Day 711: When 500,000 Americans Died and Nobody Noticed

A Redditor dredged this 2012 Vioxx story out of the wayback machine (the live page is paywalled). Once again, it stars crazed madman Ron Unz, doing the math that nobody else bothered to. In this case he extrapolates 500,000 deaths from Vioxx out of the excess mortality for the years it was on the market:

Senior FDA officials apologised for their lack of effective oversight and promised to do better in the future. The Vioxx scandal began to sink into the vast marsh of semi-forgotten international pharmaceutical scandals.

Then in 2005, as he now remembers it, Ron Unz "was reading my morning newspapers, as I always do, and noticed tiny items about an unprecedented drop in the American death rate. Hmm I said, I wonder if that might have anything to do with all those other stories about that deadly drug recently taken off the market and all the resulting lawsuits."

The year after Vioxx was pulled from the market, the New York Times and other media outlets were running minor news items, usually down-column, noting that American death rates had undergone a striking and completely unexpected decline. These were what Unz, a dedicated news browser, was reading.

Typical was the headline on a short article that ran in the 19 April 2005 edition of USA Today: 'USA Records Largest Drop in Annual Deaths in at Least 60 Years.' During that one year, American deaths fell by 50,000 despite the growth in both the size and the age of the nation's population. Government health experts were quoted as being greatly "surprised" and "scratching [their] heads" over this strange anomaly, which was led by a sharp drop in fatal heart attacks.

[...] Unz went back to those 2005 stories. Quick scrutiny of the most recent 15 years worth of national mortality data provided on the US Government's Centers for Disease Control and Prevention website offered Unz some useful clues.

"We find the largest rise in American mortality rates occurred in 1999, the year Vioxx was introduced, while the largest drop occurred in 2004, the year it was withdrawn," says Unz. "Vioxx was almost entirely marketed to the elderly, and these substantial changes in the national death-rate were completely concentrated within the 65-plus population.

"The FDA studies had proven that use of Vioxx led to deaths from cardiovascular diseases such as heart attacks and strokes, and these were exactly the factors driving the changes in national mortality rates."

The impact of these shifts, Unz points out, was not small. After a decade of remaining roughly constant, the overall American death rate began a substantial decline in 2004, soon falling by approximately five per cent, despite the continued ageing of the population. This drop corresponds to roughly 100,000 fewer deaths per year. The age-adjusted decline in death rates was considerably greater.

"Patterns of cause and effect cannot easily be proven," Unz continues. "But if we hypothesise a direct connection between the recall of a class of very popular drugs proven to cause fatal heart attacks and other deadly illnesses with an immediate drop in the national rate of fatal heart attacks and other deadly illnesses, then the statistical implications are quite serious."

Unz makes the point that the users of Vioxx were almost all elderly, and it was not possible to determine whether a particular victim's heart attack had been caused by Vioxx or other factors. But he concludes: "Perhaps 500,000 or more premature American deaths may have resulted from Vioxx [the author's italics], a figure substantially larger than the 3,468 deaths of named individuals acknowledged by Merck during the settlement of its lawsuit. And almost no one among our political or media elites seems to know or care about this possibility."

The Reddit thread also implicates Pfizer's related withdrawn drug, Bextra, which, while deadly enough, doesn't seem to have been quite the silent overlooked killer that Vioxx was.

The moral of this story is don't be so sure that you'd necessarily notice hundreds of thousands of excess deaths due to heart complications of a wonder drug that the drug company knew about all along.

In local news, an intrepid PlagueBlog reporter notes that the COVID sewage numbers are no longer shooting straight up.

P.S. Massachusetts cases were up about 1.5% for the Tuesday lull.

Cold on the Trail of the Tylenol Killer

Via Universal Hub: Boston.com reports that the FBI and state police searched a Cambridge condo today in connection with the 1982 Tylenol tampering deaths.

The first-floor condominium belongs to James W. Lewis, 62, of 170 Gore St., who spent 12 years in federal prison for trying to extort $1 million from the painkiller's manufacturers but was never charged in the murders. The authorities spent most of the day inside the six-story blonde brick building and also searched a storage facility at an undisclosed location in the city.
The Chicago office of the FBI said in a statement late today that agents, the Illinois State Police, and several local police departments were "conducting a complete review of all evidence developed in connection with the 1982 Tylenol murders," which prompted dramatic changes in the way almost all food and medical products are packaged.

A Potential Cure for Ebola

Via io9.com: PLoS reports on a potential cure for Ebola.

Here, we use a novel technology to measure penetration of Ebola virus into the cell in real time and show that Ebola virus stimulates phosphoinositide-3 kinase, a signaling molecule known to induce endocytosis. Importantly, drugs that interfere with this signaling inhibit infection by Ebola virus and block virus spread. This work provides a mechanistic insight into how Ebola virus manipulates the cell to start an infection, may explain part of virus induced pathogenesis, and provides a potential way to treat this deadly disease.

Rapamycin

Via Technovelgy:

Rapamycin, a drug approved by the FDA to stop tissue rejection after organ transplants, has been found to reverse the brain dysfunction caused by a genetic disease - tuberous sclerosis complex (TSC).
"This is the first study to demonstrate that the drug rapamycin can repair learning deficits related to a genetic mutation that causes autism in humans. The same mutation in animals produces learning disorders, which we were able to eliminate in adult mice," explained principal investigator Dr. Alcino Silva, professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. "Our work and other recent studies suggest that some forms of mental retardation can be reversed, even in the adult brain."

See Science Daily for more details.

Heavy Drugs

Via Universal Hub: Xconomy reports on a Lexington (Mass.) company that plans to build better drugs with deuterium.

Concert Pharmaceuticals may have found a way to help established drug substances pack a better punch. By substituting a few normal hydrogen atoms with the heavier form, deuterium, the company believes it is possible to create new chemical entities with greater efficacy and fewer side effects. And since these entities are based on proven drugs, the reasoning goes, it will probably take less time and money to take them to the market.

Magic Finger Powder

Via plime: the BBC reports on an Ohio man who allegedly regrew a severed fingertip using his brother's experimental extra-cellular matrix.

"There are all sorts of signals in the body," explains Dr Badylak.
"We have got signals that are good for forming scar, and others that are good for regenerating tissues.
"One way to think about these matrices is that we have taken out many of the stimuli for scar tissue formation and left those signals that were always there anyway for constructive remodelling."
In other words when the extra cellular matrix is put on a wound, scientists believe it stimulates cells in the tissue to grow rather than scar.

Cholesterol Still Good For You

Via Half Sigma again: a New York Times editorial on cholesterol never having hurt a fly. Gary Taubes explains how cholesterol got its undeserved bad reputation:

In the 1950s, two hypotheses competed for attention among heart disease researchers. It had been known for decades that cholesterol was a component of atherosclerotic plaques, and people who have a genetic disorder that causes extremely high cholesterol levels typically have clogged arteries and heart attacks. As new technology enabled them to look more closely at lipoproteins, however, researchers began to suspect that these carrier molecules might play a greater role in cardiovascular disease than the cholesterol inside them. The cholesterol hypothesis dominated, however, because analyzing lipoproteins was still expensive and difficult, while cholesterol tests were easily ordered up by any doctor.
In the late 1960s, biochemists created a simple technique for measuring, more specifically, the cholesterol inside the different kinds of lipoproteins — high-density, low-density and very low-density. The National Institutes of Health financed a handful of studies to determine whether these “cholesterol fractions” could predict the risk of cardiovascular disease. In 1977, the researchers reported their results: total cholesterol turned out to be surprisingly useless as a predictor. Researchers involved with the Framingham Heart Study found that in men and women 50 and older, “total cholesterol per se is not a risk factor for coronary heart disease at all.”
The cholesterol in low-density lipoproteins was deemed a “marginal risk factor” for heart disease. Cholesterol in high-density lipoproteins was easily the best determinant of risk, but with the correlation reversed: the higher the amount, the lower the risk of heart disease.
These findings led directly to the notion that low-density lipoproteins carry “bad” cholesterol and high-density lipoproteins carry “good” cholesterol. And then the precise terminology was jettisoned in favor of the common shorthand. The lipoproteins LDL and HDL became “good cholesterol” and “bad cholesterol,” and the lipoprotein transport vehicle was now conflated with its cholesterol cargo. Lost in translation was the evidence that the causal agent in heart disease might be abnormalities in the lipoproteins themselves.
The truth is, we’ve always had reason to question the idea that cholesterol is an agent of disease. Indeed, what the Framingham researchers meant in 1977 when they described LDL cholesterol as a “marginal risk factor” is that a large proportion of people who suffer heart attacks have relatively low LDL cholesterol.

Cholesterol Declared Good For You

Via Half Sigma: the New York Times reports that the link between "bad" cholesterol and bad outcomes has been torpedoed by two recent studies of non-statin cholesterol-reducing drugs:

In the last 13 months, however, the failures of two important clinical trials have thrown that hypothesis into question.
First, Pfizer stopped development of its experimental cholesterol drug torcetrapib in December 2006, when a trial involving 15,000 patients showed that the medicine caused heart attacks and strokes. That trial — somewhat unusual in that it was conducted before Pfizer sought F.D.A. approval — also showed that torcetrapib lowered LDL cholesterol while raising HDL, or good cholesterol.
Torcetrapib’s failure, Dr. Taylor said, shows that lowering cholesterol alone does not prove a drug will benefit patients.
Then, on Monday, Merck and Schering-Plough announced that Vytorin, which combines Zetia with Zocor, had failed to reduce the growth of fatty arterial plaque in a trial of 720 patients. In fact, patients taking Vytorin actually had more plaque growth than those who took Zocor alone.
Despite those drawbacks, that trial, called Enhance, also showed that patients on Vytorin had lower LDL levels than those on Zocor alone. For the second time in just over a year, a clinical trial found that LDL reduction did not translate into measurable medical benefits.

Statins do help people, but the mechanism may be something other than their cholesterol-lowering effects.

Follica, the Kindest Cut

Via Universal Hub: Xconomy reports on Follica, a biotech startup dedicated to curing baldness.

Cotsarelis, an expert in epithelial stem cells such as those found in the skin, was studying how skin heals and noticed that new hair follicles seemed to be forming in the middle of some of some wounds. He learned that when the skin’s top layers were removed, some cells within the wound revert to a more primitive state (what he calls an “embryonic window”) from which they can develop into either hair or skin. With more research, says Zohar, Cotsarelis found that he “could actually push them to one direction or another.” In a widely read Nature paper published last May, Cotsarelis showed for the first time that it’s possible to create new hair follicles in adult mammals—and to shut down hair growth. He could even grow thicker, darker hair.
Zohar says Follica has further developed this work and filed additional patents to protect the technology. What’s so beautiful about the approach, she says, is that translating it into a treatment for humans involves only devices and drugs that are already on the market. A doctor would first use a microdermabrasion tool, say, or a laser to remove the top layers of the skin—as is already commonly done in a number of dermatologic and cosmetic procedures—knocking some cells back into a primitive state. The doctor can then use this newly created therapeutic window to inject drugs that push the cells to develop along one pathway or another and grow hair or skin. Zohar won’t reveal what drugs Follica is using, except to say that they are small molecule drugs normally taken orally for purposes with no relation to hair growth.

Epilepsy Drugs and Asians

Via the About.com Rare Diseases Blog: the FDA has recommended that persons of Asian ancestry have a genetic test for the HLA-B*1502 gene before taking epilepsy drugs containing carbamazepine, because of the risk of rare skin reactions. Gory pictures are available in this PDF about SJS.

Dopamine Agonies

Google Alerts brought me a very odd story from the Kenilworth Weekly News, in which a masked Parkinson's sufferer accosted a British schoolgirl in her home. But it became somewhat less odd when USA Today reported on the weird obsessions of patients taking too much dopamine agonist:

They still don't have hard-and-fast proof, but as the evidence accumulates, many scientists now say the drugs can kick off compulsive urges in certain people.
And they say the side effect is anything but rare.
At a meeting in Toronto last month, Stacy and other experts reviewed the cases reported so far and concluded that the drugs appear to trigger a syndrome of bad behavior that includes compulsive gambling, shopping, binge eating and an unstoppable urge for sex.
"Fifteen percent of all Parkinson's patients might have this syndrome," Stacy says. If he's right, that could mean as many as 150,000 people in the USA are struggling with out-of-control behavior. Even those numbers may underestimate the problem.

The judge refused to jail the unfortunate patient, and the defense attorney gave a rare but unsurprising glimpse into the NHS:

"He finds everyday life very difficult. He can speak but with an almost uncontrollable stammer at times. Even a month in prison in his condition would be inhumane."
Mr Ward added that Guest, who has the support of his family, needs help, and has an appointment with a doctor at the Queen Elizabeth hospital in Birmingham later in the year.

A Drug for Down Syndrome

United Press International reports on pentylenetetrazole (PTZ) as a treatment for Down Syndrome (trisomy 21):

Craig Garner, Fabian Fernandez and colleagues found that, after they gave mice genetically engineered to develop Down syndrome 17 daily doses of PTZ in milk, they performed as well as their wild-type counterparts when asked to identify novel objects and navigate a maze that simulated difficulties faced by human children and adults with Down syndrome.
The authors said that they thought this occurred because PTZ blocks the action of a neurotransmitter called GABA that is overproduced in people with Down syndrome and inhibits their ability to learn. When the amount of GABA in the brain was brought into balance with other neurotransmitters, normal learning was possible.

If you're wondering how they gave mice, who only have 20 pairs of chromosomes to start with, a trisomy for a chromosome they don't have, here's a BBC report from 2005 on doing just that.

DCA Research Page

The University of Alberta now has a webpage of DCA Reseach Information, including plans for clinical trials:

Investigators at the University of Alberta have recently reported that a drug previously used in humans for the treatment of rare disorders of metabolism is also able to cause tumor regression in a number of human cancers growing in animals. This drug, dichloroacetate (DCA), appears to suppress the growth of cancer cells without affecting normal cells, suggesting that it might not have the dramatic side effects of standard chemotherapies.
At this point, the University of Alberta, the Alberta Cancer Board and Capital Health do not condone or advise the use of dichloroacetate (DCA) in human beings for the treatment of cancer since no human beings have gone through clinical trials using DCA to treat cancer. However, the University of Alberta and the Alberta Cancer Board are committed to performing clinical trials in the immediate future in consultation with regulatory agencies such as Health Canada.

A Cure for Cancer?

Via GeekPress: NewScientist.com reports on dichloroacetate (DCA), a cheap, unpatented potential cancer drug:

Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.

Survector

Anti-depressants are outside of my purview, but I enjoyed Jeff Percifield's history of Survector. Get your own Survector from amineptine.com.