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SPECIAL ARTICLE |
From the Rockefeller University Hospital, New York, New York
Abbreviations: SnMP, Sn-mesoporphyrin • FDA, Food and Drug Administration • G6PD, glucose-6-phosphate dehydrogenase
Severe jaundice, with its potential for producing brain damage, remains a continuing and controversial problem in newborn medicine. Central issues in this problem are the unpredictable course of hyperbilirubinemia in some newborns, the undefined susceptibility of an individual infant to bilirubin toxicity, and the uncertain blood level at which bilirubin threatens the brain, an uncertainty that is intrinsic to the clinical circumstances and therapeutic context of severe newborn jaundice.
My laboratory group at Rockefeller University Hospital, together with collaborating pediatricians at other institutions, has developed a method for effectively controlling the production of bilirubin in newborns that can help to resolve these issues. The method involves use of an inhibitor that is targeted directly at the enzyme that controls heme degradation to bilirubin and permits physicians to rapidly, and predictably, interdict hyperbilirubinemia at any point in the progression of jaundice that they choose.
Bilirubin is a normal product of heme degradation, and the rate-limiting step in its formation is controlled by the enzyme heme oxygenase (Fig 1, top). Newborns produce bilirubin faster than they can dispose of it and thus experience a mild, transient jaundice after birth. This jaundice generally peaks at 
96 hours, well after the mother and infant leave the hospital, according to current practice. In some infants, jaundice can run a severe course, unrecognized and then unmanageable. Substantial brain damage then may occur. The damage can take place rapidly and produce within hours the severe neurologic deterioration known as kernicterus. More subtle neurologic impairment caused by bilirubin is now being detected by better diagnostic means. The long-term consequences of such impairment are not known.
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Phototherapy remains a crucial treatment modality in newborns, but the procedure has recognized drawbacks. The infant is separated from the mother and is masked to prevent eye damage; treatment requires many hours and sometimes several days; there are clinical side effects; the light unit can interfere with normal nursing care; phototherapy may not be fully effective or act rapidly enough to moderate developing jaundice; rebound hyperbilirubinemia occurs in some infants; and the light apparatus may not always be available in underprivileged regions in this country as well as abroad. Additionally, its underlying medical logic is unsatisfactory—treatment is initiated only after the blood bilirubin has already reached a level at which the physician believes the central nervous system is threatened. The subjective elements in a decision made in such urgent circumstances are evident.
We focused our research on heme oxygenase, which controls bilirubin production; we purified the enzyme to homogeneity, examined its substrate interactions, studied its regulatory responses to various genetic and pharmacological interventions, and succeeded in developing a potent inhibitor of its activity, the pharmacological and other properties of which made it suitable for clinical use. The inhibitor, Sn-mesoporphyrin (SnMP; developed out of earlier studies of an antecedent compound, Sn-protoporphyrin) is a structural analog of heme that blocks the site on heme oxygenase where heme conversion to bilirubin is initiated (Fig 1, bottom). Its mode of action, competitive enzyme inhibition, is analogous to that of drugs that inhibit cholesterol production. SnMP itself is not converted to bilirubin and is not degraded by any known physiologic mechanism.
The heme moiety whose conversion to bilirubin is blocked by SnMP is not stored in tissues but rather is excreted intact by the liver via the biliary system, a new pathway of heme disposal that we discovered in our studies. Many other heme analogues were synthesized and examined for their biochemical and pharmacological properties. Some, such as those with cobalt as the central metal atom, can interact with heme oxygenase in vitro but greatly induce the enzyme activity in vivo; others, such as those containing zinc or chromium, display deleterious tissue effects.
SnMP is administered parenterally in a very small dose, it concentrates in the tissues where most bilirubin production takes place, and it is specific to the enzyme catalytic site to which it binds very tightly. It does not enter the brain, and all tests of DNA interactions show it to be innocuous. Its biological properties have been examined intensively, and the compound has a wide safety margin. SnMP does not affect the conjugation of bilirubin in the liver or alter the removal process of preformed bilirubin from the circulation. It is the only synthetic heme analog that is presently approved by the Food and Drug Administration for clinical use.
Heme oxygenase inhibition has been shown to be effective in suppressing bilirubin production and thus reducing blood bilirubin levels in all the animal models of jaundice listed in Fig 2. In the clinical studies listed in this figure, heme oxygenase inhibitors have proved effective, when administered in single, small doses, in reducing blood bilirubin levels for 7 to 10 days in all patient populations studied. This duration of action approximates the period after birth during which newborns are most vulnerable to severe hyperbilirubinemia.
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There were 279 combined control infants in these trials; 129 (46%) needed light treatment to suppress progressive jaundice. A total of 443 infants received a single dose of SnMP at a suitable time after birth; 13 (3%), all preterm, required a small amount of supplemental phototherapy to control jaundice (Fig 3, first group). In all infants, blood bilirubin levels were reduced significantly, and in 97% the need for light treatment was eliminated entirely.
In 80 newborns (Fig 3, second group) in whom bilirubin levels had already reached 15 to 18 times normal (that is, close to the level requiring phototherapy [19.5 mg/dL]), SnMP rapidly blocked further progression of jaundice, and none of the infants required supplemental light treatment. In contrast, of 86 controls who did not receive the inhibitor, 22% ultimately required phototherapy.
A direct comparison of SnMP versus phototherapy was made in other newborns (Fig 3, third group) in whom the blood bilirubin had already reached the critical level for initiating light treatment. Forty-four infants received the inhibitor instead of phototherapy; hyperbilirubinemia receded in all 44, and none required supplemental light treatment. These infants left the hospital 30 hours earlier than the 42 infants who did not receive the inhibitor (and who therefore received phototherapy). In this study, the inhibitor proved superior to phototherapy in a number of clinical criteria.
The inhibitor prevented the development of severe jaundice in newborns with ABO incompatibility (Fig 3, fourth group) and with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetic defect that predisposes them to this problem (Fig 3, fifth group). In the latter trial, of 58 infants in the control group, 31% became seriously jaundiced and required light treatment. None of the 225 G6PD-deficient infants who received a single dose of SnMP 24 hours after birth developed jaundice significant enough to require phototherapy. Prevention of severe jaundice in these infants simplified their medical care considerably.
The inhibitor effect on the average rate of progression of hyperbilirubinemia in the G6PD-deficient newborns is depicted in Fig 3 (right). The 58 infants who did not receive SnMP continued to accumulate bilirubin in their blood at a high rate during the second day after birth, and, ultimately, many required light treatment. The bilirubin-accumulation process was blocked in the 225 infants who received SnMP, and none required phototherapy.
The potency and duration of action of single doses of SnMP are demonstrated clearly in the 2 clinical studies depicted in Fig 4. Children carrying the gene defect of the Crigler-Najjar type I syndrome cannot conjugate and dispose of bilirubin in the normal way. Thus they survive for a period of time with highly elevated blood bilirubin levels as in the 4-year-old child whose data are shown Fig 4 (left). Without a liver transplant, they can experience serious neurologic deterioration or may die from bilirubin brain damage before puberty. A single dose of SnMP administered to this child reduced her blood bilirubin levels substantially, and the effect lasted many days (Fig 4, left). Repeated administration of the inhibitor prolonged this effect for weeks. These children of course continued their daily phototherapy (Phillips F20T12/BB, "special blue" tubes) while receiving SnMP, and their responses therefore may reflect some synergism between light and inhibitor treatment.
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SnMP can also replace blood-exchange transfusion, a last-resort procedure when light treatment fails to control severe jaundice. Seventy-five hours of intense phototherapy could not stop the relentless progression of hyperbilirubinemia in the preterm infant with hemolytic disease of the newborn whose data are shown in Fig 4 (right). The parents were Jehovah’s Witnesses, and blood exchange was rejected on religious grounds. With emergency FDA approval,
the inhibitor was delivered to the physician caring for the infant in South Dakota, and a single dose was administered at the time indicated by the arrow. Blood bilirubin levels declined rapidly, and within hours the threat of brain damage was eliminated, as was the need for legal action to force the exchange transfusion. This experience, now well-known in the Jehovah’s Witness community, has been repeated in other infants born to this group.
Periodic reappraisal of clinical interventions is essential if science is to advance medical care. Phototherapy, in use for 40 years, could not be reappraised properly during this period because there was no practical alternative to which it could be compared. Thus, pediatricians have essentially been bound to a single therapeutic option (except for exchange transfusion) and to the logic that newborn jaundice should only be treated when the blood bilirubin reaches such a high level that it directly threatens the brain. What this exact level is remains elusive. This is an unsatisfying and sometimes dangerous logic.
The concept of using an inhibitor of heme oxygenase to block bilirubin overproduction (a key source of the problem in severe newborn jaundice) until the bilirubin-disposal mechanism matures in the infant has a sound clinical as well as scientific basis. Interdicting the production of bilirubin to moderate the course of hyperbilirubinemia is more logical than attempting to dispose of the pigment after it has already been formed and reached a dangerous level in the bloodstream. The efficacy of this approach is now firmly supported by an extensive clinical experience comprising multiple successful trials with SnMP in which all diagnostic groups of unconjugated neonatal jaundice have been shown to be responsive to the action of the inhibitor. In these trials SnMP has demonstrated significant advantages in managing the problem of newborn jaundice.
The inhibitor acts rapidly and predictably to block heme degradation to bilirubin; it can be administered at any time point in the progression of hyperbilirubinemia at which the physician chooses to intervene; the effect of a single, small dose extends through the period during which the newborn is most likely to develop severe jaundice; no significant short- or long-term side effects have been detected in treated infants; and its use both simplifies care and reduces the medical resources required for monitoring newborns susceptible to the development of severe jaundice.
Finally, there are underprivileged societal settings in this country, as well as abroad, in which unrecognized or untreated newborn jaundice, because of its prevalence, the susceptible nature of certain newborn populations, and the paucity of resources for medical care, can constitute a significant public health problem. The method we have developed for inhibiting the production of bilirubin in newborns offers a simple and effective means for resolving this problem.
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ACKNOWLEDGMENTS |
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The studies described in this report represent collaborative efforts with many members of my laboratory group, especially Dr George S. Drummond. Clinical trials in newborns were carried out with Professor Timor Valaes in Athens, Greece, and Professor Jorge Martinez in Buenos Aires, Argentina.
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FOOTNOTES |
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Address correspondence to Attallah Kappas, MD, Rockefeller University, 1230 York Ave, New York, NY 10021. E-mail: kappas{at}rockefeller.edu
This is a summary report of research presented at the Food and Drug Administration Advisory Committee meeting, Gaithersburg, MD, June 11, 2003.
At present, the FDA allows the sponsoring pharmaceutical company to make the inhibitor available on a compassionate-use basis for situations in which the child’s family refuses exchange transfusion. The sponsor can be reached at (732) 938-5885 to request the inhibitor for this purpose. 
* References cited are limited to selected studies from this laboratory related to the discovery, pharmacological development, and clinical application of inhibitors of heme oxygenase.
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SELECTED REFERENCES* |
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 TOP SELECTED REFERENCES* |
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This article has been cited by other articles:
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  N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]
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 R. J. Wong, V. K. Bhutani, H. J. Vreman, and D. K. Stevenson Pharmacology Review: Tin Mesoporphyrin for the Prevention of Severe Neonatal Hyperbilirubinemia NeoReviews, February 1, 2007; 8(2): e77 - e84. [Abstract] [Full Text] [PDF]
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 M. J. Maisels Neonatal Jaundice Pediatr. Rev., December 1, 2006; 27(12): 443 - 454. [Full Text] [PDF]
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 M. J. Maisels and E. Kring The Contribution of Hemolysis to Early Jaundice in Normal Newborns Pediatrics, July 1, 2006; 118(1): 276 - 279. [Abstract] [Full Text] [PDF]
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 S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]
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A. F. McDonagh and M. J. Maisels Bilirubin Unbound: Deja Vu All Over Again? Pediatrics, February 1, 2006; 117(2): 523 - 525. [Full Text] [PDF]
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J. C. Martinez Argentinean Perspective of the 2004 AAP Hyperbilirubinemia Guidelines NeoReviews, January 1, 2006; 7(1): e4 - e6. [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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D. Alexander A Method for Interdicting the Development of Severe Jaundice in Newborns by Inhibiting the Production of Bilirubin Pediatrics, January 1, 2004; 113(1): 135 - 135. [Full Text] [PDF]
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