Heme oxygenase: a target gene for anti-diabetic and obesity.

Heme oxygenase-1 (HO-1) is central to the regulation of oxidative injury. The role of increased HO-1 expression and Heme oxygenase (HO) activity in mitigating the detrimental side effect of diabetes is examined. A review of the mechanism(s) of action is included. This may lead to the development of pharmacological and genetic approaches to mitigate the clinical complications associated with the progression of diabetes and obesity.

Sn-Mesoporphyrin interdiction of severe hyperbilirubinemia in Jehovah's Witness newborns as an alternative to exchange transfusion.

OBJECTIVE: The religious convictions of parents who are Jehovah's Witness adherents lead them to reject the use of exchange transfusions as therapy for severe hyperbilirubinemia in newborns in whom intensive phototherapy has failed to control this problem. Consequently, physicians caring for such infants may be obliged to initiate legal action to compel use of the procedure when severe hyperbilirubinemia not sufficiently responsive to phototherapy warrants an exchange transfusion. Our goal was to determine if we could use the potent inhibitor of bilirubin production, Sn-Mesoporphyrin (SnMP), to resolve the troubling medical-legal issues in such situations in 2 infants with hemolytic disease of the newborn who required exchange transfusions for severe hyperbilirubinemia but whose Jehovah's Witness parents rejected the procedure. SnMP was administered in a single dose, as in previous studies, at the time when exchange transfusion would have been initiated and plasma bilirubin levels were monitored at close intervals thereafter. METHODS: SnMP is a potent inhibitor of heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin. We found in earlier studies that in single doses of 6 micromol/kg birth weight, SnMP is extremely effective in moderating the course of hyperbilirubinemia and in eliminating the need for supplemental phototherapy in jaundiced newborns. In the 2 cases described, a single dose of SnMP (6 micromol/kg birth weight) was administered intramuscularly to severely jaundiced infants with immune hemolysis at a time when clinical circumstances dictated the need for exchange transfusion. CASE 1: This patient was a preterm male infant (gestational age: 35 5/7 weeks; birth weight: 2790 g) whose plasma bilirubin concentration (PBC) at 1 hour after birth was 5.0 mg/dL. Despite intensive phototherapy with 3 banks of lights and 1 biliblanket, the PBC increased steadily with no diminution in the rate of increase for 75 hours. In view of the problems of immune hemolysis, and prematurity, and the inability of phototherapy to stop progression of hyperbilirubinemia, a decision to carry out an exchange transfusion was made; the decision was, however, rejected by the Jehovah's Witness parents. Pending legal action to compel use of the procedure, a request to this (Rockefeller) laboratory for SnMP was made; its use was approved by the Food and Drug Administration; and the inhibitor was delivered to the physician-in-charge (D.P.M.) in Sioux Falls, South Dakota. The single dose of SnMP was administered to the infant at 75 hours after birth; the course of hyperbilirubinemia before and after the use of the inhibitor is shown in Fig 1. [figure: see text]. CASE 2: This female term infant (gestational age: 38-39 weeks; birth weight: 4140 g) with immune hemolysis was delivered by cesarean section and because of problems related to meconium aspiration required helicopter transfer to the Special Care Nursery in Abilene, Texas, where 10 hours after birth the first PBC was determined to be 18.0 mg/dL. Double-bank phototherapy plus a biliblanket was initiated; a third bank of lights was later ordered. The PBC fluctuated in the ensuing 2 days between 13.8 to 25.8 mg/dL during which suggestive clinical signs of possible bilirubin encephalopathy became manifest. In view of the clinical circumstances and the continued severe hyperbilirubinemia, permission for a double-exchange transfusion was requested. The parents, who were Jehovah's Witness adherents, refused the procedure. While preparing legal action to compel use of the exchange, a request was made to this (Rockefeller) laboratory for use of SnMP to attempt control of hyperbilirubinemia. With FDA approval, the SnMP was delivered to the attending neonatologist (J. R. M.) in Abilene and administered in a single dose (6 micromol/kg birth weight) at 56 hours after birth when the PBC was 19.5 mg/dL. The course of bilirubinemia before and after SnMP use is shown in Fig 2. [figure: see text]. RESULTS AND CONCLUSIONS: The use of SnMP to moderate or prevent the development of severe hyperbilirubinemia in newborns (preterm, near-term, term with high PBCs [15-18 mg/dL], ABO-incompatibility; glucose-6-phosphate dehydrogenase deficiency) has been extensively studied in carefully conducted clinical trials the results of which have been reported earlier. This inhibitor of bilirubin production has demonstrated marked efficacy in moderating the course of hyperbilirubinemia in all diagnostic groups of unconjugated neonatal jaundice. The 2 cases described in this report confirmed the efficacy of SnMP in terminating progression of hyperbilirubinemia in infants in whom phototherapy had failed to sufficiently control the problem and whose parents, for religious reasons, would not permit exchange transfusions. Interdiction of severe hyperbilirubinemia by inhibiting the production of bilirubin with SnMP can be an effective alternative to the use of exchange transfusion in the management of severe newborn jaundice that has not responded sufficiently to light treatment to ease concern about the development of bilirubin encephalopathy.

A single dose of Sn-mesoporphyrin prevents development of severe hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns.

OBJECTIVES: Severe neonatal jaundice is a common clinical manifestation of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and the most difficult to manage; kernicterus is not an uncommon outcome. We assessed in healthy, direct Coombs test-negative Greek newborns of >/=38 weeks' gestational age 1) the current burden of G-6-PD deficiency-associated severe jaundice, and 2) the efficacy of preventive use of Sn-mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase activity and thus of bilirubin production, in ameliorating jaundice in G-6-PD-deficient neonates. METHODS: The studies were conducted at Metera Maternity Hospital in Athens, Greece. Enrolled newborns had the plasma bilirubin concentration (PBC) determined in cord blood and daily thereafter until a declining level was obtained and the case was closed. Intervention with phototherapy was dictated at exact, age-specific PBC levels. In our initial study, we enrolled consecutive mature healthy G-6-PD-deficient newborns as well as a threefold excess of G-6-PD-normal neonates born at approximately the same time (control group). For the SnMP trial, G-6-PD-deficient neonates were administered SnMP as a single intramuscular dose of 6 micromol/kg birth weight within 24 +/- 12 hours of age. RESULTS: SnMP was administered at 26.7 +/- 6.1 hours of age to 172 G-6-PD-deficient newborns (group A); 168 G-6-PD-normal (group B) and 58 G-6-PD-deficient (group C) newborns who were enrolled earlier provided the comparison groups. Except for the expected excess of males in the G-6-PD-deficient groups (A and C), there were no differences in the demographic characteristics among the 3 groups. The incremental changes in PBC from cord blood to 24 hours of age also were similar (group A: 4.13 +/- 1.32 mg/dL; group B: 4.05 +/- 1.34 mg/dL; group C: 4.39 +/- 1.07 mg/dL), but there were significant differences in the next period, 24 to 48 hours of age (group A: 0.63 +/- 1.44 mg/dL; group B: 1.69 +/- 1.5 mg/dL; group C: 2.45 +/- 1.72 mg/dL). Peak PBC was significantly different (group A: 7.81 +/- 3.04 mg/dL; group B: 8.68 +/- 3.1 mg/dL; group C: 11.24 +/- 3.76 mg/dL) as was the age at which peak PBC was recorded (group A: 56 +/- 29 hours of age; group B: 69 +/- 26 hours of age; group C: 83 +/- 29 hours of age). These differences in favor of group A were observed despite the fact that phototherapy was used in 15% of the newborns in group B and 31% of those in group C, whereas none of those treated with SnMP required phototherapy. Finally, in one female, who was heterozygous for G-6-PD deficiency, in group C phototherapy failed and 2 exchange transfusions were performed. CONCLUSIONS: In comparison with normal neonates, G-6-PD-deficient neonates experienced a twofold increase in the prevalence of significant hyperbilirubinemia requiring phototherapy. A single dose of SnMP administered in the 1st day of life to the G-6-PD-deficient newborns shifted the peak PBC distribution to the left (lower values) even in relation to normal neonates and entirely eliminated the need for phototherapy. Interdiction of bilirubin production by use of a heme oxygenase inhibitor such as SnMP represents a simple and highly effective means for the preventive management of jaundice in G-6-PD-deficient newborns.

Adenoviral vector-mediated transfer of human heme oxygenase in rats decreases renal heme-dependent arachidonic acid epoxygenase activity.

Intravenous administration of an adenovirus human heme oxygenase (HO)-1 gene construct to rats resulted in functional expression of human HO-1 in brain, heart, lung, liver, and kidney. Because accurate assessment of human HO-1 mRNA in various tissues by Northern analysis is not sufficiently sensitive, we developed a method for quantifying human HO-1 mRNA copies with quantitative reverse transcription- polymerase chain reaction techniques; this allowed us to use the same primers for both the sample and internal standard. Administration of the adenovirus human HO-1 gene resulted in the detection of human HO-1 mRNA in various tissues with the highest levels seen in the kidney followed, in order, by lung > liver > brain > heart. Human HO-1 was detectable for up to 4 weeks in all tissues studied. Administration of adenovirus human HO-1 resulted in maximal increase of HO activity after 1 to 2 weeks in rats. The increase in HO activity due to gene transfer also was associated with a parallel decrease (approximately 25%) in cytochrome P-450 (CYP) content and in CYP-dependent arachidonic acid metabolism. In addition, we investigated the possibility that the human HO-1 gene altered the expression of the endogenous rat enzyme after administration of cobalt chloride s.c. Cobalt chloride administration resulted in increased HO activity in all tissues examined in rats transduced with the human HO-1 gene to the same degree as in nontransduced rats. The metal was a more potent inducer of renal HO activity than was the adenoviral-mediated human HO-1 vector. The increase in HO activity after adenoviral-mediated human HO-1 transfer was associated with a decrease in microsomal heme-CYP and CYP activity. The increase in HO-1 activity after adenovirus-mediated human HO-1 gene transfer may prove useful as a means of selectively increasing enzyme activity in a specific organ and regulating homeostasis by modulation of vasoactive molecules such as carbon monoxide and bilirubin and, in addition, providing a means of delivering the human HO-1 gene for experimental purposes.

Heme oxygenase inhibitors transiently increase serum ferritin concentrations without altering other acute-phase reactants in man.

Sn protoporphyrin (SnPP) and Sn mesoporphyrin (SnMP), potent inhibitors of heme oxygenase (HO), significantly suppress bilirubin production, lower serum and biliary bilirubin levels and increase biliary heme output in animals and man. In this study, 20 healthy volunteers, 7 patients with primary biliary cirrhosis and 4 patients with idiopathic hemochromatosis were treated with SnPP and 4 healthy volunteers with SnMP. In all cases, serum ferritin levels increased substantially but transiently after administration of these HO inhibitors. Values returned to baseline within a few days. Infusion of hematin in 4 healthy volunteers did not significantly affect ferritin levels. No increases occurred in 7 other acute-phase reactants. The observation that these HO inhibitors transiently increase serum ferritin levels implies a link between ferritin, iron metabolism and HO activity which may be usefully explored in disorders of iron metabolism.

Pharmacologic effects of the red blood cell substitutes cross-linked and non-cross-linked hemoglobins on hematopoiesis in rabbits.

The red blood cell substitutes beta-beta cross-linked (DECA-Hb, XLBV-Hb) and non-cross-linked (HbA) hemoglobins (Hbs), were transfused into rabbits and their effects on hematopoiesis examined. All rabbits receiving DECA-Hb or XLBV-Hb tolerated the Hbs well, whereas 50% of the animals transfused with similar doses of non-cross-linked HbA died. Analysis of peripheral blood and bone marrow BFU-E and CFU-GM production revealed that there was no significant variation in the generation of BFU-E and CFU-GM numbers for each cross-linked Hb transfusion group, but there were significant reductions in the HbA group. In animals transfused with cross-linked Hbs, splenic heme oxygenase (HO) activity was similar to that of controls; liver HO activity was slightly elevated, whereas HO activity was significantly increased in kidneys. Transfusion with non-cross-linked HbA produced greater inductions of HO activity in the liver and kidneys. Hepatic delta-aminolevulinic acid synthase (ALAS) activity was significantly reduced in HbA-transfused animals, whereas transfusion with cross-linked Hbs produced only minor, statistically nonsignificant, reductions in ALAS activity.

Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin.

OBJECTIVE: To assess the efficacy of Sn-mesoporphyrin (SnMP), a potent inhibitor of bilirubin production, in: a) moderating the need for phototherapy (PT) in full-term breastfed infants with plasma bilirubin concentrations (PBC) of >/=256.5 micromol/L and /=15 mg/dL and /=48 and /=256.5 micromol/L and /=15 mg/dL and

Comparative pharmacology of zinc mesoporphyrin and tin mesoporphyrin: toxic actions of zinc mesoporphyrin on hematopoiesis and progenitor cell mobilization.

The effects of two synthetic heme analogues, zinc mesoporphyrin (ZnMP) and tin mesoporphyrin (SnMP), on in vivo hematopoietic progenitor cell mobilization and in vitro hematopoiesis were examined in rabbit bone marrow. Rabbits received granulocyte colony-stimulating factor (rhG-CSF) for 7 days in order to mobilize increased numbers of erythroid (BFU-E) and myeloid (CFU-GM) progenitors in peripheral blood. Concurrent treatment of rhG-CSF-treated rabbits with ZnMP reduced mobilization of the numbers of BFU-E (76% inhibition, p < 0.0001) and CFU-GM (70% inhibition, p < 0.005) in peripheral blood. In contrast, SnMP administered at the same concentration had no significant suppressive effect on BFU-E and CFU-GM recruitment. Both metalloporphyrins inhibited bone marrow heme oxygenase activity equally in vivo, thus indicating that both compounds enter bone marrow cells. Direct in vitro addition of ZnMP to normal rabbit bone marrow cultures suppressed BFU-E and CFU-GM growth, whereas SnMP had no such effect. These results confirm, in an in vivo system, our earlier in vitro studies and demonstrate that, at the concentrations studied, ZnMP, in contrast to SnMP, displays toxicity for hematopoietic growth and progenitor cell production.

Control of hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns using an inhibitor of bilirubin production, Sn-mesoporphyrin.

BACKGROUND: Hyperbilirubinemia in new-borns with glucose-6-phosphate dehydrogenase (G6PD) deficiency is a serious clinical problem because of the severity and unpredictability of its course. An innovative approach to this problem is suggested by previous experience with Sn-mesoporphyrin (SnMP), a potent inhibitor of bilirubin production, in moderating neonatal hyperbilirubinemia caused by ABO incompatibility, immaturity, and unspecified mechanisms. OBJECTIVE: To compare the effectiveness of the preventive and therapeutic uses of SnMP in ameliorating the course of bilirubinemia of G6PD-deficient neonates. METHODS: Neonates born at the Metera Maternity Hospital, Athens, Greece, and found to be G6PD-deficient by cord blood testing were stratified by sex and gestational age (210-265 days and >265 days) and randomized in pairs to receive SnMP (6 micromol/kg birth weight, intramuscularly) either on the first day of life (preventive use) or if and when the plasma bilirubin concentration (PBC) level reached an age-specific threshold level for intervention (therapeutic use). In the case of failure of SnMP to control the rise of PBC levels, the protocol defined precisely the threshold PBC levels for switchover to phototherapy (PT) and, if necessary, exchange transfusion. PBC was measured daily until a declining value was obtained and the case was closed. RESULTS: A total of 86 G6PD-deficient neonates were randomized: 42 in the preventive arm and 44 in the therapeutic arm. Of the latter, 20 (45%) reached PBC levels requiring therapeutic intervention and thus received SnMP. Regardless of the trial arm, none of the 86 neonates required PT, whereas in a previous study in the same population, 33% of G6PD-deficient neonates required PT. In the intrapair sequential analysis, the favored arm was decided on the criterion of the age at closure of the case being shorter by at least 1 day. After plotting 30 untied pairs in the sequential analysis graph, the preventive use of SnMP proved to be the favored arm, and the trial was stopped. At this point, there were 2 unpaired neonates, 12 tied pairs, 22 pairs in which the preventive use of SnMP was favored and 8 pairs in which the therapeutic use of SnMP was favored. In the group analysis, infants in the preventive group, compared with those in the therapeutic group, had a lower maximum PBC level (8.2 +/- 3.1 and 10.9 +/- 2.8 mg/dL, respectively), which was reached at an earlier age (63.5 +/- 34.8 and 82.2 +/- 24.7 hours, respectively) as well as a lower closing PBC level (7.2 +/- 2.9 and 9.6 +/- 2.5 mg/dL, respectively) and an earlier age at closing (89.1 +/- 35.6 and 110.8 +/- 23.6 hours, respectively). Moreover, a PBC level of >/=8.0 mg/dL, a level at which jaundice is clearly visible, was not reached by 52% of the neonates in the preventive arm and 16% of the neonates in the therapeutic arm. CONCLUSIONS: In G6PD-deficient neonates, a single dose of SnMP administered preventively or therapeutically entirely supplanted the need for PT to control hyperbilirubinemia. The preventive use of SnMP offers practical advantages in populations with a high enough prevalence of G6PD deficiency to justify cord blood screening.

Sn-mesoporphyrin suppression of hyperbilirubinemia in EHBR/Eis rats, an animal model of Dubin-Johnson syndrome.

Sn-mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase (HO), controlled hyperbilirubinemia in rats of the mutant strain EHBR/Eis. This mutant strain displays pronounced conjugated hyperbilirubinuria and dark pigmentation of hepatocytes, characteristics of the Dubin-Johnson syndrome. SnMP administered at a dose of 10 mumol/kg body weight produced an immediate decrease in plasma bilirubin concentrations which could be maintained by weekly injections of this synthetic heme analogue. Marked inhibition of HO activity was demonstrated in liver, kidney and spleen but not in brain. These results demonstrate that SnMP can lower plasma bilirubin concentrations for extended periods in a new mutant rat model of Dubin-Johnson syndrome.

Zinc porphyrins: potent inhibitors of hematopoieses in animal and human bone marrow.

The effects of selected heme analogues on heme oxygenase activity in tissues and on human and rabbit bone marrow hematopoietic colony growth were examined. Zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP), at concentrations ranging between 1 and 20 microM, produced significant inhibition of human and rabbit bone marrow erythroid (CFU-E, BFU-E) and myeloid (CFU-GM) colony growth. The growth inhibition produced by ZnPP or ZnMP was not overcome with exposure of cultures to elevated levels of the growth factors erythropoietin and granulocyte-macrophage colony stimulating factor. In contrast, tin protoporphyrin and tin mesoporphyrin did not display any significant bone marrow toxicity when used at similar concentrations. In other studies, differential effects of tin mesoporphyrin and ZnMP administered intravenously on kidney heme oxygenase were demonstrated. Chromium mesoporphyrin administered intravenously proved lethal to animals. These results indicate that exposure of bone marrow to ZnPP and ZnMP can be deleterious to hematopoietic cells and raise the possibility that ZnPP, which is endogenously formed and found in high concentration in red blood cells in lead-poisoned children, may itself participate in the bone marrow toxicity produced by this metal.

Effects of a series of metalloporphyrins on adrenal, testicular and thyroid function in rats.

We have extended our earlier studies [Pharmacology 1986;34:9-16] on the effects of certain synthetic heme analogues and cobalt chloride (CoCl2) on endocrine functions mediated by the hypothalamic-pituitary axis to examine specifically the ability of Sn-protoporphyrin (SnPP) and Sn-mesoporphyrin (SnMP) to perturb adrenal, testicular and thyroid function since there is interest in the use of Sn(tin)-porphyrins in the treatment of hyperbilirubinemia of the newborn. SnPP and SnMP when administered to adult male rats did not alter serum corticosterone, testosterone, thyroxine or triiodothyronine levels when compared to control animals. In addition, administration of exogenous adrenocorticotrophic hormone produced an increase in serum corticosterone levels that was comparable in placebo-treated and SnPP- and SnMP-treated animals. These studies involved doses of both compounds substantially greater than those used clinically. The results clearly indicate that SnMP, presently the compound of choice for use in newborns, and SnPP do not in the doses studied impair adrenal, testicular and thyroid function in vivo.

Tissue distribution of synthetic heme analogues: studies with tin, chromium, and zinc mesoporphyrins.

The uptake in tissue of Sn-mesoporphyrin (SnMP), Cr-mesoporphyrin (CrMP) and Zn-mesoporphyrin (ZnMP) administered at doses ranging from 1 to 10 mu mol/kg BW and the effects of these compounds on heme oxygenase activity were examined in both adult and neonatal rats. SnMP and CrMP, but not ZnMP, were rapidly cleared from blood and taken up by liver, spleen and kidney where marked inhibition of heme oxygenase activity was demonstrated. None of the metalloporphyrins were detectable in brain, and no inhibition of heme oxygenase activity was demonstrable in this tissue after administration of the compounds to both adult and neonatal rats. These results demonstrate that SnMP, CrMP and ZnMP do not cross the blood brain barrier, a fact of interest in relation to the potential use of these compounds clinically.

Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements.

Several human heme oxygenase-1 promoter-driven chloramphenicol acetyltransferase constructs were examined in order to analyze promoter activity of the heme oxygenase-1 gene in microvessel endothelial cells. Heme oxygenase promoter activity was up-regulated by interleukin-6. This induction was shown to be down-regulated by glucocorticoids. Chloramphenicol acetyltransferase assays revealed that the promoter region (56 base pair) between -180 and -120 was responsible for up-regulation by growth factors, as well as for glucocorticoid-directed down-regulation. The same DNA fragments was shown to bind nuclear factor(s) from endothelial cells treated with dexamethasone. Formation of DNA protein complexes peaked after a 6-hour treatment. The DNA fragment was found to contain a sequence recognized by the STAT 3/acute phase response factor.

Depletion of cytochrome P-450 by thyroid hormone and cobalt-protoporphyrin IX in rat liver: evidence that susceptibility varies among forms of the heme protein.

The ability of 3,5,3'-triiodothyronine (T3) and cobalt-protoporphyrin LX (CoPP) to alter the levels of the cytochrome P-450 isoforms, CYP3A2, CYP2E1, CYP2B1 and CYP2B2, was examined in vitro in thyroidectomized adult male rats. With the exception of CYP2B2, CoPP administration resulted in a decline in each of the cytochrome P450 isoforms examined. The effects of T3 administration on immunoreactive levels of cytochrome P-450 were also examined in the liver of thyroidectomized rats. T3 treatment produced a marked depletion in all four cytochrome P-450 isoforms examined. Moreover, this T3-mediated depletion of hepatic cytochrome P-450 occurred in the absence of elevated heme oxygenase levels but in the presence of increased delta-aminolevulinate synthase activity. Thus, CoPP and T3 appear capable of producing isoform-specific downregulation of cytochrome P-450 in the liver of thyroidectomized rats. Based on relative levels of immunoreactive protein, the phenobarbital-inducible isoforms, CYP2B1 and CYP2B2, are most susceptible to T3-mediated suppression. Evidence is presented to suggest that these agents elicit these effects by entirely different mechanisms.

Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns.

BACKGROUND: 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. OBJECTIVE: To directly compare the efficacy of SnMP and PT for controlling hyperbilirubinemia in term and near-term infants. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin.

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 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. 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 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. 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.

Tin-mesoporphyrin inhibits heme oxygenase activity and heme-iron absorption in the intestine.

Long-term treatment with the heme oxygenase inhibitor tin-mesoporphyrin produces an iron deficiency anemia in rats analogous to that we reported in patients with the Crigler-Najjar type I syndrome receiving prolonged treatment with the inhibitor to ameliorate severe jaundice [Pediatrics 1992; 89: 175-182]. A dose- and time-dependent inhibition of intestinal heme oxygenase is produced by tin-mesoporphyrin which is independent of iron status of the animal. Tin-mesoporphyrin inhibits the intestinal enzyme whether administered orally or parenterally. Enzyme inhibition by either route results in diminished uptake of 59Fe from radiolabelled heme in the gut. Since tin-mesoporphyrin stimulates excretion of unmetabolized heme into bile its ability to inhibit intestinal heme oxygenase and to decrease heme-iron absorption in the gut probably accounts in part for the iron deficiency produced by the agent. The availability of an orally active agent which inhibits heme oxygenase and heme-iron absorption in the intestine may prove useful for experimental and therapeutic studies in diseases of iron metabolism.