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COMMENTARY |
National Institute of Child Health and Human Development
National Institutes of Health
Department of Health and Human Services
Bethesda, MD 20892-2425
Every now and then, in a pharmaceutical world dominated by agents that are "me-toos" or "variations on a theme," there appears a truly new molecular entity that offers an entirely new approach to treating a disorder that previously had only partially effective therapies or, sometimes, no effective therapy at all. The article by Attallah Kappas1 in this issue describes such a potential advance: tin-mesoporphyrin. This truly new entity was developed specifically by Kappas and his colleagues to block the action of heme oxygenase in converting hemoglobin to bilirubin. By shutting off the production of bilirubin at its source rather than removing it by exchange transfusion or phototherapy after it is formed, this agent has the potential to revolutionize management of jaundice from any cause just as Rh immune globulin did for preventing Rh hemolytic disease of the newborn when introduced in the 1960s.
What is remarkable (and lamentable) is that Kappas’ first reports of discovery and successful use of tin-mesoporphyrin for preventing or controlling hyperbilirubinemia appeared in the early 1980s, and despite several reports of controlled trials that demonstrated incredible effectiveness in different populations, the drug is still not approved for use. We continue to suffer the inconvenience of bilirubin lights for many hours of treatment, but we still miss significant jaundice in some infants who go on to develop kernicterus.
The National Institute of Child Health and Human Development, spurred to act by Sumner Yaffe, Director of its Center for Research for Mothers and Children, who recognized the enormous promise of tin-mesoporphyrin, moved to provide support for clinical trials that needed to be performed to evaluate it. These 3 trials, cited by Kappas and all published in Pediatrics,2–4 were supported by contracts from the National Institute of Child Health and Human Development. The first, in 517 preterm infants in Greece, demonstrated a dramatic (76%) reduction in the need for phototherapy, with no evidence of adverse reactions. The second, also performed in Greece with 283 infants with jaundice due to glucose-6-phosphate dehydrogenase deficiency, produced even more dramatic results: none of the infants given a single dose of tin-mesoporphyrin at 24 hours required phototherapy for jaundice, compared with >30% of the untreated controls. The third study, performed in Argentina, evaluated tin-mesoporphyrin in 166 term infants whose bilirubin reached a level of 15 to 18 mg/dL before receiving the drug. The results were equally dramatic: none of the treated infants reached a bilirubin level requiring initiation of phototherapy, compared with nearly one fourth of the control infants.
With results so striking, it is legitimate to ask why there is not a veritable stampede to use this drug. Certainly we do not love bilirubin lights so much that we don’t want to give them up. Certainly if there were a new anticonvulsant that was 100% effective in preventing seizures, compared with 70% with current agents, or a new asthma medication that was 100% effective in preventing asthma attacks instead of 70%, physicians would do anything to get the new medication for their patients. Yet tin-mesoporphyrin languished without an industrial sponsor for many years, and although a sponsor has appeared and designed and funded a first clinical trial to Food and Drug Administration specifications, the trial is currently on hold.
Tin-mesoporphyrin has the potential to be one of the most significant, truly new drugs introduced into pediatrics, completely solving an age-old problem in newborns that current methods address primitively and inadequately. Its safety has been extensively assessed, and it has never been shown to have a single adverse effect. Its efficacy has been dramatic, even total, in every study that has been reported.
Its ultimate use remains to be determined, and it should be tested and introduced for one population at a time, beginning with interdiction use for jaundiced term newborns with rising bilirubins, moving to preterm infants in a similar status, and later studying routine preventive use in high-risk infants. Perhaps, if safety remains clear, the day will come to evaluate routine use in all infants. Bilirubin may be like lead, where even a little bit is not very good for you. Routine use may also be the only way to completely prevent infants from slipping through the protective nursery net and developing jaundice and kernicterus after hospital discharge.
This drug has too much potential to be left on the shelf. The testing needs to be performed, and we need to get on with it.
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FOOTNOTES |
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Address correspondence to Duane Alexander, MD, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, 31 Center Dr, Room 2A03, MSC 2425, Bethesda, MD 20892-2425. E-mail: da43w{at}nih.gov
The views expressed herein are those of the author and not necessarily of the Department of Health and Human Services.
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This article has been cited by other articles:
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  Z.-W. Xia, C.-E Li, Y.-X. Jin, Y. Shi, L.-Q. Xu, W.-W. Zhong, Y.-Z. Li, S.-C. Yu, and Z.-L. Zhang Reduction of Bilirubin by Targeting Human Heme Oxygenase-1 Through siRNA Experimental Biology and Medicine, April 1, 2007; 232(4): 495 - 502. [Abstract] [Full Text] [PDF]
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 G. R. Gourley, Z. Li, B. L. Kreamer, and M. R. Kosorok A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice Among Breastfed Newborns Pediatrics, August 1, 2005; 116(2): 385 - 391. [Abstract] [Full Text] [PDF]
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