Introduction: Heavy metal ions, especially copper and iron play very important roles in the pathogenesis of neurodevelopmental and neurodegenerative diseases including Bilirubin-Induced Neurologic Dysfuction (BIND), Retinopathy Of Prematurity (ROP) and - may be - Autism Spectrum Disorder (ASD). In addition, the copper metabolism in Wilson’s disease and in newborn infants is strikingly similar. Both have large quantities of copper in the liver and brain which is contrasted by an unusually low ceruloplasmin level in the blood.

Purpose: It is a „new” drug approval for 2019: D-penicillamine (D-PA) which can administer intravenously. The most effective IV preparation of this orphan drug now is not available in the drug market.

Methods: The author analyzed the literature and incorporated the own clinical experiences which are more than 40 years. In the mean time, our studies were replicated in other institutes in Hungary, Poland, the US, 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 D-PA was used 10-20 times higher doses in the newborn period, than those in adult.

Conclusion: To the new concept, the BIND, ROP and ASD are neurodegenerative and neurodevelopmental diseases (NDs) of immature brain caused by accumulation of free metals, Unconjugated Bilirubin (UCB), and UCB-Cu complex (as prooxidant), respectively, in the Basal Ganglia (BG) and other parts of the Central Nervous System (CNS). The main factor is the hemolysis of neonatal red blood cells. This process is going with the induction of a great amount of heavy metals (mainly copper and iron) and producing reactive oxygen species (ROS). These elements are circulating in the bloodstream, and pass through the immature blood-brain-barrier (BBB), finding entrance into the CNS. In addition, ROS contribute to increased BBB permeability creating a dangerous vitious circle in the neonatal brain. The intravenously administered D-PA would be effective to prevent of these processes.

D-Penicillamine in the Neonatal Period; Orphan Drug; Copper Hypothesis of BIND, ROP and ASD; Follow-Up Studies.

Introduction: Heavy metal ions, especially copper and iron play very important roles in the pathogenesis of neurodevelopmental and neurodegenerative diseases including Bilirubin-Induced Neurologic Dysfuction (BIND), Retinopathy Of Prematurity (ROP) and - may be - Autism Spectrum Disorder (ASD). In addition, the copper metabolism in Wilson’s disease and in newborn infants is strikingly similar. Both have large quantities of copper in the liver and brain which is contrasted by an unusually low ceruloplasmin level in the blood.

Purpose: It is a „new” drug approval for 2019: D-penicillamine (D-PA) which can administer intravenously. The most effective IV preparation of this orphan drug now is not available in the drug market.

Methods: The author analyzed the literature and incorporated the own clinical experiences which are more than 40 years. In the mean time, our studies were replicated in other institutes in Hungary, Poland, the US, 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 D-PA was used 10-20 times higher doses in the newborn period, than those in adult.

Conclusion: To the new concept, the BIND, ROP and ASD are neurodegenerative and neurodevelopmental diseases (NDs) of immature brain caused by accumulation of free metals, Unconjugated Bilirubin (UCB), and UCB-Cu complex (as prooxidant), respectively, in the Basal Ganglia (BG) and other parts of the Central Nervous System (CNS). The main factor is the hemolysis of neonatal red blood cells. This process is going with the induction of a great amount of heavy metals (mainly copper and iron) and producing reactive oxygen species (ROS). These elements are circulating in the bloodstream, and pass through the immature blood-brain-barrier (BBB), finding entrance into the CNS. In addition, ROS contribute to increased BBB permeability creating a dangerous vitious circle in the neonatal brain. The intravenously administered D-PA would be effective to prevent of these processes.

D-Penicillamine in the Neonatal Period; Orphan Drug; Copper Hypothesis of BIND, ROP and ASD; Follow-Up Studies.

ASD: Autistism Spectrum Disorder; BG: Basal Ganglia; BIND: Bilirubin-Induced Neurologic Dysfunction; BBB: Blood-Brain-Barrier; CNS: Central Nervous System; Cp: Ceruloplasmin; D-PA: D-Penicillamine; ET: ExchangeTransfusion; IV: Intravenously; ND: Neurodegenerative or Neurodevelopmental Disease; ROP: Retinopathy of Prematurity; ROS: Reactive Oxygen Species; VLBW: Very Low Birth Weight

A recent report by the National Research Council found that „50% of all pregnancies in the US are now resulting in prenatal or postnatal mortality, significant birth defects, developmental neurological problems, or otherwise chronically unhealthy babies. The incidence of neurotoxic or immune reactive conditions such as autism, schizophrenia, Attention Deficit Disorder (ADD), dyslexia and learning disabilities have been increasing rapidly in recent years” [1]. In the body, misplaced iron and copper ions serve as catalysts to initiate and accelerate oxygen radical activity. The interaction between an oxygen radical and its target produces a cascade of free radicals. Left unchecked, they will in turn attack and disrupt nearby cells that will also produce torrents of additional free radicals, and also so on [2,3].

So how do we protect ourselves against the objectionable oxygen radicals? Fortunately, cells contain built-in safeguards highly effective enzyme systems that produce Superoxide Dysmutase (SOD), catalase, and glutathione peroxidase. Serving as a back-up crew are anti-oxidants such as vitamins E and C, beta-carotene, and glutathione [4], and penicillamine [5] which structurally similar to the latter molecule [6] .

Free radicals and related reactive species are drawning towards copper and iron ions [7]. They attack cells in the vicinity, disrupting cell membranes, enzymes systems, neurotransmitters, and neuroreceptors. Neuro-systems are particularly susceptible to peroxidative destruction because of their high concentration of fat insulation.

D-PA can maintain cellular health by reducing free radical pathology by removing the metal ions (especially copper and iron) that are the catalists for lipid peroxidation [8].

There is always the possibility, of course, that neonatologists who have snubbed D-PA chelation just don’t know any better. Even if doctors were to read this therapy, many probably would not understand it. All too often, rejection is based on the fear a new therapy would out-date their skills and result in lost patients, lost revenue and professional obsolescence. The chance for mega-profits is just as upt to decide which treatments are featured and marketed by the medical monopoly as in any competitive arena [9].

The ET is hazardous, expensive, and requires extensive hospitalitation; the D-PA is relatively inexpensive, pain free, safe, effective and convenient. The ET, like a surgery intervention, is traumatic, disruptive, and requires a prolonged hospital stay; chelation is easily available (unfortunately, now only the per os preparation) - no stress, no fuss, no complicated preparation like before ET [10].

This is a monotonous oft-repeated criticism agains D-PA treatment. Although a number of qualified physicians have practiced chelation in the neonatal period safely and effectively in Hungary, Poland, the US, India [11,12,13,14, 15,16,17,18,19,20,21] and other foreign countries during the last forty years, traditional medicine continues to refuse it. When sufficient time has elapsed to fully evidence its importance, someone can say: Yes, surely it is important, but it is no longer new.

Generally, which has been written in Table 1. is also valid for the intravenous treatment in the neonatal period. However, in the case of oral D-PA therapy the absorption is too slow, and the plasma concentration is very low [23]; opposite the intravenous route, which insures a high blood level promptly [24,25]. Since it has been declared by FDA that it is an orphan drug [26] the intravenous D-PA is not available in the drug market. „An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases”. Question: are neonatal disorders - BIND, ROP, ASD, ADD et cet. - rare i.e. orphan diseases??

Chowrimooto et al. more than 20 years ago [26] pointed out that: “fetal copper metabolism is different from that of the adult,...with apparent similarity to Wilson’s disease.” Fetal copper metabolism is different from that of the adult [27,28] with the fetal liver tolerating up to 20 times the adult liver copper concentration without damage. This apparent similarity to Wilson’s disease has led to the suggestion that in this disease there is a failure to change from the neonatal mode of copper metabolism to the adult mechanism. [30,31]. In both Wilson’s disease and the normal fetus biliary copper excretion is greatly reduced, with low plasma copper and absent or low plasma caeruloplasmin concentrations.

Heavy metal ions, especially copper and iron play a pivotal role in the pathogenesis of neurodegenerative diseases including BIND, having impact on both protein structure (misfolding) and oxidative stress. Our recently published case report and other healthy and highly educated patients’ (they are now 28 to 42 years old) follow-up suggest that D-PA administration to the newborn infants may have significant neuroprotective effects in cases jeopardized by BIND or ROP. In addition, it was our privilege to follow a number of children who are now adults, including sons and daughters of our relatives, colleagues and close friends. They are now highly educated persons working in health care (mostly as physicians), bank, computer, and building industry, etc. Copper dyshomeostasis and oxidative stress have also been concerned in neurodegenerative/ neurodevelopmental disorders such as ASD or ADD [32]. Our recommendation: all newborns should be screened for ASD, particularly the premature babies (especially the very low birthweight infants -VLBW) and infants suffering from NHBI. These conditions significantly increase the prevalence of NDs, including ASD and ADD. Although the 24 hour urine copper test is inconsistent in the neonatal period, the Penicillamine challenge test may be useful in the detection of higher copper in the urine. For those children who are voiding copper more than usually in the given institutes or laboratories, high doses D-PA therapy is necessary for 2 to 3 weeks. Our concept was conceived because of longterm follow up (3 to 40 years) we found only 1 ASD in the children and adults who were treated with D-PA in their neonatal period (N=550 patients so far; - According to the Johns Hopkins University Bloomberg School of Public Health U.S. autism rate up 15 percent over two-year period [33,34,35,36,37,38,39]). The intravenously administered D-PA would be effective to prevent of these processes.