Control of Jaundice in Preterm Newborns by an Inhibitor of Bilirubin Production: Studies With Tin-Mesoporphyrin

Abstract

Background. Studies in vitro, in animal models, and in adult and newborn humans have demonstrated that certain tin(Sn)-porphyrins that competitively inhibit the activity of heme oxygenase, the rate-limiting enzyme in heme catabolism, reduce production of bilirubin and can thereby substantially diminish plasma levels of the bile pigment. Objectives. To assess the effectiveness of increasing doses of the heme oxygenase inhibitor, Sn-mesoporphyrin (SnMP), in moderating the development of significant hyperbilirubinemia and thus the requirements for phototherapy in preterm newborns. Methods. In five randomized, blinded, placebo-controlled trials, SnMP in increasing doses from 1 µmol to 6 µmol/kg body weight was administered intramuscularly in the first 24 hours of life in preterm newborns of 210 to 251 days gestational age. "Special blue" lamps (Phillips F20T12/BB) were used for phototherapy in newborns exceeding a predetermined plasma bilirubin concentration, irrespective of study group. Results. A total of 517 newborns were randomized in the five trials carried out sequentially over a 4-year period. SnMP in a dose-related manner significantly ameliorated the course of hyperbilirubinemia in the treated newborns Of all gestational ages. With a SnMP dose of 6 µmol/kg body weight, the mean peak incremental plasma bilirubin concentration was reduced by 41% and the phototherapy requirements were decreased by 76% compared to control subjects. Erythema observed in a few SnMP-treated newborns who required phototherapy was mild, transient, and without sequelae. No other untoward effects were observed during hospitalization or at a follow-up at post-term age of 3 and 18 months. Conclusions. SnMP, by inhibiting the production of bilirubin, substantially moderates the development of hyperbilirubinemia in preterm newborns. This compound and similarly acting enzyme inhibitors merit further clinical study as agents for controlling neonatal hyperbilirubinemia, particularly in neonatal populations for whom other treatment modalities are not available.

Pegylated Zinc Protoporphyrin: A Water-Soluble Heme Oxygenase Inhibitor with Tumor-Targeting Capacity

“…Biliverdin, one of the products of heme degradation, is immediately reduced by the cytosolic enzyme biliverdin reductase to form bilirubin (1,2). Although excessive increases in serum bilirubin concentrations cause hyperbilirubinemia or jaundice (9), recent findings suggest that adequate levels of bilirubin play an important role in protecting cells from oxidative stress because of bilirubin's potent antioxidant activity. It was reported that bilirubin can scavenge free radicals, especially peroxyl radicals (10); prevent protein oxidation by the potent reactive nitrogen species peroxynitrite (11); and protect neuronal cells from oxidative stress injury (12).…”

HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAFV600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia

“…In our work SnMP, already used clinically to treat hyperbilirubinemic disease [ 58 ], has been used as has been proposed for the therapy of breast cancer [ 59 ] and melanoma [ 60 ]. We have now confirmed the efficacy of this inhibitor in MeOV-1 cells under physiological normoxia and hypoxia increasing its potential clinical translation.…”

Direct hyperbilirubinemia and cholestasis in trisomy 13 and 18

“…Ursodiol functions by providing protection from bile acids and stimulating bile acid secretion. Phenobarbital may also be effective in neonates by preventing the production of bilirubin, though neither has been specifically evaluated in infants with trisomy 13 or 18 (Bloomer & Boyer, 1975; Valaes et al, 1994). In our study, only a few patients received ursodiol or phenobarbital, and there was no standardized treatment protocol used to guide initiation or termination of therapy; thus, we are unable to speculate on the reasons why treatment was or was not initiated for the patients in our cohort.…”