tin-mesoporphyrin and Jaundice--Neonatal

It is estimated that about two thirds of newborns will appear clinically jaundiced during their first weeks of life. As newborns and their mothers spend fewer days in the hospital after birth, the number of infants readmitted yearly in the United States for neonatal jaundice over the last 10 years has increased by 160%. A portion of these infants present to the emergency department, requiring a careful history and physical examination assessing them for the risk factors associated with pathologic bilirubin levels. Although the spectrum of illness may be great, the overwhelming etiology of neonatal jaundice presenting to an emergency department is physiologic and not due to infection or isoimmunization. Therefore, a little more than a good history, physical examination, and indirect/direct bilirubin levels are needed to evaluate an otherwise well-appearing jaundiced newborn. The American Academy of Pediatrics' 2004 clinical practice guidelines for "Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation" are a helpful and easily accessible resource when evaluating jaundiced newborns (available at http://aappolicy.aappublications.org/cgi/content/full/pediatrics;114/1/297). There are several exciting developments on the horizon for the diagnosis and management of hyperbilirubinemia including increasing use of transcutaneous bilirubin measuring devices and medications such as tin mesoporphyrin and intravenous immunoglobulin that may decrease the need for exchange transfusions.

Topics: Bilirubin; Blood Group Incompatibility; Breast Feeding; Diagnosis, Differential; Emergencies; Erythroblastosis, Fetal; Exchange Transfusion, Whole Blood; Female; Hemoglobinopathies; Humans; Hyperbilirubinemia, Neonatal; Immunoglobulins, Intravenous; Infant, Newborn; Jaundice, Neonatal; Kernicterus; Male; Metabolism, Inborn Errors; Metalloporphyrins; Phototherapy; Practice Guidelines as Topic; Pregnancy; Rh Isoimmunization; Sepsis

The uses of synthetic heme analogues that are competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the production of bilirubin, represent a novel means of controlling severe hyperbilirubinemia in the newborn. The logic of this approach and the use of stannsoporfin (tin mesoporphyrin) as the compound of choice are discussed.

Topics: Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins

Hyperbilirubinemia is a common problem, affecting 45-60 percent of term infants and up to 80 percent of premature neonates. Phototherapy, the standard treatment for neonatal hyperbilirubinemia, is effective but has the potential for adverse effects. Prevention of bilirubin formation, rather than dependence on therapeutic measures to remove excess bile pigment, is a logical alternative. Metalloporphyrins--specifically tin-protoporphyrin (SnPP) and tin-mesoporphyrin (SnMP)--are being used experimentally to prevent and treat neonatal hyperbilirubinemia. This article reports the findings of studies exploring the use of SnPP and SnMP.

Topics: Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins; Neonatal Nursing; Phototherapy

Sn-mesoporphyrin (SnMP) is a potent inhibitor of bilirubin production. In our previous studies a single dose (6 mumol/kg birth weight) significantly moderated hyperbilirubinemia and reduced phototherapy (PT) time by > 75% when administered within 24 hours of birth to preterm infants.. To directly compare the efficacy of SnMP and PT for controlling hyperbilirubinemia in term and near-term infants.. Two randomized, sequentially analyzed trials (Study I: male term infants; Study II: infants of both sexes and gestational age [GA] 245-265 days) were conducted. SnMP (6 mumol/kg birth weight) or PT (Phillips F20T12/BB lamps) was administered to paired infants according to strict criteria of plasma bilirubin levels and age. Time of enrollment and closure of cases and crossover, if necessary, of SnMP infants to PT or all infants to exchange transfusion were precisely defined in each pair. SnMP or PT was considered superior if the time between enrollment and closure of the case was reduced by > 24 hours over the alternative treatment or if crossover had occurred.. None of the 44 SnMP-treated infants required supplemental PT. Of the 22 pairs of term infants enrolled in Study I, SnMP proved superior to PT in 20 and equal in two. Of the 20 pairs of near-term infants enrolled in Study II, SnMP was superior in 12 and PT in two; six were tied. Two SnMP-treated infants were unpaired. The PT-treated infants in Study I required an average of 33 hours of treatment; those in Study II, 48 hours. None of the enrolled infants required exchange transfusion or interruption of breast-feeding. In both studies, times between case enrollment and closure were reduced by > 30 hours in SnMP compared with PT infants; requirements for additional days of medical observation and bilirubin measurements were also significantly less in SnMP infants.. A single dose of SnMP entirely supplanted the need for PT in jaundiced term and near-term newborns and significantly reduced medical resource use to monitor hyperbilirubinemia.

Topics: Female; Gestational Age; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Jaundice, Neonatal; Male; Metalloporphyrins; Phototherapy; Treatment Outcome

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.. 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.. In five randomized, blinded, placebo-controlled trials, SnMP in increasing doses from 1 mumol to 6 mumol/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.. 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 mumol/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.. 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.

Topics: Bilirubin; Dose-Response Relationship, Drug; Gestational Age; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Infant, Premature, Diseases; Jaundice, Neonatal; Metalloporphyrins; Phototherapy

Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.

Topics: Administration, Oral; Animals; Bilirubin; Deuteroporphyrins; Enzyme Inhibitors; Female; Gene Expression; Heme Oxygenase-1; Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins; Mice; Mice, Transgenic; Protoporphyrins; RNA, Messenger

Topics: Bilirubin; Enzyme Inhibitors; Female; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins; Phototherapy; Randomized Controlled Trials as Topic

Topics: Bilirubin; Drug Approval; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins; Randomized Controlled Trials as Topic

Topics: Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Mesoporphyrins; Metalloporphyrins

Topics: Breast Feeding; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Humans; Infant, Newborn; Jaundice, Neonatal; Kernicterus; Metalloporphyrins; Phototherapy; Protoporphyrins

Pharmacological treatment of neonatal jaundice is again topical. At the beginning of the eighties, clofibrate was added to phenobarbital which was difficult to use and inefficient. Clofibrate is a better enhancer of glucuronosyl transferase induction than phenobarbital and causes 100% increase of hepatic bilirubin clearance within 6 hours. In the treatment of early jaundice in full term neonate, it significantly reduces bilirubinemia in 16 hours, and decreases the intensity and duration of jaundice and also phototherapy requirement. At the end of the eighties, new molecules inhibiting hepatic production of heme to bilirubin, like metalloporphyrins, were introduced. These molecules block the transformation of heme to biliverdin and bilirubin. Among them, the Sn-mesoporphyrin seems to have the best efficacy when used prophylactically in premature infants between 30 and 36 weeks of gestational age, and also curatively in full-term neonates, with minimal side effects. However the product is not yet manufactured and can not be used in pediatrics practice. Therefore clofibrate represents the only pharmacological treatment of neonatal jaundice actually available.

Topics: Clofibrate; Combined Modality Therapy; Enzyme Inhibitors; Female; Humans; Infant, Newborn; Jaundice, Neonatal; Metalloporphyrins; Phototherapy; Pregnancy; Treatment Outcome