Thursday, February 28, 2008

Please Understand Me--and Shut Up

This article has been making the rounds, in one form or another, for the past couple days. Naturally, most people get the beautifully condensed MSNBC version.

Let's go to the article for a quote:

“Patients aren’t sure how ill they really are, and neither is the clinician — sometimes dismissing their symptoms, sometimes overestimating them,” said Dr. Alexander Niculescu, III, a psychiatrist at the Indiana University School of Medicine in Indianapolis, who led the research published Tuesday by the journal Molecular Psychiatry. “Having an objective test for disease state, disease severity, and especially to measure response to treatment, would be a big step forward.”

Absolutely right. Granted, the test that's being discussed isn't actually anywhere near 100% accurate. Rather, it's about 60-70% at best. Plenty of room for false negatives--or false positives, though it would be irresponsible to diagnose an illness based on a single blood test with 60% accuracy.

The problem I have is that instead of cheering that we might finally have a good biomarker for a devastating mental illness, everyone is whining about ethical concerns. Let's think about this. An objective measure of bipolar disorder would not only allow for more accurate diagnosis, but it would give us better treatment benchmarks. It's easy to tell if a drug for hypertension is working; does it lower the patient's blood pressure by a significant amount when compared to a placebo? Evaluating the efficacy of treatments for bipolar disorder essentially comes down to asking patients "so how do you feel?" and hoping they're being totally honest. Is it any wonder why doing research regarding new treatments for the illness is so hard?

But no, nobody seems to be saying "this is amazing!" Instead, they're all complaining about how people with bipolar disorder are going to get discriminated against in hiring or rounded up and thrown into camps.

Let's start from the beginning. In the US, your health information is private. It is protected by federal law. Employers are not allowed to ask questions about any illnesses you may have, nor are health care providers allowed to disclose any information about your health to employers (or anyone else), including what medications you may be taking.

You might be wondering about urine screening for drug use when hiring new employees. Yes, the practice is legal, but laws vary from state to state. You could argue that this provides a foothold for pre-hire blood testing--except for the fact that most of the people whining about the blood testing procedure are saying that it's going to go beyond hiring. They're suggesting that landlords might blood test people before letting them sign leases, or banks might want people to submit blood before they'll hand out loans. You'll notice that none of these entities can legally conduct urine tests. Under current law, even if an employer were able to get a blood sample and test you for illness X or Y, you could sue them if they refused to hire you based on the results of the test--and you'd win.

Being mentally ill is a disability. Discriminating against people with disabilities in the workplace is illegal. It doesn't matter the disability is patently obvious (a person in a wheelchair) or totally invisible (bipolar disorder). As long as you're qualified for the job, that's all that matters--unless the employer wants to risk a huge lawsuit. This isn't likely to change any time soon. The ACLU would throw a fit, for starters.

The ability to definitively diagnose mental illnesses on the basis of a blood test is 99.9% good. Unless all the work of anti-discrimination proponents is suddenly reversed tomorrow, there's no reason to assume that this is going to create a problem. The only reason to think otherwise if you've watched Gattaca in the past week and it's cranked your paranoia setting up to 11.

Wednesday, February 27, 2008

All About Perspective

This is an older article, but I was digging through "news" archives tonight and I happened to stumble across this little gem.

On July 12, the cancerous growth imbedded in the brain tissue of Warren Lenders got the news no tumor ever wants to hear: chemotherapy. Facing the prospect of cancer-killing radiation, the six-month-old malignant brain tumor could have cursed the heavens for dealing it such a cruel fate. Instead, it chose to be grateful for the time it has left, viewing each new day as a gift from God.

Total brilliance.

Some Depressing News

A friend of mine sent me a link to an article yesterday, thinking it might be useful blog fodder. However, I didn't have the actual study in front of me--but thanks to The Frontal Cortex, now I do. If you ask me, Jonah has hit the nail on the head when he pointed out the biggest weakness in this study--all of the trials involved were, at most, eight weeks long.

For those unaware, this study was a meta-analysis. A meta-analysis involves doing no new research trials; instead, the results of a large number of old trials are compiled and analyzed using statistical methods. Results from fourty-seven trials were compiled for the meta-analysis; thirty-three of those were only six weeks long. Short trials are known to be less valuable in testing the efficacy of antidepressants; the longer the studies run, the farther apart the placebo and treatment groups usually get. For example, this study demonstrated that if you give patients escitalopram (an SSRI) for sixteen weeks and then switch half of them to placebo without them knowing about it, the placebo group will do significantly worse in terms of probability of relapse into depression.

It's interesting to see placebos compared to antidepressants. According to the PLoS study, placebos had about 80% of the therapeutic activity of SSRIs in the short term--that is, they were about "80% as good" in the six-to-eight week studies they analyzed. This is not actually all that surprising. For many depressed patients--or those with mental illness in general--the placebo effect is huge. Sometimes, the pro-active nature of seeking treatment is enough to bring depressed patients out of a slump, if only temporarily. Patients who feel as though they're finally doing something to fix themselves are likely to experience an emotional boost. And let's face it--not everyone on SSRIs is experiencing symptoms because they have low serotonin, one of the major neurotransmitters behind depression. Other diseases can cause patients to present with depression-like symptoms if they aren't properly ruled out before initiating treatment. That isn't likely the case with this study; before patients can participate in a drug trial for a new antidepressant, other causes of depressed mood must be ruled out.

The problem is that the mainstream media tends to get ahold of things like this and run amok making claims that "a new study proves antidepressants don't work," which is both incorrect and irresponsible. It's incorrect because all this meta-analysis (like many individual trials on the subject) suggests is that SSRIs must be taken long-term to have benefit, and that short-term reactions are largely attributable to placebo effects. There's a big difference between "antidepressants don't work" and "antidepressants have to be taken for months to see major improvement." The rate of relapse for patients switched abruptly to placebo is higher, even if the authors of the meta-analysis aren't convinced that antidepressants create "enough" improvement in the short term to be clinically significant.

To continue, this style of reporting is irresponsible because the everyman is a lot more likely to read a news article with a catchy headline than he is to seek out the original study and pore over the methods of the researchers, either because he has no idea where to look or because he hasn't taken enough statistics to have any idea what the hell these sciencey people are talking about. Which means that the everyman on antidepressants is going to take the words of some reporter at face value--perhaps higher than the words of his doctor, if enough reporters are all saying the same thing--and they're going to throw away their meds, decrying them as a useless waste of money. I've seen this happen before in clinical practice; many mentally ill patients take meds for a while, decide they don't need them any more (either because they "aren't working" or they "feel better"), pitch them, relapse, and start the whole vicious cycle over again.

Is there a tendency to "cover up" the results of clinical trials with negative outcomes? Sure. That's publication bias. But antidepressants aren't the only medications for which reporting bias is an issue--and just because some negative studies don't get published doesn't mean that the positive ones are automatically worthless. The negative studies don't necessarily get swept under the rug as part of some "grand pharma conspiracy." One negative study doesn't prove a drug is ineffective any more than one positive study proves that it is. If the overwhelming trend is positive or negative, then we can make judgments. But even trends can be misleading; you can connect the dots many different ways, depending on where the dots are and what kind of analysis you're doing. And that's one of the risks of meta-analysis studies. There's just as much room for spin there as anywhere else.

So don't throw out the Prozac. There's no such thing as an "official study" that proclaims antidepressants to be therapeutically useless. And any journalist who tells you otherwise is being sucked in by spin just as badly as the drug reps who are trying to push the products--they're just being spun in the opposite direction.

Monday, February 25, 2008

I Stand Corrected

I take back my comment in the last post about napping being a source of relaxation and stress relief. If this news article speaks the truth, seniors who fall asleep unexpectedly during the day have a higher risk of stroke, even when patient populations are controlled for diabetes, high blood pressure, and other risk factors.

You know, I fall asleep on my couch after a rough day with fair frequency. I wonder if my risk for stroke is higher as a result? Probably not.

I think (and don't quote me on this) that a much more likely explanation is that seniors who have difficulty maintaining alertness have that particular problem because of declining health in general. Medication side-effects might be part of the reason the patients are nodding off, though if the study controlled for disease states, they likely also controlled for medications likely to cause drowsiness. Either way, it's safe to say that patients who lack energy and fall asleep during the day are probably sicker than those who don't.

And even if falling asleep during the day were a direct cause of stroke risk, what would we do about it? Make daytime television more stimulating? Provide the elderly with free Starbucks?

Seriously. Correlation versus causation. Who funds these studies?

Curiosity Killed...

This article is hilarious if only because it's a great example of conflating correlation with causation.

Have you ever thought how lucky you are to have your cat with you? According to a controversial study, presented at the American Stroke Association in New Orleans on Thursday, cats reduce the risks for their owners to have a heart attack and protect them from other cardiovascular diseases.

Without the original study in front of me, I can't really analyze the statistics the authors used to conclude that cat ownership reduces the risk of heart attacks. The proposed "mechanism" for this is that cat ownership--a source of affection and companionship--reduces stress levels. Less stress means fewer heart attacks. Well, okay. That might be the case. Maybe. Heart attacks are occasionally triggered during high stress situations or periods of exertion.

However, the idea that having a cat around--and the study says nothing about man's best friend, the dog--will improve your health sounds like shoddy scholarship. I'm sure you could find a similar link between tea, enjoyment of classical music or a love of quiet meditation, or even just a tendency to take naps. Anything that helps you chill out would offer similar benefits, assuming that stress was a primary cause of heart attacks (which is isn't).

Cat ownership is pretty prevalent. You might as well connect having eaten tomato sauce to cancer or driving a car to catching the flu.

Saturday, February 23, 2008

Paging William Shatner

Normally, I don't post work rants, because I feel like that subject has been well-covered in the blogosphere. But today's "pill-counting action," to steal a phrase from the Drugmonkey, concluded with a jaw-dropping exchange that ties into some of the stuff I've been covering lately. Diabetes, that is.

I missed the initial exchange between the woman at the counter and the pharmacist. "Hey, N.B.," he said, "she needs some insulin and some syringes. Can you get her set up?" He went off to do something else. I confirmed the type of insulin in question (Humulin 70/30 mix, which is available without a prescription). I asked how many vials she wanted. "I dunno, how much are they? I'm getting tired of having to go to the pharmacy all the time, maybe I'll get a bunch." About $40. She decided she only wanted one.

"What kind of syringes do you need?" "I dunno," she said. Hmm. Perhaps her doctor sent her here with no patient counseling whatsoever, although he would've at least written her a script. "Alright, how many units do you use?"

She looked confused by this question. "I think 30. Three times a day."

This is an absolutely ridiculous amount of 70/30 for a newly-diagnosed diabetic to be using. I'd estimate she weighed less than 130 pounds; half that amount would've been reasonable. And Humulin 70/30 is an intermediate-acting insulin, so that many doses/day was outrageous. Also, the idea that she would be unsure as to how much insulin to use was mindblowing.

The pharmacist stepped over to me as I was digging around for syringes and suggested (quietly) that we go ahead and give her 40 syringes--no more--because he was convinced she was just going to pitch the insulin and use the syringes for something else. I have commented before on how I don't have a problem with providing syringes and needles to drug users because in my state I'm not liable for what they do when they leave the pharmacy as long as I follow proper sale protocols and the person has a valid photo ID. Alright. 40 syringes.

"Should I get one of these meters?" She was referring to the blood glucose meters, of course. "Yes," I said, "you should have one. How often does your doctor want you to test your blood sugar?"

"I don't know," she said, "this isn't really for me, it's for my boyfriend, he's never done this before." If she was just trying to get syringes, she could've come up with something less elaborate. There was certainly no need to buy a glucometer. I was pretty sure at this point she did, indeed, have a boyfriend with diabetes who needed insulin.

This is bad territory. Now I am not counseling my patient. I am counseling my patient's (slightly loopy) messenger.

"How often should he check his sugar?"

"Well," I told her, "it depends on what your physican wants you to do, but usually at least twice a day, more often if you're trying to monitor changes in blood sugar closely."

This is the part where we entered the Pharmacy Twilight Zone.

"So, how much insulin is he supposed to use?"

I refrained from falling over in shock. "Er. How much did your physician say to use?"

She seemingly ignored this question. "What if he takes his sugar, what should it be? What's high? What's normal?" "Depends on whether he's eaten recently, among other factors. Usually, if he hasn't eaten in a long time, it should be pretty low, like 80-120. Did the doctor tell him what his goals were?"

"So he should check his sugar and if it's above that he should take insulin?"

I was starting to get the impression at this point that this boyfriend of hers had never, in fact, seen a doctor about his diabetes. Or, perhaps, he had seen a doctor once, ignored everything he was told, went home and told his girlfriend that he had diabetes and needed insulin, and set off a bizarre chain reaction that somehow ended with "I can get a random pharmacist to sell me insulin, confirm the diganosis of diabetes, and prescribe an appropriate insulin regimen for a patient he will never see again."

Note to the reader. THIS IS WRONG.

"Yeah," she continued, "he doesn't pay attention to stuff, he can't do this himself, so I'm trying to take care of it. I'm goin' to go to nursing school, I gotta understand this stuff, I know about checking blood sugar. He can't do this stuff himself, you know how boys are."

I just blinked at her. "Uh."

"Well, some of em' anyway."

I'm not sure who to blame for this scenario. Opponents to universal health care? A careless physician? I don't think the blame belongs to a doctor. Her boyfriend came in a couple minutes later. He had no clear idea of what was going on. Apparently he knew he needed insulin--and that was it. He remarked that the insulin and glucometer were expensive. "It'd be cheaper to get the other medicine," he said. "Yeah, well," replied his girlfriend agitatedly, "you're too disorganized to do that, so we have to waste the money like this."

She produced a one-hundred dollar bill to pay her tab, at which point I requested a photo ID for the syringes. She didn't have one. He didn't either.

"We'll just use the syringes we've got at home," she said. They took the insulin and the glucometer and left the store. The pharmacist and I stood and stared at each other in total shock. We were both completely baffled by the exchange. I am moderately concerned that he's going to go home, overdose himself on insulin, and wind up in the ER, convulsing and in shock. If it had been my call, I wouldn't have sold them the insulin, but the pharmacist didn't have a problem with it. This was the most confusing exchange I'd ever had with a "patient." I had a distinct notion that both of these people were like cats without whiskers, perpetually caught behind the refridgerator, and I had just let them leave the store with a bottle of something that could easily result in an unintentional lethal overdose if used improperly.

I kind of hope these people never breed. The cynical part of me thinks that this problem will short itself out in short order when this guy removes himself from the gene pool.

Tuesday, February 19, 2008

The Heart of the Problem

Commenter Bunc on Mike the Mad Biologist's ScienceBlog has succinctly put his finger on the real reason why the whole evolution debate is such an issue. If I may paraphrase:

Part of the problem is that this is seen as atheist evolutionists versus theistic creationists. The fundamental issue is not this--it is scientific literacy versus ignorance.

The reason that many popular versions of theistic philosophy in America are "dangerous" is not because theism is a direct threat--the problem is that many prominent theists, namely American Christians, are fundamentally opposed to naturalistic theories that exclude their god from the creation of mankind (and everything else).

The interesting thing, if you ask me, is that there are well-spoken and intelligent Christians out there who don't have any problems with evolution (or science) and in fact actively promote understanding of it. If you're looking for a breath of fresh air on the subject, I recommend James McGrath's Exploring Our Matrix.

This whole issue cloaks itself as a religious debate--but it isn't. It has nothing to do with theism per se. It has everything to do with promoting ignorance over science.

Friday, February 15, 2008

Whisky'd Away

After a week consisting of five exams over the course of three days, it's the simple things in life that get you back on track.

Like a bottle of Dalmore 12-year single highland malt. If I wanted to take a leaf out of several other blogger's books, I'd do weekly whisky reviews, but good Scotch isn't exactly in the typical college student's weekly budget. Certainly not mine.

Needless to say, it was a good buy--excellent for the price at only $25.

Tuesday, February 12, 2008

Diabetes Discussed: Part 3

Thus PalMD and I continue our cross-blogging endeavor to explain what researchers have figured out about diabetes in light of recent proclamations from the mouthpiece of science that type II diabetics may not benefit from dropping blood glucose levels to their minimum levels as much as previously thought.

Treatment of diabetes is multifaceted. As Pal pointed out, insulin is the mainstay of therapy, especially for type I diabetes. In type I, insulin is the only reasonable therapy; right now, nothing else works. They don't make insulin. They need insulin. Simple enough.

Insulin was the first protein drug product developed and widely used--it was originally derived from pigs or cows. Nowadays, we get our insulin from E. coli that have been genetically "reprogrammed" to produce human insulin through bioengineering. And we also have a huge variety of insulin products that are essentially just modifications made to the basic insulin design. Some insulins act more rapidly (like Humalog or Novolog) whereas others are intended to last up to 24 hours to provide an insulin "baseline" (like Lantus or Levemir). Insulin dosing may initially be based on weight, but after that, dosages are recalculated based on trial and error. It is difficult to predict precisely what quantity of insulin will produce the desired result, and there are several different rules and protocols for optimizing insulin dose. In short, insulin doses must be individualized to the patient, requiring a lot of careful monitoring by both the health care provider and the patient (with a home blood glucose monitor).

Treatment of type II diabetes is way, way more complicated.

Because type II diabetics can create insulin, but their cells are less responsive to its effects, the initial treatment of choice is usually metformin. Metformin is amazing. It's the only drug in its pharmaceutical "family" on the market, and nearly every type II diabetic is on it. It works by increasing the sensitivity of cells to insulin and by decreasing the amount of glucose the liver makes--it's that gluconeogenesis process again--which results in an overall decrease in blood sugar. It even causes some patients to lose weight, which is excellent; losing weight generally decreases the severity of type II diabetes.

Pal covered metformin and the other "oral hypoglycemics" already--sulfonylureas, like glipizide, force the pancreas to spit out more insulin. And thiazolidinediones (TZDs for short; that word is quite a mouthful) have multiple body effects, including increasing insulin sensitivity, but by a different mechanism than metformin--which means that they can be combined, and sometimes this produces better results.

I would like to stress at this point that if you or a loved one have diabetes, while this series may be thought-provoking and raise interesting questions, that you should discuss the matter with your primary care physician when it comes to individual treatment recommendations--not here. I'm not a licensed medical practitioner*, just a student of pharmacy with a flair for words and a desire to share his knowledge with the world. And even if I were licensed, reading some article written by an anonymous blogger is not an appropriate substitute for face-to-face medical advice.

With that out of the way. What does recent research tell us? Past research tells us that blood glucose is important. But new research says other things might be just as important--maybe more.

Heart disease is a number one killer of patients with type II diabetes. Kidney failure is more common in type I. They're both considered to be manifestations of the same disease. But they're clearly different in several ways. Pal mentioned ketoacidosis--that's common in type I, but incredibly rare in type II. What explains these differences?

If I wanted to indulge my inner conspiracy theorist I'd blame the drugs used to treat type II diabetes, which is kind of like the absurd claims made by tinfoil-hatwearing HIV denialists that AZT causes AIDS.

Much more likely is the difference in co-morbidities ("other diseases/conditions the same patient has") for both type I and type II patients. Type II patients are typically obese, or at least overweight. The Framingham heart study has demonstrated that being overweight (as defined by medical science, not People magazine) is a risk factor for cardiovascular disease. So is having wonky cholesterol levels--and those are pretty common for type II diabetics, too.

This study is kind of interesting. Essentially, cholesterol deposited on beta-cells--the part of the pancreas that secretes insulin--can induce beta-cell failure. Cholesterol essentially "clogs the pipes." Even more interesting is the fact that this whole problem may be tied to a gene that codes for a protein called ABCA1. ABCA1 is essentially the "conductor" responsible for regulating lipid transport in and out of beta-cells. People whose genes incorrectly code for the ABCA1 transmembrane protein may be more susceptible to lipid-based damage to the pancreas. It is entirely possible that controlling lipids is at least as important as controlling blood sugar in type II diabetes, which means that dietary modifications, exercise, and cholesterol-lowering drug therapy may all play an even greater role in achieving good treatment outcomes than previously thought. This is exciting research!

That study's too neat to just be a throwaway link. I might come back to it later.

I think the point of recent research basically demonstrates that we can't just treat blood sugar. It doesn't mean we're completely mean about how we're treating diabetes. It just gives us a new direction to focus our research. Diabetes may be conceptualized as a problem with glucose metabolism, but that isn't the end of the story. Physicians, pharmacists, and patients have to work together to design treatment regimens that address cholesterol and sugar, among other factors.

*Well, I have a pharmacy intern's license. Which permits me to practice pharmacy, compound medications, and counsel patients under the guidance of a licensed pharmacist. But it's essentially a learner's permit. And you shouldn't be using the internet as your sole source of health advice anyway. It's not a good resource. In pharmacy, we call using a drug by itself that shouldn't be used alone "inappropriate monotherapy." Getting all your medical information online is the same. Go talk to your doctor!

Lose Weight--Naturally!

I'd like to plug an entertaining (and short, this time) entry by Pharmacy Girl.

In Arizona, naturopathic doctors can legally prescribe any legend drug or controlled substance (except IV medications, chemo drugs, and antipsychotics). The only prescriptions I see from naturopaths are for phentermine and metformin. Usually for the same patient.

This is why licensing naturopaths doesn't help. No, I don't have statistics that this is true, just one pharmacist's observations. I would like to get detailed statistics. And sure, you could argue that without licensing they would be doing something less savory than handing out amphetamines to any yuppie who wants to lose ten pounds before swimsuit season. But you give them legal power to prescribe medications and this is what they do.

This isn't even me saying that naturopaths are irresponsible or incompetent at treating illnesses. There is always the possibility that there are some naturopaths that actually know their anatomy, physiology, and pharmacognosy. What annoys me about this is that they are hypocrites. Aren't proponents of so-called natural medicine always advocating things like diet and exercise instead of drugs? You know, letting the body work itself out "naturally" as opposed to dumping in synthetic compounds that speed up the central nervous system? Wouldn't a real naturopath prefer you get on a treadmill to raise your heart rate than take speed? Hell, prescribe bitter orange or guarana extract. Those, at least, are derived from plants--even if they are just sources of caffeine or ephedra.

There are a lot of physicians with questionable motives and practices out there, too. They aren't blameless by any means. Look at the plastic surgeons who put up phony "board certified" credentials and operate on patients in their offices. But if becoming a naturopath is quantitatively easier in terms of time and money investment, and you can get your naturopathic license and rake in the cash by seeing patients for five minutes and throwing phentermine at them, isn't that a bad system? You simply can't expect me to believe that getting a degree from Bastyr takes the same amount of work and time as going to Johns Hopkins. Why should we give people a short-cut to opening crooked practices?

When Pharmaceuticals Fail, Consider Possession as an Etiology

Bad of The Bad Idea Blog, one of my favorite sites for silly and skepticism, has posted an excellent article about demonic possession and the rising popularity of exorcisms in Europe. I am not ashamed to admit that I nearly fell out of my chair laughing. I'd quote my favorite sections, but that would spoil the article for you. So go read it! Keep yourself amused somehow while I work on part three of the diabetes series PalMD and I are co-blogging about!

Monday, February 11, 2008

Diabetes Explained: Part 1

The medical world is abuzz regarding the recent revelation that driving blood sugar to its lowest theoretical level may not be the optimal treatment regimen. PalMD of WhiteCoat Underground has already addressed the issue in a short post, noting wisely that this whole issue just raises more questions about the nature of diabetes and how it should be treated.

But what is diabetes, anyway? There are a lot of misconceptions, perhaps the most popular being that diabetes is a disease you contract as a result of eating too much sugar. My own mother was convinced that a diet proportionally high in carbohydrates was likely to cause diabetes until I made an attempt to explain otherwise. It also gets likened to a sort of food intolerance--the idea that diabetics can't eat sugar because it will cause acute damage. Naturally, the truth is far more complicated; patients with diabetes won't keel over and die in minutes if they eat cake.

Diabetes is often conceptualized as a problem with glucose metabolism. When you or I eat, the body breaks down complex carbohydrates into simple glucose units. Certain amino acids, the building blocks of proteins, are converted into glucose by complex pathways in the liver (the big, scientific word for this is "gluconeogenesis"). Glucose then circulates through the blood and is delivered to various sites; it is the preferred fuel for every cell type in the body, especially neurons. Something like 80% of the glucose in your body is utilized by the brain and nerve tissue.

The issue is that glucose is unable to enter cells unless the drawbridge is down, because glucose molecules are too big to freely pass through cell membranes. In order for glucose to enter cells, special pores on the cell surface need to open. And the trigger that opens those pores is insulin. Without insulin, most of the body's cells have no way to utilize glucose--and therefore, they are unable to fuel themselves efficiently.

It isn't that sugar is somehow toxic to patients with diabetes--the problem is more like having a blocked fuel line in your car. No matter how much gas you put in, your car can't get the gas because of the obstruction. And if you keep filling the tank anyway, you're going to cause it to overflow and spill gas onto the street, harming the environment with damaging emissions.

There are two types of diabetes. Type I diabetics are unable to make insulin; this could be because of a genetic defect, damage to the pancreas by infection or trauma, etc. The net effect is that no matter how much the type I diabetic eats, he is essentially starving, because his body's cells have no way to use glucose. Instead, they rely on far less efficient fuel sources like ketone bodies, which is sort of like putting the lighter fluid-soaked charcoal remnants from last night's bonfire into your car's gas tank and expecting it to operate well. The typical untreated type I diabetic is thin and malnourished. There is tons of glucose floating around in the bloodstream and none of it is accessible, so it gets excreted in the urine.

Type II diabetics make insulin--in fact, they frequently make tons of insulin, especially in the early stages of the disease. The problem is that their cells are less responsive to the effect of insulin, so they use glucose very inefficiently. If type I diabetes is an obstructed fuel line, type II diabetes is a leaky gas tank. Type II diabetics are commonly overweight--having large amounts of fat cells decreases the body's response to insulin. Fat doesn't just sit there; it secretes hormones that regulate glucose usage and appetite, among other things. The bizarre thing is that from a metabolic standpoint, your type II diabetic, despite being overweight, is functionally starving.

If I were stranded on a desert island with nothing to eat, my body's metabolic machinery would switch gears in less than 24 hours. We're starving, it would say, and the pancreas would release a hormone called glucagon to remedy the situation. Glucagon would tell my body to break down my fat stores (the few that I have), cannibalize muscle tissue, and instruct the liver to release its glucose hoard to feed the brain. Eventually, the stores would run out and my brain, cut off from its supply of necessary glucose, would shut down, taking the rest of the body with it. My heart, ever a trooper, would keep on truckin' until the autonomic nervous system crashed, because it is perfectly happy to feed on metabolic scraps.

An untreated diabetic's body is doing this all the time, and the only reason it doesn't kill them is that the brain, kidneys, and nerves don't need insulin to take in glucose. They're the exception to the rule, and if they weren't, diabetes would be fatal a lot more quickly than it actually is.

The reason sugar is harmful to diabetics has less to do with the essential properties of sugar itself and more to do with the effects of wildly fluctuating glucose levels on those three tissues. When glucose levels are high, glucose rushes into the big three--the nerves, the nephrons (the functional units of the kidney), and the retina of the eye. When blood glucose finds its way back down, frequently by being excreted in the urine, there is a huge disparity between the amount of glucose in the nerves and in the blood.

Those of you who remember basic chemistry will recall that such concentration differences are considered unfavorable in accordance with physical law. If we put a tablespoon of sugar in a glass of water, the sugar molecules would slowly spread out throughout the glass (though more slowly than we might like, which is why most people opt to stir the glass). Given enough time, the concentration of the sugar will be uniform throughout the water, and we will have a solution.

But what if we put a barrier in the glass dividing it in half from top to bottom, and the barrier permitted the passage of water, but not sugar? If we put sugar in one partition, the sugar-water on that side will be much more concentrated. Physics doesn't especially like this scenario; equal concentrations on both sides would be preferable. Sugar can't move through the barrier, but water can. As a result, water is going to pass through the no-sugar side to the sugar side in an attempt to equalize the concentrations.

This is the precise scenario that takes place in the human body. Once sugar concentrations in the bloodstream go down, the sugar concentration inside cells (retina, nephron, and neuron) is higher than the sugar concentration outside the cells. Since the sugar can't come out, water goes in. But the cells are limited in size by the boundaries of their membranes. When enough water rushes into the cells, they burst and are destroyed like overfilled water balloons.

So the big problem with sugar and diabetes has less to do with sugar itself being harmful and more to do with osmotic pressure, the situation described above with the barrier that will permit water to cross but not glucose. This is why diabetics with poorly-controlled blood sugar--blood glucose that fluctuates from low to high with great frequency--are more likely to suffer nerve damage, blindness, or kidney failure.

The recent study suggests that type II diabetics (NOT type I diabetics) were just as likely to die from their condition if they maintained low blood glucose levels than if they didn't (this isn't the whole story, so nobody panic). This is a surprise mostly because prior research has fairly conclusively confirmed that controlling blood sugar reduces the risk of those three problems I mentioned earlier in addition to reducing the likelihood of heart attacks, strokes, and other cardiovascular complications.

Why might this be? To understand this issue, we'll need to look at the way diabetes is treated, which will make absolutely no sense without an understanding of what diabetes is. Next post, we'll explore the issue of treatments for diabetes, how they work, and what this new research might mean.

Optimizing Your Caffeine Intake

This article by Chris Chatham of Scienceblogs' Developing Intelligence is worth a look. It's a fascinating read, and if you're a caffeine enthusiast like I am, it might even be practical knowledge!

I predict my intake of the world's favorite stimulant will increase significantly over the course of the week--with five exams coming up between Tuesday and Thursday, there're going to be a lot of cups of coffee and cans of No Fear finding their way down my gullet.

Friday, February 8, 2008

Why Bioavailability and Drug Delivery Make the "Simple" Complicated

A co-worker, colleague, and fellow student of mine approached me a long time ago saying she had a story that I absolutely had to hear. While home for the Christmas holidays, she wound up talking with some in-laws and family friends. One of these people turned out to be some sort of naturopathic practitioner. There was some disagreement about the value of statins, as could be expected (apparently someone suggested that everyone on statins should just take high-dose vitamin E instead). But the part that interested me was the fact that my colleague wound up having to explain the dopamine hypothesis of ADHD.

In short, the naturopath didn't understand why hyperactivity was commonly treated with stimulants. This is a reasonable question if you don't understand how amphetamines work. Most ADHD drugs are prescription amphetamines, essentially "Speed" used for a legitimate medical purpose. The same drugs are also sometimes used for narcolepsy. On the surface, it really does seem like a massive contradiction. Why give children who are having trouble focusing because they can't sit still stimulants?

The current hypothesis supposes that ADHD is at least in part caused by an insufficient quantity of the neurotransmitter dopamine in the brain and central nervous system. Dopamine is associated with pleasure and reward; in fact, all addictive drugs, directly or indirectly, have some effect on dopamine pathways in the brain. In ADHD, insufficient dopamine results in "lack of satisfaction," resulting in children and adults with ADHD being unable to focus on tasks. In essence, their brains are not programmed to acknowledge task completion as worthwhile, making it difficult to concentrate; the brain is too busy trying to find something else to do that is worthwhile. Many stimulants, amphetamines included, increase the concentration of dopamine in the brain. Appropriate stimulation of the brain and central nervous system increases "satisfaction" in patients with ADHD and allows them to focus more effectively.

Unfortunately, amphetamines have other side-effects. They speed up the heart, increase blood pressure, and, if the dose is too high, may cause insomnia, jitteriness, and anxiety. So the naturopath's next question was reasonable. "If dopamine is low, why can't you just give kids with ADHD dopamine?"

I don't expect laymen to know the answer to that question. I do expect anyone with an understanding of pharmacology to know. Naturopaths claim they understand the workings of the human body. Clearly, drug bioavailability is beyond their expertise.

There are a whole slew of reasons why you can't just take dopamine tablets. Some of them are specific to dopamine; others are general drug issues. Bioavailability sounds like a tough word, but its meaning is actually fairly simple. Essentially, bioavailability is a measure of how much of a drug the body can use after the drug is given. In order for a drug to have an effect, it has to reach its site of action. An anaesthetic has to diffuse into nerves before it can produce a numbing effect. Drugs designed to lower blood pressure have to be able to access the heart, arteries, and veins.

When you swallow a tablet, it goes to the stomach and is broken down to release its contents. In order to get into the bloodstream, the active drug must cross body membranes; otherwise, it will proceed through the intestines and be expelled unchanged. Luckily, your intestines have a large surface area and are good at absorbing things--otherwise, eating would be rather pointless, because you wouldn't be able to get any of the nutritional value from your food. However, there are limits to what is allowed to cross the intestinal membrane. Some drugs or chemicals can't cross it at all. In fact, some drugs are designed not to cross the membrane; they stay in the intestine and do their work right there. Alli is a good example. It doesn't need to be absorbed into the body. It stays in the intestine and binds fat molecules, preventing them from being absorbed.

Once a drug is across the intestine and in the bloodstream, the first stop is the liver. The liver is responsible for removing poisons from the body; it would be irresponsible for your body to deliver absorbed substances directly to organs like the heart and brain without filtering the contents first!

The liver is responsible for breaking down many drugs introduced to the body, usually by adding or removing a chemical group to inactivate the drug or make it water-soluble so that it can be excreted more readily. The liver does this to substances your body makes naturally, too; when red blood cells die (they only live about 120 days), the liver modifies the remnants, recycles them, and converts the waste products to a form your body can easily get rid of.

There's an enzyme called COMT (or catechol-O-methyl transferase) that's responsible for breaking down neurotransmitters like epinephrine (also called adrenaline, depending on which side of the pond you're on), norepinephrine, and dopamine. If we gave dopamine by mouth, COMT in the liver would rapidly inactivate most of the dose, assuming it were absorbed across the intestinal membrane.

So give a higher dose, you say. Or give it by some other route. You can bypass the liver in a lot of different ways; inhalation, injection, tablets absorbed through the cheek or under the tongue, skin patches or creams...

Let's go for broke and say we inject ADHD patients with dopamine shots like we give insulin to diabetics. What's going to happen?

Increased heart rate, first of all. Dopamine acts directly on the heart. It has different functions in different parts of the body, though dopamine isn't the primary regulator of heart rate (that would be due to the combined efforts of epinephrine and acetylcholine, which is also the neurotransmitter that is responsible for muscle contractions). It will increase blood pressure, too. Same side-effects as amphetamines, more or less. In fact, dopamine is sometimes used in emergency situations to raise patient BP and heart rate (though a synthetic alternative, dobutamine, is actually better for the task). But isn't it a more natural way to deal with dopamine insufficiency in the brain?

Nope. Here's why.

The blood-brain barrier is essentially the brain's defensive perimeter. It is composed of tightly-jammed cells that are designed to keep out miscellaneous poisons and waste products to prevent damage to the central nervous system. In order for a drug to affect the brain, it has to cross the BBB. Lots of drugs do. But dopamine doesn't. The brain would like to keep the dopamine it the brain. The BBB prevents dopamine from escaping or entering.

Let's summarize. Extensive metabolism will break down an oral dose of dopamine very quickly. And even if we bypass the liver, the dopamine will never enter the brain. We'd have to inject the dopamine directly into the brain with a long needle. Try to get your kid to hold still while you do that. Even if we could get dopamine directly into the brain, neurons are good at recycling or re-absorbing stray neurotransmitters. The best case scenario is that we'd get a very brief improvement. The worst case scenario is that we'd go overboard on the dopamine level and the kid would have hallucinations.

Dopamine, in short, is a crappy drug. The solution is to give other substances (amphetamines) that indirectly increase dopamine levels to push the brain in the right direction. And you know what? It works. Sometimes the chemical your body would use to naturally regulate a function isn't something we can easily replace or modify directly.

So that's why we give hyperactive kids uppers to chill them out. It seems counterintuitive at first, but there is a good explanation. And the theory behind the dopamine hypothesis holds up in clinical trials; kids (and adults) treated with amphetamine do get better.

Isn't pharmacology fascinating?

Wednesday, February 6, 2008

Oops, I Patented Your Natural Product

What are good ways to lower your cholesterol? You could eat less cholesterol. That helps, but the human liver is great at making cholesterol. In fact, it tends to do so pretty much constantly--but entertainingly enough, the liver works the hardest at producing LDL cholesterol (the "bad" cholesterol) while you're sleeping. No, you shouldn't give up sleep. But what's worth recognizing is that diet isn't the only source of cholesterol, and in fact, the liver probably contributes more bad cholesterol than diet. In fact, removing part of the liver reduced circulating LDL concentrations in animal studies. You could also exercise, drink less alcohol, and give up smoking. All of these things work. But what if they aren't enough?

Statins are a popular target for proponents of "alternative medicine." You don't need statins, they say, you can just take vitamins and eat healthy. Sometimes they promote other unproven supplements or "treatments." Statins are dangerous. Statins are worthless. The lipid hypothesis is false; scientists are lying to you and cholesterol has nothing to do with cardiovascular disease. Here, drink this Kool-aid.

Pigs fed high-cholesterol diets are more likely to develop cardiovascular disease (CVD). And Watanabe rabbits lack a specific gene that prevents them from manufacturing receptors for LDL cholesterol in the liver. Normally, the liver's LDL receptors sense circulating cholesterol levels as a regulatory mechanism; if there's a lot of cholesterol floating around, the liver will react by making less cholesterol. Since the rabbits' livers are unable to compensate for high levels of LDL, they develop arterial plaques with astounding frequency. If fed a high-cholesterol diet, the rate and probability of plaque formation increases. And if animal studies aren't good enough, check out the Framingham heart study, which involves an entire town in Massachusetts that's been followed for three generations to learn more about CVD risk factors. Scientists didn't just pull the lipid hypothesis of atherosclerosis out of thin air. There's a lot of very thorough research and credible data that's been taken into consideration.

All the attempts to "debunk" the lipid hypothesis and the value of statins are crackpottery. Are they miracle drugs or cure-alls? Of course not; no one says they are.

Anyway. "Natural" methods for treating illness are popular with a lot of patients. There's something wholesome-sounding about the word, like your mother would want you to take natural products. Nevermind that natural does not mean safe; botulinum toxin is one of the most dangerous substances in the world, and it's made by bacteria. All-natural! Maybe that's why people are willing to inject it into their faces to get rid of wrinkles.

Here's a secret. Statins are natural.

Have you heard of red yeast rice? It's an interesting product. Monascus purpureus, a fungus that grows on rice, produces a wide variety of chemical compounds, including a group called mevinic acids. Naturally fermented red rice yeast is about 0.4% mevinic acids by weight. Red yeast rice supplements are not always what they claim to be on the label, but there's presumably some statin-equivalent content in there.

How about mevastatin? Mevastatin was isolated from Penicillium citrinum mold. Man, mold is great stuff. We play with mold long enough and we have this interesting tendency to serendipitiously find antibiotics and anti-cancer compounds.

Like penicillin, statins were originally isolated as naturally-occuring substances. The major mevinic acid compound in red yeast rice was named lovastatin. And guess what? It got patented. It's called Mevacor. Huh. I thought the natural medicine folks were always saying that the reason Big Pharma isn't willing to seriously investigate "natural remedies" is because they can't be patented?

That claim, of course, is a load of Penicillium fungus. Sure, you can't patent vitamin C, but you can patent unique compounds that you discover, no matter where they come from. Statins are some of the top money-makers for Pharma today (for better or for worse), and they got their start in yeast and mold colonies. Pharma would have to be incredibly to stupid to ignore nature as a potential source for useful drug compounds. It's true that most of the statins prescribed are synthetic compounds like simvastatin (Zocor). But simvastatin was made by modifying lovastatin to increase its effectiveness. Inspired by nature, proven by science. Saying Zocor is unnatural is like saying cutting trees into two-by-fours to build houses instead of just using felled logs is unnatural. By altering a naturally-occuring substance, we can make it a better drug than it would be otherwise.

If something proves to be useful, medicine will use it, whether it's "natural" or not--a false dichotomy to begin with. And if it isn't, medicine will discard it. Scientific analysis is the only way to tell the difference. And anyone who tries to tell you differently needs to go read about penicillin.

Rx Essentials: Are They Really?

You may have seen a product line on the shelves recently called RxEssentials. The marketing for these new vitamin supplements is actually pretty slick; Nature Made is a big company, and they do produce some quality products. A lot of their supplements are USP Verified, which means that the United States Pharmacopoeia has verified that what's on the label is what's in the bottle. Always a good thing. I have to commend them for going the extra mile to meet those standards.

RxEssentials, on the other hand, is a clever way to get you to pay more for your vitamins than you would otherwise.

The basic claim behind RxEssentials is that each formulation supplies key nutrients for people taking specific medications. Sometimes this is the case because the drug blocks or reduces nutrient absorption; in other cases, the manufacturers seem to be taking a page out of Pauling's orthomolecular medicine, which posits that nutritional deficiencies (or, for extra woo flavoring, "imbalances") are the root cause of basically every disease ever. There's a little bit of truth to some of this reasoning. Some drugs do reduce absorption of specific vitamins or minerals. Isoniazid, which is used to treat tuberculosis, can reduce vitamin B6 levels to the point where patients may actually suffer neurological problems if they fail to supplement. And methotrexate, an immune system modifying drug, is usually given with folic acid to prevent deficiency--methotrexate actually works by inhibiting the conversion of folic acid to its active form, tetrahydrofolate.

So let's look closely at RxEssentials. What do they offer that your basic multivitamin might not? They cost, on average, about $10 a bottle for 60 tablets, a two-month supply.

The arthritis formula is recommended for anyone taking ibuprofen, naproxen, or aspirin to relieve arthritis pain. It contains vitamin C, vitamin D, and folic acid. Fail. None of these drugs are going to significantly impair absorption of these nutrients, and most of that 500 mg of vitamin C is going to end up excreted in the urine. Vitamin C is abundant in the diet, and vitamin C tablets are dirt cheap ($6 for 250 tablets is pretty common). The most valuable component of the formula might be the vitamin D; most people with arthritis are older, and most older people get insufficient vitamin D. But vitamin D isn't expensive, either. An inexpensive multivitamin a day is going to cover everything.

The cholesterol formula is designed for patients on statin drugs--Lipitor, Zocor, or their close cousins. As expected, it contains CoQ10. Oh, and B-vitamins, but those are in everything, including bread. CoQ10, or coenzyme Q10, is commenly touted as a means of preventing muscle damage due to statin use. Unfortunately, the evidence doesn't hold up. Some studies show benefit; others don't. One study using 200 mg of CoQ10 daily showed no benefit but noted that patients might respond due to the placebo effect. Another showed some benefit with a 100 mg dose. The evidence is inconclusive. CoQ10 is also kind of expensive, as much as $20 for a bottle of 30 softgels containing 100 mg each. RxEssentials might actually be the better buy if you're dying to try CoQ10, but that's not saying much.

I have to admit that I find the depression formula particularly lacking. B-vitamins, folic acid (maybe for pregnant, depressed women?) and vitamin D. Yes, it's the old "depression is caused by vitamin deficiencies" gambit, except that they're telling you to stay on your Zoloft or Prozac and "supplement." More orthomolecular medicine at work. B-vitamins are important cofactors in energy production; the idea is that a lack of B-vitamins results in "decreased energy," which somehow translates into "depressed mood," "sleep disturbances," "loss of pleasure in daily activities," and, my personal favorite, "suicidal ideations." There is no evidence whatsoever that nutrient deficiency is a primary cause of depression; B-vitamin deficiencies can cause neurological problems, but B-vitamins are so prevalent in the diet that hardly anyone has a problem meeting their needs. You're going to get all this stuff in your (much cheaper) multivitamin. Vitamin D is great for bone health, but store brands are generally cheaper. The manufacturers are clearly assuming depressed people don't get enough sun.

I was really hoping that they'd get their heartburn formula right. An acidic environment is important for the absorption of iron, and chronic acid-suppression therapy coupled with low iron intake creates a situation where deficiency is a very real possibility. Except that there's no iron in the supplement! None! Instead, they're pushing B-vitamins again. B-vitamins are a very necessary component of nutrition. They aren't worth paying a lot of money for; they're in everything, including enriched flour, grains, vegetables, bananas, and even beer (although alcoholic beverages are not a good source of nutrients and chronic alcohol consumption, in excess, can cause other problems). Oh, and they throw in some calcium, but only 120 mg per dose. For reference, most people need 1200 to 1500 mg of calcium per day in divided doses (you can only absorb 500 mg "at a time"). It would've been easy to formulate an iron-replacement regimen for patients with acid reflux; I can't believe they blew this one.

Finally, we have the diabetes formula. In case you hadn't guessed by now, their supplement for diabetics includes--yeah, it really should've been obvious--B-vitamins! Oh, and folic acid. We wouldn't want anyone giving birth to babies with neural tube defects. Except that, of course, that's not why the manufacturers chose to include folic acid in the supplement; it's to "maintain energy." Argh! Yes, patients with diabetes have problems with "energy" metabolism; they can't properly utilize glucose to fuel cells because they produce insufficient insulin. But taking extra B-vitamins doesn't help the body utilize glucose any better, unlike oral diabetes medications or insulin injections.

To summarize, RxEssentials gets the big thumbs-down. The manufacturers claim that RxEssentials "provide specially selected nutrients." But as you can see, most of the products contain the same ingredients: B-vitamins and folic acid. At least they're being responsible and telling people that RxEssentials are not a replacement for their prescription drugs.

There are therapeutic precedents for taking specific nutrient supplements for various conditions or with particular medications. I already mentioned a few. But any responsible physician is going to prescribe those nutrients alongside the medication--especially if serious harm will result from not having them. Note that none of these products are for people on methotrexate! Arbitrarily deciding you need to supplement is a waste of time and money.

So what should you do if you think you have a nutritional deficiency? Talk to your doctor. Evaluate your diet with information from appropriate food guides. Nutritional deficiencies have a set of clear diagnostic criteria; less-specific concerns like "I feel tired sometimes" or "I get a lot of colds" are generally not indicative of a problem. Everyone feels tired sometimes. B-vitamins are not effective in reducing the effects of "stress" or a replacement for a good night's sleep. You probably don't need RxEssentials. And even if you did, a cheaper multivitamin would offer the same benefits.

Like most dietary supplements, RxEssentials relies on good marketing to make sales. It's too bad that marketing is all they have.

Saturday, February 2, 2008

Alternative Flying

I'm incredibly amused by this recent offering by Science-based Medicine. Here's a small taste:

Current airplane design is based upon a white male Western European model of what powered flight should look like. Long metal tubes with wings are a phallic design that insults the sensibilities of women, who have an alternative, more natural, emotional, way of understanding airplane design. In the one size fits all design of allopathic airlines, alternative designs are ignored and airplane design utilizing the ideas and esthetics of indigenous peoples and ancient flying traditions are derided as primitive and unscientific, despite centuries of successful use.

I don't think I've laughed so hard in quite a while. Isn't it great how painfully ridiculous the notions of "faith-based treatment" become when applied to any other area?

Friday, February 1, 2008

Skeptico: Extraordinary Claims and Extraordinary Evidence

Skeptico has posted a brilliant entry about why extraordinary claims require extraordinary proof. It's a common phrase, but Skeptico has done a remarkably good job of explaining its significance.

Link courtesy of PalMD's WhiteCoat Underground, another fantastic skepticism/critical thinking blog with a medical angle.