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China, Heparin, And Heterogeneity

The antithrombin-III binding domain of heparin illustrates the chemical variety of the drug.

Back in 2007 and 2008, tainted heparin from China was responsible for the deaths of over 80 people in the U.S. If you had some sort of warm and fuzzy reassurance that authorities were looking into the matter, a new congressional probe should quash that feeling pretty quickly. Today the Wall Street Journal reported that the probe, by two congressmen from Texas, has found that China never looked into the heparin scandal at all. This is despite repeated warnings from FDA, as C&EN wrote last year.

The probe comes ahead of FDA Commissioner Margaret Hamburg’s first trip to China in her new official capacity. The congressmen, Reps. Joe Barton and Michael Burgess, urged the commissioner to bring the issue up during her trip. According to the WSJ, a spokeswoman for China’s State Food and Drug Administration said the results of the probe were “not true.”

It’s a shame this scandal had to happen at all- all because heparin, a drug so many people rely on, is easier to harvest from a pig intestine than it is to make in the lab. As a refresher, heparin is a blood thinner, and chemically speaking, it’s a variably sulfated glycosaminoglycan polysaccharide composed of alternating D-glucosamine and uronic acid residues. Now, the blood thinner term is sort of a misnomer- heparin doesn’t actually thin the blood. What it really does is inhibit coagulation- prevent blood clots from forming or reduce clots actively present.

Heparin does this by binding to a protein called antithrombin III, ultimately affecting the proteases thrombin and Factor Xa, which both play important roles in blood clot formation. You can read some of C&EN’s heparin coverage here and here.

We’ve known that heparin affects blood clotting since 1916, but the stuff’s been extraordinarily tough to replace. Today there exist many different heparin-type products. Garden-variety unfractionated heparin is used in certain surgeries and in kidney-dialysis patients. Fractionated heparins like the low-molecular-weight heparin Lovenox are used to prevent and treat dangerous blood clots in the leg veins of patients on bedrest or who are having a hip or knee replacement. And there are synthetic pentasaccharides like fondaparinux, essentially made from the business end of heparin, which affect only Factor Xa.

All of these products have the same inconvenience- they all must be given via injection. And outside the fondaparinux-type drugs, it’s not easy to manufacture them from scratch in a lab because the structures are so unwieldy and heterogenous.

There are a slew of drugs in the pipeline that target Factor Xa or thrombin directly, that are straightforward molecular entities, and that drugmakers would love to see replace heparins and their coagulation blocking buddy, warfarin, at least for some applications. See here for an explainer in Forbes about one of the potential new drugs, Merck’s betrixaban.

Drugmakers have many reasons to replace heparin and its ilk. But the ability to manufacture a drug in a controlled way has to be one of them. Heparin itself might be cheap, but its human cost has already been too high.
Image:C&EN

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