex even when their parents disapprove or without their parents knowledge. If they suddenly find themselves in a situation where they need EC, either because they have a condom failure or (shocking, I know) they had unprotected sex, having to ask their parents to get it comes with a huge amount of baggage. And we haven't even gotten to situations where the pregnancy is a result of abuse by a family member. None of this applies to tattoos, body piercings, or tanning salons. Again, it may be the case that it's still better policy to require parental consent (I don't think so, but that's not my point here), but it's disingenuous to suggest that there's a straight line from tattoo parlors to Plan B.

I question that, when we are cutting a doctor out of the decision to administer a powerful drug. Timing is essential to the drug's effectiveness, Plan B supporters say, so getting parents and doctors involved would unnecessarily delay the teen's ability to pop the pill the "morning after." Does it really take that long to get a prescription

This is a joke, right? Try to put yourself in the position of a 17-year-old girl who just had a condom break. You've got to get up the nerve to tell your parents you're having sex with your boyfriend and then calm them down enough to get to the doctor and get a prescription, all within 72 hours? That doesn't seem like a lot to ask? Even if all you have to do is see a doctor without your parents, might there not be some logistical difficulties, like figuring out where to get one that won't show up on your families insurance paperwork? And because of the time limit, this essentially sentences some girls to either an abortion or carrying the pregnancy to term, neither of which is that attractive if you didn't want to get pregnant in the first place.

I also don't buy the argument that this will help with unplanned pregnancies and abortions. The Center for Reproductive Rights says making Plan B more widely available could reduce them, but The New York Times reports that since 18-year-olds were allowed to get Plan B without a prescription in 2006, there has been no evidence of it having an effect on the country's teen pregnancy or abortion rates.

This is distressing, but I don't see how this is an argument against giving 17-year-old girls choices.

But let's get back to the first point: We are making it available to high school girls. We're enabling teenagers to act carelessly with an easy way out. During a recent discussion on my show, Jackie Morgan MacDougall, supervising producer of the Web site Momlogic.com, said it best. "Teenagers are known for thinking they're untouchable and here we are saying that they can continue to do that and that there aren't any consequences." With Plan B, they can do it now and deal with it later.

Don't tell me high school dynamics won't play in here. The boyfriend will talk his girlfriend into unprotected sex with the promise of buying the "morning after pill" the next day. Any 17-year-old boy will be able to buy this drug, just as any 17-year-old girl will.

Yes, this could encourage unprotected sex and that means a greater risk for sexually transmitted diseases. What about the 17-year-old girl who may get Plan B for her 15-year-old sophomore friend? These are the kind of decisions high school girls will make.

Wait, what? In my book, things that are fun (like sex) are good. Things that aren't fun (like getting pregnant when you don't want to) are bad. Things that make it possible to do things that are fun without experiencing things that aren't fun are also good. This is the part that makes me nuts about this kind of article (and also William Saletan's article, to some extent); what's careful and what's not is situation-dependent. Just like you can safely climb more aggressively when you're roped up than when you're not, a different level of care is appropriate if you can get EC than if you can't. Having sex (or any other activity) involves a certain level of risk, and it's not careless or irresponsible to take such calculated risks, nor is it careless or irresponsible to adjust your behavior when superior protection becomes available.

Now, clearly there's still a pretty significant level of residual risk in terms of STDs to be concerned about, but consider that as an argument against EC. The underlying logic of Galanos's position is that we should deny girls EC so they'll be more afraid of pregnancy and thus use protection against STDs. That's a pretty crude kind of reasoning (paternalistic again) and it's imposing a significant cost on those girls who get pregnant when they otherwise would not have for a more or less theoretical incentive benefit.

I think the 15-year old part is your hint to the real objection: we don't want teenage girls having sex, so anything that makes it less risky is bad. Needless to say, I don't subscribe to this theory.

 

March 4, 2009

The Supremes decided today that the fact that a drug is FDA approved doesn't pre-empt damages lawsuits for inadequate labelling. The most interesting part of this case for me, though is that Phenergan (promethazine) can cause "irreversible gangrene" is accidentally injected into an artery rather than a vein. Moreover, it's apparently somewhat tricky1 to administer correctly via an IV injection:

Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection. Reports compatible with unintentional intra-arterial injection of PHENERGAN Injection, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs. Sympathetic block and heparinization have been employed during the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants. Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with PHENERGAN Injection. Use of syringes with rigid plungers or of small-bore needles might obscure typical arterial backflow if this is relied upon alone.

I knew that some phenothiazines caused injection site irritation, but until recentl didn't know that promethazine was this bad. This seems like an excellent reason to avoid promethazine injections altogether, and if you must get them, have them done in your non-dominant hand.

1. Off-topic rant: why does Baxter think it's a good idea to password protect the PDF to prevent cutting and pasting? Further, why does Apple's PDF viewer—let along GMail's "view as HTML" feature—think it's a good idea to enforce this kind of caveman DRM? That said, Ghostscript seems to have your interests rather more at heart.

 

February 27, 2009

Read this article:
Eight different blood markers, including hemoglobin, are examined, said Robin Parisotto, a researcher from Australia. He is one of the nine scientists on an independent panel that reviews the abnormal blood profiles for the International Cycling Union, which is known as the U.C.I.

The markers are put into formulas and models that determine the statistical probabilities that an athlete is doping. Mr. Parisotto said the goal was to reach a 99.9 percent probability.

"The beauty with the blood passport is that you don't need to know each and every drug that is out there because you see the indication that something is being used," said Mr. Parisotto, who was the principal researcher in the creation of the first test for EPO used at the Olympic Games.

Now read this and ask yourself how well these tests were validated. The WADA writeup isn't very informative. Here's an overview of the research and here's a poster.

In this work, we estimated and integrated into a Bayesian network different components of variance of blood doping markers (hemoglobin, OFF-score, ABPS, tHb-mass) and steroid doping makers (T/E). The created network also included models of heterogeneous factors such as the influence of altitude on blood markers on the basis of a model proposed by the WHO. The Bayesian network has been validated and applied to more than 20,000 blood or steroid profiles. A software application, available upon demand, is capable of storing and interpreting an Athlete's Biological Passport.

These documents are pretty incomplete and it's a bit hard to figure out exactly how thorough the testing is. Intuitively, it seems like you'd need a pretty large baseline of samples to get a sufficiently high level of confidence. I wonder if 20,000 is the number of samples, athletes, or what? If it's 50 samples from 400 athletes, that's pretty different from 50 samples from 20,000 athletes.

 

February 12, 2009

The US Vaccine court has ruled in three cases that autistic children (or rather their parents) aren't entitled to compensation. From a technical persective, this is of course correct: there's just no evidence that vaccines cause autism except in exceptional cases. From a social perspective, I'm not sure it's such a great idea. As I understand it, the rationale for the Vaccine Injury Compensation Program is to provide stability in the vaccine system by providing a form of insurance for manufacturers. Since the parents of these children (and the thousands of other autistic children) don't show a lot of signs of giving up their beliefs about a vaccine-autism link, paying off these suits might be a cheap tradeoff to remove what's turning into a real (though imagined) disincentive for parents to vaccinate their children.
 

February 5, 2009

What's there to say about the whole idiotic Michael Phelps flap? The guy's 23. He smoked dope. Or not. What did you expect? Who cares? But then I read something like this:
U.S. swimming officials Thursday suspended Olympic hero Michael Phelps from competition for three months, the latest fallout from a photo that caught him puffing on a bong at a party.

USA Swimming, the sport's national governing body, also cut off its financial support to Phelps for the same three-month period, effective Thursday.

"This is not a situation where any anti-doping rule was violated, but we decided to send a strong message to Michael because he disappointed so many people, particularly the hundreds of thousands of USA Swimming member kids who look up to him as a role model and a hero," the federation said in a statement. "Michael has voluntarily accepted this reprimand and has committed to earn back our trust."

So, I've never been a USA Swimming kid, but I remember competing in high school sports and I don't think that I would have been disappointed to discover that some athlete I respected (for their physical skills, remember!) had smoked marijuana. It wasn't like my teammates weren't getting drunk at parties. This whole meme that kids need to be protected from the very notion that professional athletes aren't perfect has a pretty strong odor of "I'm shocked, shocked, to find that gambling is going on in this casino." Can people really have this little memory of what it was like to be kids themselves?

It's important to remember that from the perspective of the sport, smoking marijuana is really qualitively different from using steroids. Marijuana doesn't confer any kind of performance advantage so it doesn't undermine the sport [I'm not taking a position on whether steroids should be allowed or not. However, as long as they're banned, using them is cheating. Fair competition depends on rules, no matter how arbitrary.] The grounds for punishing athletes for using marijuana are (1) it's illegal so it "contravenes the spirit of the sport" and (2) it's bad for you. You might or might not think those are legitimate grounds for WADA to be doing anything, but certainly they're a lot less legitimate than those for regulating steroids or EPO. There's no real connection to the sport; WADA is just punishing athletes for behaviors they disapprove of.

One more observation: the selection of marijuana is fairly arbitrary. Remember that alcohol is illegal in some jurisdictions, but it's not a prohibited substance for athletes to use outside of competition.

 

September 4, 2008

In another entry in the bisphenol-A sweepstakes, Leranth et al. report cognitive impacts in a primate model (abstract only, full text behind paywall) [aside: it's super-annoying how much biomed research gets walled off like this. In CS we've reached this sort of uneasy compromise where people mostly post their papers on their own web sites, but you still have to pay to get the official versions. I suspect there's an interesting story to be told about this cultural divergence...]
Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.

As background, this Sigg-sponsored study, which uses pretty extreme conditions (90°ree;C water, 3+ days dwell times) to maximize leaching produces levels of around 70 ppb (110ng/cm^2 of bottle surface) in polycarbonate bottles. The EPA reference ("safe") dose for BPA is 50 ug/kg/day. A 1 liter Nalgene bottle is about 18cm high, which implies a radius (this is a bit tricky to measure with my lousy ruler) of 4.2cm, and an internal surface area of about 600 cm^2 (counting the top and the bottom). At a leaching level of 110ng/cm^2, this comes out to about 66 ug of BPA in a one liter Nalgene bottle. I weigh 75 kg, so even if I drank 10 l of water a day out of a Nalgene bottle, I'd be consuming about a factor of 7 less than the safe dosage. It's also worth noting that the amount of leaching at day 1 was less than a tenth of that at days 2 and 3, so you'd only get this level of exposure if you had a lot of bottles and left your water sitting around in them. Note that I'm not saying that polycarbonate bottles are safe, just trying to get some perspective on what we know about the risk. Obviously, the situation is different for baby bottles and the like because the subject's mass is so much smaller.

Interestingly, the Sigg study shows significant amounts of leaching (19.0 ppb) from "generic aluminum" bottles. This isn't explained, but I suspect that what's going on is that those bottles are lined with a polycarbonate-based plastic (I understand that some aluminum cans are lined that way as well). The Sigg bottles use an (undisclosed) but apparently non-BPA-based lining and so don't leach BPA, which presumably is why they were eager to have such a study.