Use of D-Penicillamine in the Neonatal Hyperbilirubinemias
György Balla, István Pataki and Lajos Lakatos*
Department of Pediatrics, University of Debrecen, Hungary
Submission: March 21, 2017; Published:May 05, 2017
*Corresponding author: Lajos Lakatos, Department of Pediatrics, University of Debrecen 4032 Debrecen, Egyétem tér 1, Hungary, Tel: +36 52 225335; Email: lakatosl@kenezykorhaz.hu
How to cite this article:Gyorgy B, Istvan P, Lajos L. Use of D-Penicillamine in the Neonatal Hyperbilirubinemias. Theranostics Brain Spine Neuro Disord. 2017; 1(1): 555552. DOI: 10.19080/TBSND.2017.01.555552
Abstract
D-penicillamine (DPA) was first recognized as a potential benefit for neonatal hyperbilirubinemia (NHBI) caused by hemolytic diseases or immaturity of UDP-glucuronyltransferase enzyme. During this time there was a remarkedly low incidence of retinopathy of prematurity (ROP) in the infants treated with DPA. Later, our studies were replicated in other institutes in Hungary, Poland, U.S. A., India and Mexico. It is important to note that there was no intolerance or short- or long-term toxicity of the medication, in spite of the fact that in the newborn period DPA was used 10-20 times higher doses than those in adult.
Keywords: D-Penicillamine treatment; ABO- and Rh hemolytic diseases; Orphan drug; Follow-up studies
Introduction
It appears that bilirubin IXa has unique structural properties which might have been predicted on the basis of modern concepts of organic chemistry but whose biological implications certainly were not fully appreciated [1]. The initial breakdown product of haemoglobin is UCB (unconjegated or indirect bilirubin) which is insoluble in water but soluble in lipids. This process is catalyzed by an important rate limiting enzyme, heme oxygenase (HO). UCB is carried in the blood bound to albumin. It is taken up by the liver and conjugated by the enzyme uridine 5'-diphospho-(UDP)- glucuronyltransferase to conjugated bilirubin (direct bilirubin) which is water soluble and excreted in bile into the gut and is detectable in urine when blood levels rise [2].
- The term "kernicterus" is reserved for the chronic and permanent clinical sequelae of bilirubin toxicity.
- There are no bilirubin levels which are known to be safe or which will definitely cause kernicterus or BIND.
- "Vigintiphobia" = ifthe serum bilirubin concentration is 20 mg/dL (340 μmol/L); at a level at which ET was recommended.
In rhesus hemolytic disease (Rh-HDN), it was found that kernicterus could be prevented if the bilirubin was kept below 20mg/dL. 30-35 years ago this recommendation was applied to other hyperbilirubinemias as well. The guidelines are much more permissive now days [3] concerning jaundice at 2 days to 2 weeks of age. Some studies have found that the use of risk scores is as accurate as universal screening for predicting NHBI [4].
The age of onset is useful guide to the likely cause of the jaundice. Icterus starting within 24 hours of age usually results from hemolysis. This is particularly important to identify as the bilirubin is un conjugated and can rise very rapidly and reach extremely high levels. So, this condition requires close monitoring [5]. Jaundice occurring at 2 days to two weeks of age is usually due to other, more benign, causes but never be complacent.
When in the early 1970s, we reviewed the role of D-PA in the treatment of NHBI the drug was new to most neonatologists [6,7]. The idea that D-PA might be a suitable drug to act as a copper- binding agent for use to control icterus neonatorum occurred, serendipituously, to one of us (L.L), while reflecting on the similarity of copper storage in Wilson's disease and neonates. It is well known that all neonates have increased concentration of copper in their liver and brain, and a decreased concentration of a specific plasma copper-protein, ceruloplasmine (Cp), in comparison with individuals over one year old [8]. D-PA has been found effective to decrease the concentration of bilirubin in blood samples in vitro. Subsequent clinical studies for control of NHBI was introduced to our department in March 1973. This drug, given intravenously to newborns, greatly reduces the plasma bilirubin concentration or prevents its increase, which is usually seen during the first few days of life. This treatment is especially effective in jaundice of hemolytic origin, such as AB0-or Rhesus incompatibility, and is used together with phototherapy in several neonatal units in Hungary where it has largely replaced exchange transfusions [9].
Bizarrely, D-PA is a very cheap, low-cost drug, but at the same time it is developed under the Orphan Drug Act of 1983 in the U.S. which is a federal law concerning rare diseases (orphan diseases) [10]. This means that pharmaceutical companies produce this "homeless, not a money-maker” drug with reluctance. For example the IV form of D-PA is now a days not available in the market and the per os preparation is produced by a few companies in the world.
Dosages and use of D-PA in neonates
Safety and efficacy data regarding intravenous D-PA (MetalcaptaseR) use in neonates have not been available. So, we had to establish the safe portions and the adequate UCB-lowering doses. When we have observed a favorable clinical outcome occurred in all cases with NHBI without side effects (no patient had or developed renal impairment or other not desired adverse effects), we have decided to use an unusually high IV administration of this drug Table 1.
The bioavailability of intravenously administered drug is 100% since no absorption process is involved. The rate of absorption of orally administered drugs is slower in neonates and young infants due to delayed gastric emptying resulting to prolongation in time required to achieve maximal plasma concentration. In the early period of D-PA therapy we used lower doses and, observing the lack of any adverse effects, we raised the dose gradually until the achievement of optimal bilirubin decrease. Compared with older children and adults, neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination. Fortunately, the developmental pharmacology and the age related effects of D-PA largely favoured by the administration of unusually high doses of this drug [11].
In this survey we will review our D-PA research, which embraces a period of more than 40 years. We intend to focus on only a few aspects of this field which we feel to be important.
D-PA therapy in various hyperbilirubinemias of the newborn infant
Table 2. shows the effects of DPA-therapy in ABO- Hemolytic Disease of the Newborn (HDN) in term infants (IV administration starting at <24 hours of age - group I). In the ABO-HDN, D-PA significantly reduced the need for both initial and repeated ETs. The number of ET per infant was 1.32 in the control and 0.11 in the treated group. The infants who received D-PA therapy had significantly lower mean serum bilirubin (SEBI) concentrations than the control infants [12]. In the group II (25 treated and 27 control infants) D-PA therapy was started after the third day of life. In group I D-PA caused a marked decline of SEBI concentrations at a time when such levels were rised in the control infants. II D-PA considerably reduced the number of ETs (0.70 : 0.24 = control : treated) but the difference was statistically not significant. In the latter patients the mean bilirubin values showed a smaller difference compared to the controls than in group I. Since group I represented the results of early or preventive treatment, while group II those of late or therapeutic treatment, it is obvious that, for ensuring success, D-PA treatment should be begun as early as possible in AB0-HDN.
In Rh-HDN the number of ET per infant was 1.6 in the control and 0.7 in the treated group. In addition almost the half of cases no ET was performed in the D-PA-treated groupllTable 3 [13].
Hyperbilirubinemia
In another clinical study [14] we examined the ability of D-PA therapy to modify the course and duration of so-called idiopathic hyperbilirubinemia in term infants in comparison with ETs (Table 4). Patients were randomly selected to receive D-PA therapy or ET when the SEBI reached values of more than 20 mg/dL. It is to be noted that ET was also performed in cases treated with D-PA where the level of bile pigment did not decrease within 4-6 hours after the first single intravenous dose. No infants studied had any laboratory or clinical evidence of illness or hemolytic process or any sings of disturbances of the central nervous system (CNS). It was found that infants who received ET had a significantly lower SEBI 8-12 hours after intervention than infants in the DPA-treated group, but there was no significant difference between the two groups at 32-36 hours of the post exchange period, respectively.
In the course of conducting clinical trials to investigate the presumably beneficial effects of D-PA in the reduction of retinopathy of prematurity (ROP), we routinely measured the SEBI of VLBW infants. There was no significant difference between the D-PA-treated and control groups either in the mean peak SEBI or in the number of ETs needed [15]. This suggests phototherapy alone proved to be just as effective as phototherapy plus D-PA in babies with a birth weight under 1500g Table 5. The most frequent clinical factors in the severity of NHBI of VLBW infants include increasing immaturity, unrecognized neonatal hemolysis, array of genetic conditions or concurrent conditions of dehydration, sepsis, or acidosis, hypoalbuminemia, and/or poor feeding. With current clinical practice, icteric complications are exceedingly infrequent given the liberal, prophylactic, and effective use of phototherapy
Case Reports
There were some very impressive cases in our practice in neonatology deserved to show them individually. The first patient received D-PA treatment in the neonatal period was an AB0- incompatible preterm infant with birth weight of 2000 g. At an extremely high TSB (32.5mg/dL) intravenous administration of D-PA was begun. The first dose caused a spectacular fall of 6.5mg/ dL in the level in 4 hours, and under the influence of such treatment we were able to witness a gradual disappearance of the NHBI. She is now a member of a famous operhouse in Germany as an opera singer Table 7. This case is all the more remarkable because this baby showed typical symptoms of acute bilirubin encephalopathy at 3-6 days of age: somnolence, hypotonia, and loss of the Moro reflex and sometimes opisthotonus. In addition, she was in need of CPR (cardiopulmonary resuscitation) just at the beginning of the ET because of a cardiac arrest, so, the intervention (ET) was not performed and it proved to be unsuccessful concerning the high UCB level. Surviving of the neonatal period, however, she did not demonstrate any of the chronic manifestations of bilirubin encephalopathy, including the most common sequelae of sensorineural hearing imperment [16]. The lack of chronic (residual) symptomes is due to the neuroprotective effects of D-PA in the neonatal period. In 1999 we published a case of an AB0 incompatible term infant girl born to parents who were Jehovah's Witnesses [17]. The infant was admitted to our neonatal unit with a high SEBI necessitating ET. The parents signed a request that blood should not be administered under any circumstances. However, they authorised us to use of alternative treatments: orally administered D-PA, phototherapy, intravenous fluids, and recombinant human erythropoietin (200U/kg bw. subcutaneously on every second day for two weeks). This infant was discharged from our unit in good health. Her physical growth and motor milestones at 3 years of age revealed no red flags for neurodevelopmental maturation. In addition, the follow up audiometric tests performed on this infant were normal. She was the first baby in the world who received such a combined alternative (and “bloodless”) treatment for serious AB0-HDN.
We recently cared for a term infant boy blood group B, Rh- positive who was born at 37. gestation to a 33-year old, blood group B, Rh-negative mother [18,19].The baby was born as an 11. offspring of his mother and appeared jaundice at 10 hours of life and had moderate anemia. The direct Coombs test was strongly positive (++++) in the cord blood. The clinical characteristics of the infant with Rh-HDN are shown in the Table 6.
Before we attempt to summarize the possible mechanisms of action of D-PA in the neonatal period, it is appropriate to elucidate its interference with the binding of UCB to human serum albumin. Such testing seems to be particularly necessary with a plasma bilirubin-lowering drug, since theoretically the effect might be explained by displacement of the pigment from its albumin binding. We performed detailed investigations using three in vitro methods in addition two in vivo testing in Gunn rats. Results were negative in all cases (Table 7). Quantitatively, the doses of D-PA administered to the neonates do not displace UCB from its binding to albumin. Consequently, the ameliorating effect of D-PA on NHBI must be due to other mechanisms [20].
Mechanisms of Action of D-PA in the Neonatal Hyperbilirubinemia
Since heme metabolism is a crucial stage in bilirubin production, we examined the activity of heme oxygenase, the initial and rate- limiting enzyme of heme degradation [21,22]. The 3 days of DPA treatment in the adult animals did not lead to any significant change in heme oxygenase activity. In contrast, in neonates a marked reduction in enzyme activity was observed following DPA treatment. At the same time, the activity of UDP glucuronyltransferase was measured in liver homogenates of newborn and adult rats. After DPA treatment we could not observe any changes in enzyme activity [23,24].
The plausible explanation of age-relating mechanisms of action of DPA: bilirubin production will be inhibited by the decreased activity of heme oxygenase. The age-related differences in the effect of DPA concerning heme oxygenase is supported by the experimental works of Maines & Kappas [25].
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Other beneficial effects of D-PA, together with bilirubin, in the neonatal period are as follows: neuroprotection against copper-induced oxidative/ nitrosative stress and excitoxicity in the neonatal period [26].
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