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Ann Thorac Surg 2000;70:1530
© 2000 The Society of Thoracic Surgeons
Discussion
DR JOHN W. BROWN (Indianapolis, IN): First of all, this sounds almost too good to be true. Are there any side effects to the use of this drug? And number two, are there any planned clinical trials for the use of this drug in the treatment of pulmonary hypertension in the newborn?
DR DOMKOWSKI: Thank you, Dr Brown, for your comments and questions. To address your first question, there are no reported toxic side effects to bosentan as of yet in the literature, but it is still too early to know because it really has not been used chronically yet. So the answer to that question is, I just do not know because the data are not there.
Secondly, there are clinical trials under way in Europe where they have used this in systemic hypertension. There has been some clinical use here in the United States, specifically in Colorado, where they plan to use it in, obviously, a research mode for infants after congenital heart surgery. It is a last-resort drug. It has been used in Europe when some babies have been refractory to nitric oxide treatment.
DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): Have you used this agent in other conditions where perhaps endogenous endothelin-1 is overexpressed such as in a pulmonary ischemia-reperfusion injury model or posttransplant model?
DR DOMKOWSKI: That is an excellent question. And to answer it quickly, we have not. In clinical examples where documented elevated levels of endothelin have been seen, a selective inhibitor of ETA receptors known as BQ123 has been used, and has lowered pulmonary artery pressure. But one of the side effects with that drug is that it also lowers systemic pressure, whereas bosentan does not.
DR JOHN E. MAYER, JR (Boston, MA): I guess the only comment that I would make is that one does not necessarily need to have an increased endothelin-1 level to potentially see some positive effects from this agent because what one really needs to know is what the balance is between the endogenous vasodilators and endothelin-1 as an endogenous vasoconstrictor. So that if one simply has a reduced ability, for instance, to produce nitric oxide, there still might be a benefit in blocking endothelin-1 because one would then be redressing the balance, if you will, back toward normal.
DR DOMKOWSKI: Thank you, Dr Mayer for your comments.
DR MARK A. AWOLESI (Minneapolis, MN): What is the effect of bosentan alone on the pulmonary vasculature? And if you don’t mind going back to your last graph, I would like to look at the effect of bosentan on those animals in the graph. It seems to me that in group 2, the baseline pulmonary pressure is higher than in group 1, if you can explain it?
DR DOMKOWSKI: That is actually a systemic arterial pressure, and we were concerned about that as well. They are not significantly different. Since the submission of these data, we have actually done now 25 animals; and the baseline has come down. I think that is attributable to the physiologic variations you’re going to get in animals that are this young. We have done experiments on animals that are 48 hours old and seen a completely different response to endothelin-1 compared with 2-week-old animals. And that maturation process over the first 2 weeks of life is incredibly dramatic. So what we might be seeing are animals that are 14 days and 12 hours. And differences as small as that in the first few weeks of life actually dictate very different responses.
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