The brazilian bovine heparin saga

Onésimo Ázara Pereira – Dezembro 2014:

My name is bovine heparin. In fact, more explicitly and for chemical reasons, my name is sodium bovine heparin. This name was given to me in Portuguese by the Brazilian Pharmacopoeia Thematic Technical Committee (CTT in Portuguese) and therefore I received the number 10,807. Internationally, for commercial negotiation, I am identified by Mercosur Code 3001.90.10.

Heparin is a polymer of a sulfated mucopolysaccharide and appeared on the global therapeutic scenario in 1916. It is one of the most used biological products in medical practice, losing only to the insulin. I, the bovine heparin, entered to the scene in the 1940s experimentally and clinically, and experts consider myself an effective drug in preventing deep vein thrombosis and pulmonary thromboembolism. However, my most frequent use in medical procedures took place after the Second World War, more precisely starting in 1947, when I was produced from bovine lungs. From the 60s, for reasons of efficiency and therefore commercial, I became to be produced by extraction from bovine intestinal mucosa, where I have a major presence. I have a cousin called sodium porcine heparin which is extracted from the intestinal mucosa of pigs. We are both used indistinctively, with similar efficacy, however, for being organic products from different tissue origins, we are not one hundred percent interchangeable, which means that we should not be mixed in the same treatment. Therefore, we are not bioequivalent.

Historically in Brazil, I as bovine heparin was used most of the time. I even was the component of the one pioneers drugs, namely Liquemine of Roche Laboratories. It is also worth remembering that for a long time I was used by a major national laboratory, who estimates that from July 2008 to December 2012 approximately 2,932,563 patients have been treated in Brazil with Heptar (look at me there!), with excellent results and with only 47 cases of adverse reactions registered by the company, what gives, only, 2.35 cases per 100,000 patients. We, the heparins (bovine and porcine), may cause an adverse effect called thrombocytopenia (thrombocyte depletion), which may cause bleeding, perfectly manageable by medical procedures.

Turns out that I, bovine heparin, was greatly impaired with the advent of an outbreak in the United Kingdom from 1993, a disease called Bovine Spongiform Encephalopathy (BSE in English), or more popularly called Mad Cow Disease. Although this disease is historically very old, its peak in January 1993 in the UK, reached 1,000 new cases per week. During the following 17 years the annual number of BSE cases fell sharply from 14,562 in 1995 to 1,443 in 2000 and then to 225 in 2005 and to 11 cases in 2010. Cumulatively, by the end of 2010, more than 184,500 cases of BSE have been confirmed, in the UK alone, in more than 35,000 herds. In North America (USA and Canada) between 1993 and April 2012 were registered 23 cases of death in humans from BSE.

I have participated a lot as bovine heparin, to the huge North American pharmaceutical market. In fact, the first market authorization for my use in the United States occurred in 1939 and several subsequent authorizations followed.

My withdrawal from the market of USA and Europe was due to the fear that, being from bovine origin, I could transmit the agent that causes Mad Cow Disease. Despite the favorable experience of 50 years in production and clinical use of bovine heparin, I was withdrawn from the American market at the Food and Drug Administration (FDA) request, accepted voluntarily by the manufacturers in 1990, for the reason outlined above.

For me, it was a big blast. But as “there is no evil that lasts much …” the North American authorities, are seriously studying my reintroduction into its huge market. They claim that the interest to reintroduce me stems from the fact that heparin is scarce worldwide and recent market analysis showed that most of porcine heparin used in the USA comes from China. The authorities concern comes form the fact that the power supply of its market involves only one animal source (in this case, pigs) and one country (in this case, China), which is a high risk factor for its supply. What if the Chinese swine herd might be victim of some epidemic disease such as “blue-ear disease”! … Then what?

The US’ health authorities believe that its supply chain of porcine heparin is safe at the moment. However, historically heparin showed some kind of contamination. However, the biggest problem is the potential for heparin adulteration, considering its international high price being a stimulus to this kind of offense.

To facilitate my (bovine heparin) return into the North American market, it has been shown that there are cases of bovine heparin manufacturing that have an intrinsic ability to remove or inactivate the BSE agent if it is present in my (bovine heparin) manufacturing process. The FDA has safety standards that can be applied to the bovine heparin production, for example: (i) the origin of the animals, (ii) the selection of tissues to be used and (iii) the implementation of risk reduction steps in the production processes.

Due to these concerns and considerations from the american authorities, my return is to be soon. Incidentally, the authorities are already dealing with an unique monograph only for myself (sodium bovine heparin) in the American Pharmacopoeia (USP). What an honour!

Meanwhile, here in the southern hemisphere, specifically in Brazil, the situation goes in the opposite way. What a shame!

Due to the emergence of BSE in Europe in 1990, I have not been withdrawn from the Brazilian market because the herd of which I originate is green and the occurrence of BSE did not significantly happened. I am present here since the early decades of the last century, with greatest success. All went well until 2010 when the Brazilian Pharmacopoeia published its 5th edition. Unlike my monograph and the porcine heparin in the 4th edition, which demanded to the potency 140 IU/mg of dry material, this 5th edition, demanded 180 IU/mg of dry material to the potency, without having a Public Consultation for my producers to express their opinion on the practicability of production with this new potency. As I (bovine heparin) and the porcine heparin are originating from different tissues, as already explained in the beginning of this saga, the porcine heparin has no problem to reach 180 IU, but I do have it even maintaining the purity and efficacy. My producers say they can reach this number (180 IU), but it would be so costly to produce that would make it commercially unfeasible, in detriment of thousands and thousands of patients. They should make me reach a level of 160 IU/mg of dry material.

With the publication of this monograph, (at the 5th edition) unfeasible for me, they also made it impossible to produce the corresponding product Heptar, with severe damage to its manufacturer, since the product is about two years out of the market. The Brazilian health authorities believed, in still good time, that it was important that we, I and the porcine heparin, have separate monographs in the Brazllian Pharmacopoeia (FB).

Bingo! Then, the Brazilian pharmochemical industry asked the FB that, to alleviate the problem, to publish an ‘errata’ (which is a tool provided by the FB) to consider the 5th edition sodium heparin monograph just for the swine heparin.

Moreover, I still need urgently that my new monograph, separated from the swine heparin, have my potency and the analytical methods to determine myself, perfectly clear and practicable, to the level of my industrial production.

Ah! I almost forgot! I also need a reference standard (SQR), so I can be clearly identified on the day-to-day productions. Wow!

While I await for these urgent and consistent actions, I see the Brazilian market heparin totally discouraged, with a manufacturing facility already closed, with the Brazilian exports simply reduced to porcine mucous intestinal membrane, which is rapidly increasing at extremely low prices, feeding the industries that purify this heparin abroad, disturbing even more the deficit in the foreign balance of the Brazilian manufactured goods.

I am the bovine heparin! I have more than 200 million head of cattle in Brazil, raised in green grass, at my disposal. It is an enviable treasure that cannot be abandoned. The country cannot give it up. Soon the day will come when the world will thank us for this natural resource that is called biodiversity.

Someone said that the pharmochemicals are myriads of stars pointed out by God for the benefit of the humanity. To God, honor and glory. I, the sodium bovine heparin, agree. Bravo! I say without modesty: Of them I’m a first magnitude star! The doctors attest and the patients thank…

To remember the details of this my tumultuous history (or story), I resorted to the following sources, which I thank you in advance:

1. Prof. Dr. Anthony Wong – Doctor, Hospital das Clinicas, Faculty of Medicine, University of São Paulo (USP).
2. Dr. Janet Woodcock MD -. Director of Science Board to the Food and Drug Administration (FDA) – USA.
3. Prof. Dr. Marcelo A. Lima – Federal University of São Paulo and University of Liverpool – England.
4. Information for FDA Science Board – June 4, 2014: Proposal to Encourage the Reintroduction of Bovine Heparin to the US Market.

Onésimo Ázara Pereira – Presidente-Executivo da abiquifi