A Nanoceutical Agent for Chemoprevention of Bilirubin Encephalopathy

ABSTRACTBackgroundTargeted degradation of bilirubin in vivo may enable safer and more effective approach to manage incipient bilirubin encephalopathy consequent to severe neonatal hyperbilirubinemia (SNH). This report builds on the use of a spinel structured mixed-valence transition metal oxide (trimanganese tetroxide) nanoparticle duly functionalized with biocompatible ligand citrate (C-Mn3O4 NP) having the ability to degrade bilirubin without photo-activation.MethodThe efficiency of C-Mn3O4 NP in in vivo degradation of serum bilirubin and amelioration of severe bilirubin encephalopathy and associated neurobehavioral changes was evaluated in C57BL/6j animal model of SNH.ResultsOral single dose (0.25 mg kg-1 body weight) of the NPs efficiently reduced serum bilirubin levels (both conjugated and unconjugated) in study mice. It prevents bilirubin-induced neurotoxicity with reduction of SNH as observed by neurobehavioral and movement studies of SNH-mice. Pharmacokinetic data suggests intestinal reabsorption of the NPs and explain sustainable action. Biodistribution, pharmacokinetics, and biocompatibility of the NPs were tested during sub-chronic exposure.ConclusionThus, we report preliminary studies that explore an affordable chemoprevention mechanism to acutely prevent or minimize bilirubin neurotoxicity in newborn infants.IMPACT STATEMENTDespite several attempts, no pharmaco-therapeutics are available for the treatment of severe neonatal hyperbilirubinemia (SNH) and associated neurotoxicity.Our newly developed nanodrug, citrate functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), can efficiently ameliorate SNH and associated neurotoxicity as investigated in preclinical rodent model.Chemoprevention effect of the nanodrug is found to be safe and sustainable.If successfully translated into clinical trials, C-Mn3O4 NPs could become the first drug to treat SNH.

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Correlation between Neonatal Hyperbilirubinemia and Serum Magnesium and Copper Levels in Dhaka City

Current Journal of Applied Science and Technology ◽

10.9734/cjast/2020/v39i4531165 ◽

2020 ◽

pp. 125-131

Author(s):

Mohammad Anwar Hossain ◽

Md. Ekramul Islam ◽

Ashik Mosaddik ◽

Md. Saiful Islam ◽

Md. Nazmul Huda ◽

...

Keyword(s):

Serum Bilirubin ◽

Serum Magnesium ◽

Colorimetric Method ◽

Newborn Infants ◽

Sulfanilic Acid ◽

Neonatal Hyperbilirubinemia ◽

P Value ◽

Control Groups ◽

Automated Method ◽

Acid Reaction

Background: Neonatal hyperbilirubinemia is a condition when a newborn has an excessive amount of bilirubin in the blood and is one of the most prevalent problems in neonates. Many studies reported that copper and magnesium play an important role in the pathogenesis and development of neonatal hyperbilirubinemia. Objectives: The aim of this study is to find out the correlation between the level of magnesium and copper with hyperbilirubinemia. Methodology: Serum bilirubin was assayed with colorimetric method by the use of diazotized sulfanilic acid reaction. A photometric automated method was used to determine the levels of magnesium and copper in the serum of neonates in both controls group (162) and cases group (220). Results: In the present study a significantly higher levels of Mg was found in hyperbilirubinemia of newborn infants when compared with control groups (23.67 ±2.33 mg/L versus 19.74 ±2.18 mg/L respectively and p value <0.001 which was significant) and correlation between hyperbilirubinemia and magnesium also significant (p value <0.001). Copper levels was significantly higher in hyperbilirubinemia of newborn infants (0.74 ±0.08 mg/L) compared with control groups (0.41 ±0.12 mg/L), where p value was <0.001, which was significant and correlation between hyperbilirubinemia and copper also significant (p value <0.001). Conclusion: It can be concluded that current study showed the concentrations of magnesium and copper levels were found to be significantly greater than control groups and may have a correlation with neonatal jaundice.

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Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700232114 ◽

2017 ◽

Vol 114 (8) ◽

pp. E1432-E1440 ◽

Cited By ~ 14

Author(s):

Shujuan Chen ◽

Wenqi Lu ◽

Mei-Fei Yueh ◽

Eva Rettenmeier ◽

Miao Liu ◽

...

Keyword(s):

Acid Metabolism ◽

Serum Bilirubin ◽

Neonatal Hyperbilirubinemia ◽

Intestinal Epithelial ◽

Targeted Deletion ◽

Bilirubin Encephalopathy ◽

Intestinal Maturation ◽

Immunohistochemistry Analysis ◽

Developmental Maturation ◽

Target Activation

Severe neonatal hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. HumanizedUGT1(hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes hyperbilirubinemia inhUGT1neonates because of intestinalUGT1A1gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated inhUGT1mice with targeted deletion of intestinal IKKβ. Physiological events during neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and hyperbilirubinemia.

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Adverse Events of Exchange Transfusion in Neonatal Hyperbilirubinemia

Journal of Nepal Paediatric Society ◽

10.3126/jnps.v34i1.9030 ◽

2014 ◽

Vol 34 (1) ◽

pp. 7-13 ◽

Cited By ~ 1

Author(s):

M Chitlangia ◽

GS Shah ◽

P Poudel ◽

OP Mishra

Keyword(s):

Adverse Events ◽

Respiratory Distress ◽

Exchange Transfusion ◽

Serum Bilirubin ◽

Tertiary Care ◽

Neonatal Hyperbilirubinemia ◽

Total Serum Bilirubin ◽

Total Serum ◽

Bilirubin Encephalopathy ◽

The Common

Introduction: Jaundice is an important problem during neonatal period. When total serum bilirubin (TSB) level exceeds a critical limit, it crosses the blood brain barrier and results into bilirubin encephalopathy. The main aim of therapy for neonatal hyperbilirubinemia is prevention of bilirubin encephalopathy by phototherapy and/or exchange transfusion. The aims of this study were to evaluate the efficacy of exchange transfusion (ET) and observe the adverse events during and following three days of ET in neonates with hyperbilirubinemia. Materials and Method: Hospital based cross-sectional descriptive study. All neonates admitted to neonatal intensive care unit and /or paediatric wards of a tertiary- care centre between September 2010 to March 2012, requiring ET were enrolled. Results: A total of 139 ETs were performed in 120 neonates. The common causes were ABO incompatibility (30.8%), prematurity (30.8%), idiopathic (27.5%), Rh isoimmunization (6.7%) and cephalhematoma (4.2%). Mean pre- ET total serum bilirubin (TSB) was 24.2 mg% dL. There was 58% reduction in TSB in post ET and 31% net reduction in 6 hr post ET. Term and preterm neonates showed equal percentage of TSB reduction. Respiratory distress (10.8%) and bradycardia (6.7%) were the common adverse events during, and hypocalcemia (98.3%) and thrombocytopenia (34.2%) in 3 days following ET. The sick neonates had significantly higher incidence of thrombocytopenia (p= 0.031), respiratory distress (p=0.009), apnea (p<0.001) and cardiorespiratory arrest (p<0.001). Overall mortality was 4.2%, and non-survivors were mostly low birth weight, born outside the present hospital and had higher incidence of adverse events. Conclusion: Exchange transfusion is an effective intervention in reducing the serum bilirubin level. However, these neonates require monitoring of ionised calcium and thrombocytopenia. Sick neonates had higher incidence of adverse events than healthy and close clinical monitoring is needed to improve the outcome. DOI: http://dx.doi.org/10.3126/jnps.v34i1.9030 J Nepal Paediatr Soc 2014;34(1):7-13

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Outcome of Neonatal Hyperbilirubinemia from a Tertiary Care Hospital in Eastern Nepal: A Cross-sectional Study

Journal of BP Koirala Institute of Health Sciences ◽

10.3126/jbpkihs.v4i1.36324 ◽

2021 ◽

Vol 4 (1) ◽

pp. 37-42

Author(s):

Shyam Prasad Kafle ◽

Mukesh Bhatta ◽

Ramesh Shrestha ◽

Sarita Sitaula ◽

Namu Koirala ◽

...

Keyword(s):

Exchange Transfusion ◽

Serum Bilirubin ◽

Cross Sectional Study ◽

Neonatal Hyperbilirubinemia ◽

Total Serum Bilirubin ◽

Total Serum ◽

Sectional Study ◽

Cross Sectional ◽

Bilirubin Encephalopathy ◽

Poor Outcome

Background: Timely detection and treatment of pathological hyperbilirubinemia in newbornscan prevent acute bilirubin encephalopathy and its consequences. We aimed to identifyitsoccurrence, presentationtime, phototherapyduration, need for exchange transfusion,and outcome. Methods: In this cross-sectional study, we enrolled all the babies admitted for pathological neonatal hyperbilirubinemia in the university hospital ofBPKIHSin a one-yearduration. Babies with life-threatening congenital malformations or conjugated bilirubin >20% of total serum bilirubin or >2 mg/dl were excluded. Obstetric profile of mothers, clinical and laboratory parameters of babies, onset time of pathological jaundice, duration of phototherapy, need for exchange transfusion or intravenous immunoglobulin were recorded. Neonatal outcome was classified as good and poor and its association with potential predictors analyzed. Results: One-hundred and fifty babiesdeveloped neonatal jaundice requiring treatment. The most common causes includedABO and Rh setting. No cause was found in 26 (18%) babies. One-hundred and eight babies (72%) were only managed withphototherapy whereas 42 (28%) required both phototherapy and double volume exchange therapy. The majority (84.5%) had good outcome without any residual neurological deficit at discharge.Babies with total serum bilirubin >20 mg/dl at presentation, duration of phototherapy >44.8 h, ABO setting, hemolysis, and out born statussignificantly developed poor outcome (p < 0.05). Conclusion: About 15% of the babies with hyperbilirubinemia had acute bilirubin encephalopathy at discharge suggestive of poor outcome. Babies with high bilirubin at presentation, longer duration of phototherapy, ABO settings, hemolysis, and out born statusdeveloped poor outcome.

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The Combined Effect of Phototherapy and Phenobarbital on Serum Bilirubin Levels of Premature Infants

PEDIATRICS ◽

10.1542/peds.49.1.110 ◽

1972 ◽

Vol 49 (1) ◽

pp. 110-112

Author(s):

Michael G. Blackburn ◽

Marcello M. Orzalesi ◽

Penelope Pigram

Keyword(s):

Premature Infants ◽

Serum Bilirubin ◽

Combined Therapy ◽

Newborn Infants ◽

Neonatal Hyperbilirubinemia ◽

Combined Effect ◽

Sufficient Evidence ◽

Monochorionic Twins ◽

Photo Oxidation ◽

Prevention And Treatment

The effectiveness of phototherapy in the prevention and treatment of neonatal hyperbilirubinemia is well established. There is also sufficient evidence to indicate that phenobarbital is effective in decreasing serum bilirubin levels in newborn infants. Since light is thought to break down bilirubin in the skin by photo-oxidation, and phenobarbital is known to induce bilirubin conjugating activity in the liver, the possibility of an additive effect in combined therapy was investigated in the present study. Materials and Methods Six sets of premature identical (monochorionic) twins (33 to 35 weeks' gestation) were studied after obtaining parental permission. Each set of twins was admitted to the study at 12 hours of life if both infants were considered normal with the exception of prematurity.

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....Beginning to See the Light

PEDIATRICS ◽

10.1542/peds.75.4.792 ◽

1985 ◽

Vol 75 (4) ◽

pp. 792-795

Author(s):

M. JEFFREY MAISELS

Keyword(s):

Randomized Controlled Trial ◽

Exchange Transfusion ◽

Serum Bilirubin ◽

Neonatal Period ◽

Controlled Trial ◽

Newborn Infants ◽

Bilirubin Encephalopathy ◽

Randomized Controlled ◽

Prospective Randomized Controlled Trial ◽

Postmortem Finding

In March 1952, Mollison and Walker1 reported the results of their prospective, randomized, controlled trial on the effect of exchange transfusion v simple transfusion in infants with severe erythroblastosis fetalis. They showed that exchange transfusion led to significantly lower mortality and a much lower incidence of fatal kernicterus. In the interim, numerous published studies have examined the relation between serum bilirubin levels in the neonatal period and the postmortem finding of kernicterus or the presence of later, clinical, bilirubin encephalopathy. With few exceptions, the design of these studies has made interpretation of their results hazardous, if not nugatory.2 We now have a study from the National Institute of Child Health and Human Development (NICHD)3 in which the population is sufficiently large and the study design sufficiently rigorous to permit actual, if tentative, conclusions concerning the effect of a different intervention (phototherapy) upon the immediate and later outcome of jaundiced newborn infants.

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Effect of phototherapy with alumunium foil reflectors on neonatal hyperbilirubinemia

Paediatrica Indonesiana ◽

10.14238/pi55.1.2015.18-22 ◽

2015 ◽

Vol 55 (1) ◽

pp. 18 ◽

Cited By ~ 1

Author(s):

Tony Ijong Dachlan ◽

Tetty Yuniati ◽

Abdurachman Sukadi

Keyword(s):

Serum Bilirubin ◽

Aluminum Foil ◽

Neonatal Hyperbilirubinemia ◽

Inclusion Criteria ◽

Term Neonates ◽

Bilirubin Encephalopathy ◽

American Academy Of Pediatrics ◽

Increased Risk ◽

Common Problems ◽

The Difference

Background Neonatal hyperbilirubinemia (NH) is one of the most common problems in neonates, but it can be treated with blue light phototherapy. Developing countries with limited medical equipment and funds have difficulty providing effective phototherapy to treat NH, leading to increased risk of bilirubin encephalopathy. Phototherapy with white reflecting curtains can decrease the duration of phototherapy needed to reduce bilirubin levels. Objective To compare the duration of phototherapy needed in neonates with NH who underwent phototherapy with and without aluminum foil reflectors. Methods This open clinical trial was conducted from July to August 2013 at Dr. Hasan Sadikin Hospital, Bandung, Indonesia. The inclusion criteria were term neonates with uncomplicated NH presenting in their first week of life. Subjects were randomized into two groups, those who received phototherapy with or without aluminum foil reflectors. Serum bilirubin is taken at 12th, 24th, 48th hours, then every 24 hours if needed until phototherapy can be stopped according to American Academy of Pediatrics guidelines. The outcome measured was the duration of phototherapy using survival analysis. The difference between the two groups was tested by Gehan method. Results Seventy newborns who fulfilled the inclusion criteria and had similar characteristics were randomized into two groups. The duration of phototherapy needed was significantly less in the group with aluminum foil reflectors than in the group without reflectors [72 vs. 96 hours, respectively, (P<0.01)]. Conclusion The required duration of phototherapy with aluminum foil reflectors is significantly less than that of phototherapy without reflectors, in neonates with NH.

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LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

Acta Endocrinologica ◽

10.1530/acta.0.047s028 ◽

1964 ◽

Vol 47 (3_Suppl) ◽

pp. S28-S36

Author(s):

Kailash N. Agarwal

Keyword(s):

Red Cells ◽

List Type ◽

Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

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STUDIES IN CONGENITAL GENERALIZED LIPODYSTROPHY

Acta Endocrinologica ◽

10.1530/acta.0.0720495 ◽

1973 ◽

Vol 72 (3) ◽

pp. 495-505 ◽

Cited By ~ 7

Author(s):

Oddmund Søvik ◽

Svein Oseid

Keyword(s):

Biological Activity ◽

Insulin Response ◽

Epididymal Adipose Tissue ◽

Large Individual ◽

Immunoreactive Insulin ◽

List Type ◽

Glucose Load ◽

Congenital Generalized Lipodystrophy ◽

The One

ABSTRACT The biological activity of plasma insulin from 4 cases of congenital generalized lipodystrophy has been studied, using rat diaphragm and epididymal adipose tissue in vivo. The results are compared with previous data on plasma immunoreactive insulin obtained in these patients. 2 of the 4 cases exhibited unusually high biological insulin activities during the fasting state as well as after an intravenous (iv) glucose load. In the fat pad assay activities as high as 10 000 μU insulin per ml were observed. During childhood the biological insulin activities were generally high, although there were large individual variations. However, in the one case studied after the age of puberty, the insulin response to a glucose load was negligible. Taken together, the biological and immunological activities observed strongly suggest the presence of pancreatic insulin in these patients. It appears that the circulating insulin has a fully biological activity. The decreasing insulin activities after cessation of growth are in agreement with the appearance of frank diabetes at this time.

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