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Background: Retinopathy of prematurity remains a common problem. A low rate of this disorder was unexpectedly observed among infants treated with intravenous d-penicillamine to prevent hyperbilirubinemia. This observation led to the investigation of its use to prevent retinopathy of prematurity., Objectives: To answer the question: Among very low birth weight infants, what is the effect of prophylactic administration of d-penicillamine on the incidence of acute ROP or severe ROP, and side effects including death?, Search Strategy: Searches were made of multiple electronic databases, previous reviews including cross references, abstracts, conference/symposia proceedings, and expert informants. The search was updated to November 2000., Selection Criteria: Randomized or quasi-randomized controlled trials that administered d-penicillamine to infants less than 2000g birth weight within the day following birth were considered relevant to this review. Additional case series were examined for potential side effects., Data Collection and Analysis: Data on clinical outcomes were excerpted by 3 reviewers independently, and consensus reached. Data analysis was conducted according to the standards of the Neonatal Cochrane Review Group., Main Results: Two randomized trials on the effects on ROP were identified. When combined, they showed a significantly lower incidence of acute ROP in the treated infants, relative risk of 0.09, 95% CI [0.01,0.71]. Severe stages of ROP could not be analyzed. There was no effect on death rates, relative risk 0.99 95% CI [0.70,1.39]. No side effects were reported, and follow up at one year revealed no significant differences in spasticity or developmental delay, although there were more rehospitalizations among the controls. In other reports of using d-penicillamine in over 140 infants for hyperbilirubinemia, skin rashes were reported in 2 infants and one had vomiting that may have been related., Reviewer's Conclusions: D-penicillamine is unlikely to affect survival, and may reduce the incidence of acute ROP among survivors. Studies to date justify further investigation of this drug in a broader population; careful attention to possible side effects is needed.

Pulmonary hypertension is one of the major problems in the neonatal period. Free oxygen radicals play important role in the activation of pulmonary vasoconstriction. Since D-penicillamine has proved to be a strong antioxidant in newborns it was of interest to investigate the effect of the drug in the oxygen radical induced pulmonary hypertension. According to our animal experiments D-penicillamine inhibits the xanthine oxidase induced pulmonary hypertension in piglets. The same inhibitory effect was observed in the prostanoid metabolism. Could D-penicillamine be used in the treatment of pulmonary hypertension in the newborn?

D-penicillamine was introduced to treat neonatal hyperbilirubinaemia in 1973 and to prevent retinopathy of prematurity in 1980. In this study we investigated the renal and liver functions of neonates treated with DPA and the in vitro effect of the drug on superoxide anion generation and beta-glucuronidase release as well as on phagocytic and intracellular killing activation on human peripheral blood granulocytes. Our data concerning the renal and liver functions before and after 3 to 4 days DPA treatment reveal no pathological change during short-term administration in the neonatal period. Furthermore, none of the examined DPA concentrations influenced the phagocytic or killing activity of neutrophils.

Influence of D-Penicillamine (DPA) on metabolic and functional activities of neutrophil granulocytes was investigated in vitro by measuring superoxide anion production and beta-glucuronidase release as well as by determining phagocytic and intracellular killing activities of cells. Preincubation with DPA in the concentration range of 0.5-5.0 mM resulted in 28-53% increase in superoxide anion production by granulocytes stimulated with 10(-7) M FMLP. DPA in the same concentration range resulted in 145-371% rise in the FMLP-stimulated beta-glucuronidase release. However, uptake and subsequent killing of viable Staphylococcus aureus was not influenced by incubation of granulocytes with various concentrations of DPA (0.5-5.0 mM). From these results we conclude that DPA may influence the superoxide anion production and beta-glucuronidase release in granulocytes without altering the phagocytic and intracellular killing activities of these cells. We suppose that the unchanged antibacterial activity of neutrophil granulocytes is resulted by the two opposite DPA effects: acting extracellularly reduces free radical level while the direct membrane effect results in enhancing metabolic activity in granulocytes.

D-penicillamine, a drug used clinically for the treatment of neonatal hyperbilirubinaemia, was tested for interference with the binding of bilirubin to human serum albumin by three methods: 1) The peroxidase technique, investigating the effect of D-penicillamine on the equilibrium concentration of unbound bilirubin in a solution containing a molar excess of albumin; 2) the MADDS method, measuring the concentration of vacant bilirubin binding site on albumin in a solution of pure albumin, or infant blood serum, with added D-penicillamine; and 3) injection of D-penicillamine into Gunn rats and determination of any decrease of plasma bilirubin which would be caused by displacement of the pigment. Results were negative in all cases. Quantitatively, the doses of D-penicillamine used clinically cannot displace bilirubin from its binding to albumin. The ameliorating effect on hyperbilirubinaemia in the newborn must be due to some other mechanism.

A prospective controlled trial has recently been reported to show the effectiveness of D-penicillamine (DPA) in the prevention of retinopathy of prematurity (ROP) among infants less than 2000 g birth-weight. The present paper is a comprehensive overview of a cohort of 204 prematures enrolled in the above study, with respect to mortality and outcome. Survival rate in the DPA treated group was the same as of those receiving conventional therapy. When the outcome of the DPA treated and the control infants was compared in terms of both major and minor impairments, the frequency of disabled and handicapped infants was higher in the control group. The same was observed with respect to the number of repeated hospital treatments, which was significantly higher among the control babies. The results suggest that DPA effectively prevents ROP among very-low-birth-weight infants, and also that the drug has no adverse effect on either mortality or late development.

A 3-day D-penicillamine treatment of neonatal rats caused a significant decrease in heme oxygenase activity. This change was not observed in adult rats. The data indicate age-related differences in the effects of D-penicillamine.

This study comprises 120 full-term infants with ABO hemolytic disease admitted to the neonatal department during a period of 60 months from 1970-1975. During the first 30 months newborns (n = 61) received no D-penicillamine therapy, whereas all infants (n = 59) received this treatment (300-400 mg/kg/day, divided into 4 equal doses, for 2-5 days) during the last 30 months. The patients were further subdivided into two groups according to the point of time when D-penicillamine treatment was begun, viz. group I (34 treated and 34 control infants) within the first 24 h of life; group II (25 treated and 27 control infants) after the third day of life. In group I D-penicillamine therapy caused a marked decline of serum bilirubin concentrations at a time when such levels were rising in the control infants. The number of exchange transfusions per infant was 1.32 in the control and 0.11 in the D-penicillamine-treated infants. In group II D-penicillamine considerably reduced the number of exchange transfusions (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-penicillamine treatment should be begun as early as possible in ABO hemolytic disease of the newborn.

In the liver of neonate rats and in tissues of adult rats a study was made of the effect of D-penicillamine treatment in vivo on the enzymes of peroxide metabolism, lipid peroxidation and other components. It was found that D-penicillamine primarily acts by decreasing lipid peroxidation, thus stabilizing the membrane.

204 infants with birthweights between 751 and 2000 g and 26-35 weeks gestational age (100 treated and 104 control subjects) were enrolled in a prospective controlled trial of the effectiveness of D-penicillamine (DPA) in the prevention of retinopathy of prematurity (ROP). The two groups did not differ significantly in gestational age, birth weight, Apgar scores, the time of exposure to oxygen and in the incidence of PDA or in the number of exchange transfusions and RBTs. Of the treated infants 29, and of the control infants 34 died before the tenth week of life. These cases were not included in further analysis. Patients were subsequently examined and assessed by two ophthalmologists independently, who did not know which babies were receiving DPA. Six of the 70 surviving control infants and none of the 71 surviving treated infants had ROP stage II or graver. The results suggested that ROP may effectively be prevented with DPA in very low-birth-weight-infants, and that the drug has no serious adverse effects during the neonatal period.

D-Penicillamine, previously suspected to have a beneficial effect on the occurrence of severe retrolental fibroplasia among very low birth weight infants, was tested to determine the extent to which this drug modifies acute radiosensitivity on 3- to 4-day-old mice in comparison with adult animals. It was found that the radioprotective effect of penicillamine, given in doses of 3,000 mg/kg i.p. 60 min before whole-body exposure to 6-10 Gy of 60Co gamma rays, was greater in 3- to 4-day-old mice than in adult animals. These data seem to be compatible with the view that D-penicillamine, by virtue of its antioxidant action, may reduce the toxic effects associated with exposure of the newborn infant to hyperoxia, specifically retrolental fibroplasia and bronchopulmonary dysplasia.

The protecting effect of D-penicillamine against hydrogen peroxide and phenylhydrazine induced haemolysis and lipid peroxidation is discussed. It might represent a possible way of action of the drug in some neonatal disorders like hyperbilirubinaemia and retrolental fibroplasia.

D-Penicillamine (DPA) was introduced to treat neonatal hyperbilirubinemia in 1973 and to prevent retinopathy of prematurity in 1980. In this study we investigated the renal and liver functions of neonates treated with DPA and the in vitro effect of the drug on superoxide anion generation and beta-glucuronidase release as well as phagocytic and intracellular killing activation of human peripheral blood granulocytes. Our data concerning the renal and liver functions before and after 3 to 4 days DPA treatment reveal that the drug does not produce any pathological change during short-term administration in the neonatal period. Furthermore, it was found that superoxide anion generation was slightly increased, and beta-glucuronidase release markedly increased by preincubation with DPA at concentrations of 0.5-5 mM. The rise was directly proportional to the concentration in the examined range. On the other hand, none of the examined DPA concentrations influenced the phagocytic or killing activity of neutrophils.

A total 330 newborns suffering from haemolytic disease of the newborn and hyperbilirubinaemia was treated with D-penicillamine. The therapy resulted in a significant decrease in the frequency of exchange transfusions and of high serum bilirubin levels among preterm and fullterm babies with or without sensitization. Concerning the drug's mechanism of action, reduction of the bilirubin level is achieved by means of the copper stored in the liver. The intravenous route is suggested for application of the drug. In preterm infants D-penicillamine treatment proved more effective than phototherapy.

Superoxide dismutase activity of alveolar macrophages, lung, liver, retina and choroid has been studied in rats and rabbits exposed to oxygen at high concentration by itself and in combination with D-penicillamine. Prolonged hyperoxia caused an increase in superoxide dismutase activity while D-penicillamine was found to inhibit the inductive effect of oxygen. It is assumed that the antioxidative effect of D-penicillamine makes it unnecessary to augment the production of superoxide dismutase.