Scientists Near Source Of Altered Heparin

Scientists investigating a mystery contaminant in the blood thinner heparin are closing in on what they believe is a counterfeit substance, most likely made in China from animal cartilage, that was chemically altered to act like the real drug.

The United States Food and Drug Administration declined to confirm that statement and a spokeswoman said the agency would have no comment.

But in interviews, heparin experts in China and the United States — including one researcher involved in the inquiry — said that a chemically altered substance called over-sulfated chondroitin sulfate is probably the contaminant that the F.D.A. says is linked to hundreds of allergic reactions and 19 deaths.

Even so, researchers said they were not certain that the contaminant, constituting between 5 percent and 20 percent of the drug, is what is causing the allergic reactions, nor do they know precisely how or when it was mixed into the active ingredient.

Chondroitin sulfate is a widely used supplement to treat joint pain. In its unaltered state, it does not have the blood-thinning properties found in the contaminant. But scientists and researchers say the act of changing the molecule gives the substance anti-coagulating properties.

Scientists who have examined batches of the contaminated heparin distributed by Baxter International in the United States said in interviews that they suspected that the heparin-like molecule was intentionally mixed into the drug.

“A child could tell you it’s counterfeiting,” said Dr. Jawed Fareed, a professor of pathology and pharmacology at Loyola University Chicago, who has been studying batches of heparin since the problems with the drug were discovered.

Dr. Fareed said he was conducting his own investigation because he was concerned that the quality problems with heparin were far more widespread than acknowledged.

“Of seven or eight batches I have, six are contaminated,” said Dr. Fareed. “And these were used by doctors at Loyola University Medical Center.”

One American chemist, who asked not to be identified because he had signed a confidentiality agreement, said he and the F.D.A. had looked at chondroitin sulfate, a substance derived from animal cartilage, as a possible contaminant because of its structural similarities with heparin. “It is something that is a little bit different,” said the chemist, “like a distant family relative you don’t recognize.”

He added, “Once we have the exact fingerprint, we will try to figure out how it got into the product.”

Zhang Tianmin, 80, a retired professor at the Shandong University School of Pharmaceutical Sciences, said counterfeiters would likely choose chondroitin sulfate, from animal cartilage, or chitosan, from shellfish, as a base substance to create a heparin-like molecule, because both substances are cheap.

But since neither has natural blood-thinning activity, counterfeiters would have to add something that does.

“Sulfate groups appear naturally in the heparin molecule,” Mr. Zhang said, “but they can also be produced by chemical synthesis.”

On March 5, the Food and Drug Administration announced that its scientists had found a “heparin-like compound that is not heparin” in batches of the drug sold by Baxter. The molecule bore such a close resemblance to heparin that it had fooled standard quality tests and made it into the United States drug supply.

Earlier this month, German health authorities notified the F.D.A. of 80 adverse reactions to heparin that had been sourced from China.

The F.D.A. has said it has the world’s top heparin chemists working on the contaminant at two F.D.A. laboratories, three American universities and several European academic institutions. There are more than a dozen scientists working to identify the contaminant, or contaminants, an F.D.A. spokeswoman said.

Chinese investigators are “working with the F.D.A. to do our best to find the root cause of these adverse reactions,” said a spokeswoman for China’s drug agency, Yan Jiangying. “China has not had reports of adverse reactions that resemble those in the United States.”

Tang Haitao, president of Guanglong Biochemical Factory in eastern Shandong Province, said Chinese drug regulators made a surprise visit to his factory on Sunday, suggesting that a broader sweep is under way. Mr. Tang said he told regulators his company did not produce heparin anymore.

Cui Huifei, a heparin expert at Shandong University School of Medicine, said, “It appears that a foreign substance has been added.”

Baxter has recalled virtually all of its heparin products in the United States and since that recall there have been no new deaths, the F.D.A. said last week.

As of last week, F.D.A. and Baxter said they had not visited any workshops that make crude heparin from pig intestines. Many of them are family owned and are largely unregulated.

Dr. Fareed said it was too early to say whether the contaminant is causing the adverse reactions. A variety of reactions have been observed, including abdominal pain, hypotension, burning sensation, vomiting, diarrhea, rising temperature and anaphylaxis, he said, “but one cannot link all of these to one substance.”

“This is a deliberate act of chemically manipulating a heparin-like substance and mixing it with heparin to increase the yield,” he added.

But some batches of heparin containing the contaminant did not elicit adverse reactions, casting uncertainty on their root cause, Dr. Fareed said.

Scientists interviewed by The New York Times had different views about whether such an over sulfated molecule could occur naturally.

The F.D.A., Baxter International, and Scientific Protein Laboratories, the company whose Chinese plant produced the active ingredient in the tainted batches, are all conducting independent inquiries, according to a scientist participating in the investigation.

External experts hired by each share their findings with the F.D.A., though they do not talk with one another because of non-disclosure agreements.

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