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The FDA tackles tainted drugs from China

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(This story was #3 in Discover Magazine’s top 100 stories of 2008.)

Following a series of high-profile scandals concerning tainted food and drugs imported from China, the U.S. Food and Drug Administration (FDA) announced in March that it would establish a drug-monitoring office in that country.

The most alarming report involved contaminated batches of the blood thinner heparin, which caused at least three deaths and is under suspicion in dozens of others. In February FDA officials admitted that they had never inspected Changzhou SPL, the manufacturing plant in Changzhou, China, to which they traced the contaminated heparin. When the FDA eventually inspected the Changzhou SPL plant (in February), it found a host of quality-control and hygiene problems.

Many drugs sold in the American marketplace are now imported, transforming what was once largely a domestic agency to one that must police products from more than 200 countries, notes Murray M. Lumpkin, FDA deputy commissioner for international and special programs. “The reality of globalization has hit the products for which we’re responsible very, very significantly,” he says. The pharmaceutical production process is also vastly more complex than it used to be. Individual ingredients are made in one place, put together in another, and bottled and labeled in still other sites.

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Two Alzheimer’s drugs show promise

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(This story was #18 in Discover magazine’s top 100 stories of 2008.)

Two unconventional treatments for Alzheimer’s disease show promising early results. Both Rember (methylthioninium chloride) and Dimebon (dimebolin hydrochloride) appear to slow the mental decline associated with the illness.

No effective medicines exist for Alzheimer’s, which is estimated to afflict more than 4 million people in the United States alone. The disease is characterized by a decline in cognition and function and usually strikes after age 60. Most Alzheimer’s treatments have targeted amyloid, the main protein component of the associated plaques that form in the brain; Rember is the first to target the tangled, abnormal fibers of a protein called tau. At an Alzheimer’s conference in Chicago, the drug, made by TauRx Therapeutics, was reported to slow the progress of mild to moderate Alzheimer’s disease by 81 percent over the course of a year. In a phase 2 trial of 321 people with mild to moderate disease, those on the drug stayed at about the same cognitive level for up to 19 months, while those on the placebo got worse. A final trial is expected to begin in 2009.

The second drug, Dimebon, is an allergy drug used in Russia 20 years ago. A Lancet article in July reported that over 26 weeks of treatment, Dimebon significantly improved memory, thinking, and overall functioning in 68 Alzheimer’s patients, compared with a 66-member control group. Although researchers don’t know exactly how Dimebon does this, it may work by protecting mitochondria—the powerhouses of cells—from injury, says Rachelle Doody, the study’s lead author and a neurology professor at Baylor College of Medicine in Houston. A phase 3 trial for the drug began recruiting participants in June.

Cholesterol drugs are prescribed for high-risk kids

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(This article was #38 in Discover Magazine’s top 100 stories of 2008.)

In July, in an update of a 1998 policy statement, the American Academy of Pediatrics (AAP) recommended dropping the age at which at-risk children should be given statins—a class of cholesterol-lowering medication—from 10 years old to 8 years. The drugs would be prescribed to children with an LDL (the “bad” cholesterol) above 190 milligrams per deciliter, or above 160 with a family history of heart disease.

“The idea is to address risk factors as early as possible because we know plaques start to accumulate during infancy,” says Nicolas Stettler, an assistant professor of pediatrics and epidemiology at the Children’s Hospital of Philadelphia and a member of the AAP’s nutrition committee.

Critics say the drugs are a risky fix to broader lifestyle problems. Darshak Sanghavi, chief of pediatric cardiology at the University of Massachusetts Medical School in Worcester, notes that although the FDA has approved some statins for use in children with a genetic problem leading to high cholesterol, there are no studies on the drugs’ long-term side effects in children.

Sanghavi and others also took issue with the AAP’s recommendation of cholesterol screening starting at age 2 for children who are overweight or have other risk factors for heart disease. In this country, that could apply to as many as 10 million children every three to five years. “The screening costs alone will be hundreds of millions of dollars,” Sang­havi says.

New insights into an old foe: TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

WHITE PLAGUE. KING’S EVIL. WASTING disease. Phthisis. Consumption. Tuberculosis (TB) is an old disease with many names and guises. But it wasn’t until last year that scientists discovered how old this ancient scourge really is. Egyptian mummies, skeletal remains, and genetic analysis had all suggested that TB had been around for at least a few thousand years. But in a block of rock mined from a quarry in Western Turkey, anthropologists discovered the fossil of a young male dating back some 500,000 years and infected, unexpectedly, with tuberculosis. They announced in December 2007 that the young man had lesions on the inside of his skull, the imprint of brain membranes that the disease has been ravaging humans for much longer than anyone had ever suspected.

An estimated 2 billion people — nearly one-third of the world’s population — are thought to harbor Mycobacterium tuberculosis (M. tb), the bacterium that causes TB. It grows slowly, lurking in the lungs for years, and outwits the body’s immune system, in part by waiting for the host’s defenses to weaken. In most people, that opportunity never arises, and they show no symptoms of the disease. But once M. tb takes hold, it literally consumes the body from within, eating through lung tissues and the blood vessels that run through it. Every time someone with a full-blown infection speaks, sings, coughs, or sneezes, the bacteria expelled linger in the air for hours, ready to invade the next victim.

This is why TB has so often been a disease of the poor, because it is at its most deadly in overcrowded, unsanitary conditions. In 2006, TB infected 9.2 million people worldwide, claiming the lives of 1.5 million people, most in the developing world. In some parts of South Africa, as many as 70 percent of those with TB are also infected with HIV, because TB is opportunistic.

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Worst case: HIV + TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

When HIV joins forces with TB, the results can be horrific. The neck bulges with lumps as big as an orange, filled with pus-like fluid teeming with the germs that cause TB. Occasionally, these bacteria travel through the blood and lymph vessels, forming lesions in the liver, spleen, and beyond. In chest X-rays, it looks as if the lung were studded with small nodules the size of millet seeds.

This gruesome scenario is rarely seen when TB is the sole affliction. But as HIV ravages the immune system, TB quickly and effortlessly spreads through the body. HIV’s compounding effect on TB has long been known, but recently scientists have discovered that this pernicious partnership works both ways. TB, in turn, eases the path of HIV, dismantling the system that keeps the virus under control in the lungs, allowing it to mutate and multiply.

“If you have HIV and TB, then TB 
will kill you much more rapidly,” notes Michael Weiden, M.D., associate professor of medicine and environmental medicine. In fact, TB is the leading cause of death among people who are HIV-positive, accounting for one-third of AIDS deaths worldwide.

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Fighting drug-resistant TB in New York City

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

For a few weeks last summer, Americans were riveted by news that Andrew Speaker, then a 31-year-old Atlanta native, may have been flying on commercial airplanes, exposing hundreds of people to a virtually untreatable type of tuberculosis (TB).

They could be forgiven for having thought of TB as strictly a third-world disease. In 2006, 13,767 people in the U.S. had TB — the lowest prevalence in the country recorded since 1953 — while elsewhere 1.5 million people died of the disease.

Speaker was diagnosed in early May 2007, but against medical advice he flew to Greece for his wedding later that month. Tracked down in Rome on his honeymoon, he was told he had extensively drug-resistant tuberculosis (XDR-TB) and was asked to stay put.

Instead he and his wife, Sarah, flew to Prague and Montreal and then drove to New York City. On May 24, officials from the Centers for Disease Control and Prevention directed Speaker to report to Bellevue Hospital, where he was served with a federal warrant that isolated him for medical evaluation, the first such order issued in 44 years.

Bellevue is no stranger to TB. The hospital’s Chest Service, established in 1903 to treat the disease, has contributed a great deal of knowledge about its pathophysiology, clinical behavior, and treatment. In the late 1980s and early 1990s, Bellevue endured a long bout with this familiar foe, grappling with nearly 4,000 cases in New York City, many of them homeless people addicted to drugs and infected with HIV.

“I came here and I found everything was all TB and AIDS,” recalls William Rom, M.D., M.P.H., director of the Chest Service.

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Hope grows for new TB test

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

To confirm that you have TB, the doctor will ask you to cough up at least a teaspoonful of phlegm, or sputum. You’ll have to come back to the hospital twice more to provide samples, and technicians will painstakingly culture the slow-growing bacteria from the sputum.
 A few weeks after that third visit — by which point you may have exposed others — the doctor should be able to tell you whether you have TB.

This crude sputum diagnostic test is 100 years old. “The situation is fairly horrendous,” says Dr. Suman Laal, Ph.D., associate professor of pathology and mircrobiology.

There are a
few expensive alternatives: fluorescent microscopy, automated culture systems, and tests for the bacterial DNA. But 90 percent of the disease is concentrated in the poorest parts of the world, where these options are not feasible.

Clinically, TB symptoms can be difficult to distinguish from those of
 other bacterial or fungal infections, pneumonia, or certain tumors. Diagnosis with X-rays is subjective and all but useless 
in people who are HIV-positive, and
 a commonly used skin test gives false positives in anyone who has been immunized with the BCG vaccine or 
has been infected with the TB bug’s bacterial cousins.

The ideal test for TB would be fast, cheap, and would deliver a simple Yes or No answer — much like a dipstick pregnancy test. But developing a test like that has proved challenging.

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Microbiology: Straight from the gut

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(I first heard about gut transplants when I was interviewing Michael Zasloff of Georgetown University for a different piece. The idea that you can transplant someone’s entire intestines blew my mind. None of the Nature editors had ever heard of it, either. The implications–that you can study how bacteria colonize a gut after birth–really make this story compelling. And yes, I got to see some gruesome stuff. I’ll never quite forget the startlingly yellow poop Stuart Kaufman raved about. You can download a pdf of this article.)

The human body teems with microbes. Apoorva Mandavilli meets the surgeons who have a rare opportunity to watch an ecosystem being established as they transplant guts from one person to another.

Dirty business: gut transplants give bacteria and scientists new choices.

Stephanie is the first to admit that she never had the guts for life. She was born with familial adenomatous polyposis, a genetic disorder in which thousands of polyps form in the colon. By the age of 22, much of the organ had to be removed. Four years later, a massive benign tumour choked off the blood supply to her small intestine, so doctors cut out all but a metre of it. For the next six years, she was fed by a tube every night until the feeding left her liver badly scarred and fighting recurring infections. “I was given a month to live,” she says.

That’s when doctors referred Stephanie to Georgetown University Hospital in Washington DC. There, on 17 April 2006, surgeons cut out her stomach and what was left of her small and large intestine and replaced it with new organs from a donor who had died days earlier in Tennessee. “Oesophagus to anus, her entire gastrointestinal tract was in the garbage can,” says Tom Fishbein, who directed the surgery. “She got a brand new one.”

All organ transplants are complicated, but there are only a handful of centres in the United States that have the
 expertise to transplant
 a small intestine, the seven metres of coiled tissue connected up to the stomach at one end and the large intestine at the other. The technique is complicated because the gut is teeming with trillions of bacteria and other microbes, plus the bulk of the body’s lymphocytes.

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Genetic variant predicts heart disease risk

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(This article was originally published in Technology Review online on January 30, 2008.)

A newly identified risk factor for heart disease also seems to indicate which patients will benefit from popular statin therapies.

Heartsick: There have been many false leads in identifying risk genes for heart disease, so the burden of proof for those studies should be much higher than usually required, some experts say.

Testing for a genetic variation could predict the likelihood that a patient will respond well to certain statins. But some researchers say it’s too soon to use the variation to determine treatment.

Researchers from Celera reported yesterday in the Journal of the American College of Cardiology that a single substitution in the sequence of a gene called KIF6 makes people both more susceptible to heart attacks and more responsive to certain drugs that lower cholesterol. Though there is no known biological explanation linking the variation to heart disease, the study found that it increases the risk of heart attacks and strokes by 55 percent.

Celera, the company best known for sequencing the human genome, examined 35 single-nucleotide polymorphisms (SNPs) in 30,000 patients. Of those, “KIF6 is by far the most significant,” says Thomas J. White, chief scientific officer at Celera. In fact, nearly 60 percent of the study population was found to carry the KIF6 variant. (According to the study, these findings take into account other factors, such as smoking, high blood pressure, and cholesterol levels.)

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Cloned hamburger, anyone?

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(This article was #64 in Discover Magazine’s top 100 stories of 2007.)

Meat and milk from cloned cattle, pigs, and goats are safe to eat, the Food and Drug Administration has declared, setting the United States on course to become the first country to approve such products. The agency’s draft risk assessment says food from clones can safely be marketed without any labels to distinguish it.

In an article in the journal Theriogenology last January, agency scientists analyzed dozens of studies—many of them from cloning companies Viagen and Cyagra—and concluded that meat and milk from clones showed no “nutritionally or toxicologically important differences” from products now consumed.

But some advocacy groups aren’t buying it. “We’re very concerned,” says Charles Margulis, spokesman for the Washington-based Center for Food Safety. “We don’t think there’s really enough science to show that clones are safe.”

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