– If the U.S. is concerned about the quality of raw heparin imported from China, the Americans need to make sure the proper controls are in place, China’s State Food and Drug Administration said last week.

The Chinese FDA said it works with foreign regulators to monitor factories, but the ultimate responsibility for “safeguarding the legality, quality and safety of active pharmaceutical ingredients” lies with the importing nation, the WSJ’s Gordon Fairclough reports.

A version of the blood thinner heparin, sold by Baxter International, has been associated with illnesses and deaths in this country. Some of the key raw ingredient for the drug comes from China. In today’s statement, China’s FDA put concerns about the Chinese product at arm’s length, noting that the Chinese manufacturer that supplied the raw heparin is majority U.S. owned, its production technology was supplied by an American firm and all of its output was exported to the U.S.

Chinese producers of active pharmaceutical ingredients must be drug companies that are “registered and certified” by the Chinese FDA, an agency spokeswoman told the WSJ. Foreign buyers should confirm this certification and importing countries “should make strict tests” on ingredients. The company that sold the raw heparin used by Baxter wasn’t certified by the Chinese FDA because it was registered as a chemical company, not a drug company.

The WSJ’s Gordon Fairclough snapped this picture at the Yuan Intestine & Casing Factory, where men “wring pulp from pig intestines, then heat it in concrete vats.”

Heparin sold by Baxter International in the U.S. has recently been associated with hundreds of adverse reactions and a few deaths. Scientific Protein Laboratories, Baxter’s main supplier of the active ingredient in the blood thinner, says that the Yuan Intestine & Casing Factory isn’t in its company’s supply chain.

But the company does have a joint-venture that sources raw heparin, which is derived from pig intestines, from a handful of Chinese facilities. It’s not clear whether the Chinese operation is the source of the ingredients that seem to be causing harm in patients who receive the blood thinner.

Still, the heparin issue is raising questions over whether heparin makers should be able to track their product back to individual pigs. The drug goes through a complex purification process between pig and person, which some regulators say eliminates the need to identify the source animal. Others argue, though, that even the raw materials should be traceable in order to quickly contain any problems that arise.

Raw heparin makers have come under some scrutiny in China, but that wasn’t really about drug safety. In 2006, the WSJ reports, authorities shut down 16 companies making heparin and chondroitin sulphate, an ingredient in arthritis medications derived from animal cartilage, for illegally discharging waste water. (For more on the production of heparin, click on the image at right to see a slideshow.)
In another case, officials closed sausage-casing companies that were producing heparin on the side. Dirty water on the floor of one factory contained ten-centimeter-long worms, according to a local paper that covered the case.

News From

Heparin Discovery May Point to Chinese Counterfeiting

New York Times – Mar. 20, 2008

Federal drug regulators, in announcing Wednesday that the mystery contaminant in heparin was an inexpensive, unapproved ingredient altered to mimic the real thing, moved closer to concluding that Americans might be the latest victims of lethal Chinese drug counterfeiting.

The finding by the Food and Drug Administration culminated a worldwide race to identify the substance discovered early this month in certain batches of heparin, the blood-thinning drug that had been linked to 19 deaths in the United States and hundreds of allergic reactions.

The contaminant, the regulators said, is a chemically altered form of chondroitin sulfate, a dietary supplement made from animal cartilage that is widely used to treat joint pain. The agency’s announcement followed a report Wednesday in The New York Times that was the first publicly to identify the modified substance as the likely contaminant. That report was based on nearly two dozen interviews with researchers and scientists in China, the United States and Canada.

Federal officials stopped short of saying that the contaminant — constituting as much as 50 percent of the active ingredient in heparin — was counterfeit. ”At the moment we don’t know definitely whether the contaminant was introduced intentionally or by accident,” said Dr. Janet Woodcock, director of the Food and Drug Administration’s center for drug evaluation and research.

Even so, the authorities left little doubt that they believed that the contaminant was not an unintended byproduct of some manufacturing process.

In its natural state, chondroitin sulfate does not have anticlotting properties. But it mimics heparin when altered to form what is called oversulfated chondroitin sulfate. That is what made it difficult for Baxter International, the manufacturer of the heparin associated with the allergic reactions, to detect the impurity. ”This compound to our knowledge is not naturally occurring,” Dr. Woodcock said. ”It should not be in heparin. And it obviously should not be in the form it is in.”

While identifying the contaminant was a significant breakthrough, investigators still do not know if it is responsible for causing the allergic reactions. Nor do they know why the modified ingredient ended up in heparin, though they have raised the possibility that the substance was used as cheap filler.

”The base compound, chondroitin sulfate, is very abundant and an inexpensive compound,” said Moheb Nasr, director of the agency’s office of new drug quality and assessment. Chemically modifying it, Mr. Nasr added, ”will not be that expensive either.”

The F.D.A. said it had found the contaminated heparin at Changzhou SPL, the Chinese plant that supplies the active ingredient to Baxter. Changzhou in turn buys its heparin from two companies, called consolidators, that gather crude heparin from workshops that make it from pig intestines.

Many workshops that make crude heparin are unregulated family operations.

Erin Gardiner, a spokeswoman for Baxter, said Wednesday that tests found the supplies were contaminated before they arrived at the Changzhou plant. ”The consolidators and workshops handle the crude material, so that is where our focus is turning,” Ms. Gardiner said.

So far, Ms. Gardiner said Baxter’s investigators had been denied access to the consolidators and workshops. ”We will continue to seek access.”

Last week, the F.D.A. said it had not yet visited the workshops.

Some heparin producers in China also sell chondroitin sulfate, which can be derived from pig cartilage. Traders and producers say it is far cheaper than heparin, as little as one-twentieth the cost. That could be an enticement for counterfeiters, especially in the wake of a virulent pig virus that swept across China last year, substantially reducing the availability of the starting materials needed to make the active ingredient in heparin.

Contaminated heparin sourced from China has also turned up recently in Germany, where about 80 allergic reactions have been reported. But investigators there have yet to identify the contaminant. F.D.A. officials said their discovery of chemically modified chondroitin sulfate came exactly one year after the discovery that a pet food ingredient shipped from China contained toxic levels of melamine, which was added to make it appear higher in protein. Many pets became ill, and some died.

Around the same time, The Times reported that an unlicensed Chinese chemical plant sold a cheap counterfeit ingredient, diethylene glycol, that was mixed into cold medicine in Panama, killing nearly 120 people and disabling dozens more.

Diethylene glycol mimics its more expensive chemical cousin, glycerine, a safe ingredient used in medicine, food and toothpaste.

The F.D.A. said its search for answers in the heparin case had been made easier because of the cooperation it had received from China’s State Food and Drug Administration. That was not the case when United States officials inquired last year about the melamine and diethylene glycol.

The agency cited an accord signed in December by the governments of China and the United States as one reason for the cooperation they had received recently, which they said allowed American investigators to quickly begin their investigation of the additive.

Baxter has recalled virtually all of its heparin products. The F.D.A. has also asked that all heparin entering the country be stopped and tested for the contaminant. Heparin is commonly used in dialysis and cardiac surgery. ”We feel doctors and patients can be confident that the product on the market for the large volume uses of heparin, for dialysis and so forth, has been tested and is safe,” Dr. Woodcock said.

Harvard University Medical School

Reactions to Common Heart Medications

March 2008

Harvard University Medical School – Bad reactions to a prescribed medication send more than 175,000 older Americans to the emergency room each year. Just 10 commonly used medications—almost all of them for heart disease or diabetes— account for half of these reactions. The March 2008 issue of the Harvard Heart Letter offers tips about safely taking these important but potentially tricky medications.

Warfarin: Check your bleeding time (INR) regularly. Take care if you are also taking a nonsteroidal anti-inflammatory drug such as aspirin, ibuprofen, or naproxen. Keep your intake of green, leafy vegetables and alcohol steady from day to day.

Insulin: Check your blood sugar several times a day. Take care to store your insulin properly and carry a ready supply. Be aware of the signs of low blood sugar.

Digoxin: Check your pulse when you are calm and relaxed. If it is slower than it should be, call your doctor. Take care if you begin using an over-the-counter medication that may interfere with digoxin, such as antacids, cold or sinus medicine, or laxatives. Call your doctor if you experience vision changes, drowsiness, or confusion.

Aspirin and clopidogrel: Check that you are taking the right dose at the recommended times. Take care when you are using these medications together or with warfarin. Call your doctor if you experience any bleeding warning signs.

Oral medications for diabetes: Check your blood sugar as your doctor directs. Take care with these drugs if you have any type of kidney or heart disease. Be aware of the signs of low blood sugar.

Dangers of Hookah Smoking

March 2008

Harvard University Medical School – A new fad among college students and other young people—smoking from a hookah—is raising public health concerns. The centuries-old tradition of smoking from a hookah, or waterpipe, is widely perceived to be less harmful and addictive than smoking cigarettes or other forms of tobacco. Yet a number of studies suggest that hookah smoking may be just as addictive and perhaps even more harmful because of the way people smoke while using a waterpipe, reports the March 2008 issue of the Harvard Mental Health Letter.

Researchers have found that hookah smokers inhale more often and for longer periods than typical cigarette smokers. Scientists estimate that by puffing longer and in greater volume, a waterpipe smoker inhales the equivalent of 100 cigarettes or more during a single waterpipe session.

Proponents of hookah smoking argue that it isn’t necessary to inhale the smoke into the lungs. Instead they puff as if on a pipe—and believe this reduces the health hazards. However, studies indicate that hookah smokers are absorbing high levels of toxins and carcinogens that may contribute to heart disease, lung cancer, and respiratory disease. And although some nicotine is filtered through the water contained at the base of the pipe, scientists conclude that waterpipe smokers are still exposed to enough nicotine to become addicted.

Dr. Michael Miller, editor in chief of the Harvard Mental Health Letter, suggests that until more is known about how to help hookah smokers quit, clinicians and smokers should be aware of the potential dangers.

Folic Acid and Cancer Risk

March 2008

For 20 years, the United States has been fortifying some foods with folic acid (the synthetic form of folate, a B vitamin) as part of a public health effort to prevent neural tube defects in newborns. The effort is paying off: the rate of neural tube defects is down by 30%. But there’s also evidence that the added folic acid is contributing to colorectal cancers, reports the March 2008 issue of Harvard Women’s Health Watch.

In the early years after folic acid fortification was mandated, the average level of folate in the blood of Americans nearly doubled. During that same period, a 15-year decline in colorectal cancers suddenly reversed. Although this link is not proof of cause and effect, there are biological reasons why extra folic acid may be to blame.

Only long-term monitoring can reveal whether fortifying foods with folic acid is safe—and clarify who is more (or less) likely to benefit. For now, unless you’re pregnant, lactating, or have a recognized folate deficiency, the daily recommended intake of folic acid is 400 mcg—the amount found in a multivitamin. The maximum safe amount from fortified foods and supplements is 1,000 mcg per day. With all the folic acid in fortified foods, you may exceed that limit, especially if you are taking a multivitamin. So it’s a good idea to check nutrition labels and make sure your daily folic acid intake is within bounds.

Harvard Women’s Health Watch notes there’s no known health risk from foods naturally high in folate, so try to get much of your daily requirement from a diet rich in fruits and vegetables.