allopurinol and Hypoxia-Ischemia--Brain

Neonatal encephalopathy (NE) that purportedly arises from hypoxia-ischemia is labeled hypoxic-ischemic encephalopathy (HIE). Perinatal asphyxia is a clinical syndrome involving acidosis, a low Apgar score and the need for resuscitation in the delivery room; asphyxia alerts one to the possibility of NE. In the present systematic review, we focused on the noninflammatory biomarkers in cerebrospinal fluid (CSF) that are involved in the development of possible brain injury in asphyxia or HIE. A literature search in PubMed and EMBASE for case-control studies was conducted and 17 studies were found suitable by a priori criteria. Statistical analysis used the Mantel-Haenszel model for dichotomous data. The pooled mean difference and 95% confidence intervals (CIs) were determined. We identified the best biomarkers, based on the estimation approach in evaluating the biological significance, out of hundreds in three categories: cell adhesion and proliferation, oxidants and antioxidants, and cell damage. The following subtotal-population comparisons were made: perinatal asphyxia versus no asphyxia, asphyxia with HIE versus asphyxia without HIE, asphyxia with HIE versus no asphyxia, and term versus preterm HIE newborn with asphyxia. Biological significance of the biomarkers was determined by using a modification of the estimation approach, by ranking the biomarkers according to the difference in the bounds of the CIs. The most promising CSF biomarkers for prognostication especially for the severest HIE include creatine kinase, xanthine oxidase, vascular endothelial growth factor, neuron-specific enolase, superoxide dismutase, and malondialdehyde. Future studies are recommended using such a combined test to prognosticate the most severely affected patients.

Topics: Asphyxia Neonatorum; Biomarkers; Creatine Kinase; Female; Humans; Hypoxia; Hypoxia-Ischemia, Brain; Infant, Newborn; Malondialdehyde; Oxidants; Phosphopyruvate Hydratase; Pregnancy; Superoxide Dismutase; Vascular Endothelial Growth Factor A; Xanthine Oxidase

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

Topics: Acetylcysteine; Allopurinol; Animals; Antioxidants; Asphyxia Neonatorum; Biomarkers; Brain Injuries; Clinical Trials as Topic; DNA; Erythropoietin; Free Radicals; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Malondialdehyde; Melatonin; Nitric Oxide; Oxidative Stress; Prostaglandins; Proteins; Uric Acid

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Topics: Allopurinol; Asphyxia Neonatorum; Biotin; Cerebral Palsy; Clinical Trials as Topic; Epilepsy; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Intellectual Disability; Ischemic Postconditioning; Melatonin; Neuroprotective Agents; Pregnancy; Reactive Nitrogen Species; Reactive Oxygen Species

Neonatal brain injury (NBI) remains a major contributor to neonatal mortality and long-term neurodevelopmental morbidity. Although therapeutic hypothermia is the only proven treatment to minimize brain injury caused by neonatal encephalopathy in term neonates, it provides incomplete neuroprotection. There are no specific drugs yet proven to prevent NBI in preterm neonates. This review discusses the scientific and emerging clinical trial data for several neuroprotective drugs in development, examining potential efficacy and safety concerns. Drugs with the highest likelihood of success and closest to clinical application include erythropoietin for term and preterm neonates and antenatal magnesium for preterm neonates.

Topics: Adrenal Cortex Hormones; Allopurinol; Anesthetics, Inhalation; Anticonvulsants; Antioxidants; Cerebral Intraventricular Hemorrhage; Cyclooxygenase Inhibitors; Darbepoetin alfa; Erythropoietin; Free Radical Scavengers; Hematinics; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Indomethacin; Infant, Newborn; Leukomalacia, Periventricular; Magnesium; Melatonin; Neuroprotection; Prenatal Care; Topiramate; Xenon

Perinatal asphyxia-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and disability including cerebral palsy in the long term. The brain injury is secondary to both the hypoxic-ischemic event and the reoxygenation-reperfusion following resuscitation. Early events in the cascade of brain injury can be classified as either inflammation or oxidative stress through the generation of free radicals. The objective of this paper is to present efforts that have been made to limit the oxidative stress associated with hypoxic-ischemic encephalopathy. In the acute phase of ischemia/hypoxia and reperfusion/reoxygenation, the outcomes of asphyxiated infants can be improved by optimizing the initial delivery room stabilization. Interventions include limiting oxygen exposure, and shortening the time to return of spontaneous circulation through improved methods for supporting hemodynamics and ventilation. Allopurinol, melatonin, noble gases such as xenon and argon, and magnesium administration also target the acute injury phase. Therapeutic hypothermia, N-acetylcysteine2-iminobiotin, remote ischemic postconditioning, cannabinoids and doxycycline target the subacute phase. Erythropoietin, mesenchymal stem cells, topiramate and memantine could potentially limit injury in the repair phase after asphyxia. To limit the injurious biochemical processes during the different stages of brain injury, determination of the stage of injury in any particular infant remains essential. Currently, therapeutic hypothermia is the only established treatment in the subacute phase of asphyxia-induced brain injury. The effects and side effects of oxidative stress reducing/limiting medications may however be difficult to predict in infants during therapeutic hypothermia. Future neuroprotection in asphyxiated infants may indeed include a combination of therapies. Challenges include timing, dosing and administration route for each neuroprotectant.

Topics: Acetylcysteine; Allopurinol; Argon; Asphyxia Neonatorum; Cannabinoids; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Magnesium Sulfate; Melatonin; Neuroprotective Agents; Oxidative Stress; Pregnancy; Treatment Outcome; Xenon

Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal mortality and neurological morbidity, even despite hypothermia treatment. Neuronal damage in these infants is partly caused by the production of superoxides via the xanthine-oxidase pathway and concomitant free radical formation. Allopurinol is a xanthine-oxidase inhibitor and can potentially reduce the formation of these superoxides that lead to brain damage in HIE.. The aim of this review is to provide an overview of the animal and clinical data about the neuroprotective effect of allopurinol in HIE and the relevant mechanisms leading to brain injury in HIE.. A possible neuroprotective effect of allopurinol has been suggested based on several preclinical studies in rats, piglets and sheep. Allopurinol seemed to inhibit the formation of superoxide and to scavenge free radicals directly, but the effect on brain damage was inconclusive in these preclinical trials. The neuroprotective effect was also investigated in neonates with HIE. In three small studies, in which, allopurinol was administered postnatally and a pilot and one multi-center study, in which, allopurinol was administered antenatally, a possible beneficial effect was found. After combining the data of 2 postnatal allopurinol studies, long-term follow-up was only beneficial in infants with moderate HIE, therefore, large-scale studies are needed. Additionally, safety, pharmacokinetics and the neuroprotective effect of allopurinol in other neonatal populations are discussed in this review.. The available literature is not conclusive whether allopurinol is a neuroprotective add-on therapy in infants with HIE. More research is needed to establish the neuroprotective effect of allopurinol especially in combination with hypothermia.

Topics: Allopurinol; Animals; Brain Injuries; Enzyme Inhibitors; Free Radical Scavengers; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Xanthine Oxidase

This article explains the mechanisms underlying choices of pharmacotherapy for hypoxic-ischemic insults of both preterm and term babies. Some preclinical data are strong enough that clinical trials are now underway. Challenges remain in deciding the best combination therapies for each age and insult.

Topics: Acetylcysteine; Allopurinol; Antioxidants; Ascorbic Acid; Biopterins; Erythropoietin; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Fructose; Humans; Hypoxia-Ischemia, Brain; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Melatonin; Memantine; Neuroprotective Agents; Nitric Oxide Synthase Type III; Resveratrol; Stilbenes; Topiramate; Vitamin E; Xenon

Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in experimental models of perinatal asphyxia and in people with organ reperfusion injury.. To determine the effect of allopurinol on mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy.. We used the standard search strategy of the Cochrane Neonatal Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012, Issue 1), MEDLINE (1966 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), conference proceedings, and previous reviews.. Randomised or quasi-randomised controlled trials that compared allopurinol administration versus placebo or no drug in newborn infants with hypoxic-ischaemic encephalopathy.. We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors.. We included three trials in which a total of 114 infants participated. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately severe encephalopathy. These studies were generally of good methodological quality, but were too small to exclude clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death (typical risk ratio 0.88; 95% confidence interval (95% CI) 0.56 to 1.38; risk difference -0.04; 95% CI -0.18 to 0.10) or a composite of death or severe neurodevelopmental disability (typical risk ratio 0.78; 95% CI 0.56 to 1.08; risk difference -0.14; 95% CI -0.31 to 0.04).. The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy. Much larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude important effects on mortality and adverse long-term neurodevelopmental outcomes.

Topics: Allopurinol; Free Radical Scavengers; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Randomized Controlled Trials as Topic

Several experimental models on adult and newborn animals showed that in cerebral hypoxic-ischemic conditions similar to clinical states the main source of the excessive production of free oxygen radicals is the highly activated xanthine oxidase (XO) enzyme reaction. Long before this data were available, it became known that the main role of allopurinol (AP) is the inhibition of XO. On the basis of these results, many therapeutic trials with AP were performed both in experimental and clinical studies of ischemia and reperfusion. However, it has been shown that only preventive administration of AP has favorable effects. The explanation for the poor results of AP treatment in human fetal brain damage (FBD) cases is that the drug was applied postnatally. The clinical studies performed in healthy laboring mothers whose deliveries were complicated with FBD showed that placental transfer after prenatal administration of AP may be effective in protecting newborns at increased risk of hypoxic-ischemic cerebral damage. Further controlled trials are required to determine if the prophylactic use of the drug might prevent hypoxic-ischemic injuries when the drug is administered immediately prior to impending fetal hypoxia, or even in deliveries at risk of developing hypoxia.

Topics: Allopurinol; Animals; Animals, Newborn; Brain Injuries; Enzyme Inhibitors; Female; Fetal Hypoxia; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Pregnancy; Reperfusion Injury; Xanthine Oxidase

In this review we discuss current challenges faced by researchers and clinician-scientists in the pursuit of therapeutics to treat hypoxic-ischemic (HI) brain injury in term infants. At present, there is an absence of neuroprotective drugs that are safe and effective for the protection of neonates from neurological sequels after HI. We discuss secondary neurotoxic processes elicited by HI that may be targets for therapeutic interventions with a specific focus on inflammatory mechanisms. Advances in research to unravel these cellular processes and molecular mechanisms that drive injurious processes after HI have traditionally been plagued by conflicting results when assessing different times for intervention, different models for brain injury, and the adult versus neonate brain. We attribute impeded drug development in part to such disparate results and general difficulties to conduct a stringent, comprehensive analysis of candidate drugs prior to clinical trials. It will be imperative to implement changes in the clinic and laboratory in order for future drug initiatives to achieve success. We also provide a brief discussion on the pursuit of anti-inflammatory molecules and monitoring methods that are the focus of current patents and that, in our opinion, may lead to important new developments in the treatment of HI brain injury in newborn infants.

Topics: Adult; Allopurinol; Animals; Brain Injuries; Clinical Trials as Topic; Drug Evaluation; Drug Monitoring; Free Radical Scavengers; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Nervous System Diseases; Neuroimmunomodulation; Neuroprotective Agents

Topics: Allopurinol; Antioxidants; Antipyrine; Edaravone; Erythropoietin; Free Radical Scavengers; Free Radicals; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Neuroprotective Agents; Oxidative Stress

Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and in human patients with other forms of organ reperfusion injury.. To determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy.. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), conference proceedings, and previous reviews.. Randomised or quasi-randomised controlled trials that compared allopurinol administration vs. placebo or no drug in newborn infants with suspected hypoxic-ischaemic encephalopathy.. The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference.. Three trials in which a total of 114 infants participated were identified. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately-severe encephalopathy. These studies were generally of good methodological quality, but were underpowered to detect clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death during infancy [typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11)], nor in the incidence of neonatal seizures [typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11)]. Only one trial assessed neurodevelopment in surviving children and did not find a statistically significant effect.. The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.

Topics: Allopurinol; Free Radical Scavengers; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Randomized Controlled Trials as Topic

Oxidative stress plays an important role in causing organ injury in the compromised fetus and neonate. Recent experimental research and clinical studies have clarified important pathways in the production of reactive oxygen and nitrogen species. Free radicals are involved in causing cerebral damage after perinatal hypoxia-ischemia affecting membrane lipids, proteins, and DNA. Anti-oxidant strategies can be used as add-on neuroprotective therapy after perinatal oxidative stress. Selective inhibitors of neuronal and inducible nitric oxide synthase, allopurinol, melatonin, and erythropoietin are among the first compounds that are ready for clinical trials.

Topics: Allopurinol; Animals; Antioxidants; Clinical Trials as Topic; Erythropoietin; Free Radicals; Humans; Hypoxia-Ischemia, Brain; Neuroprotective Agents; Nitric Oxide Synthase; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species

The aim of this paper is to review the results of recent clinical studies of some therapies that have demonstrated a neuroprotective effect in perinatal hypoxic-ischemic encephalopathy (HIE) and to present the future perspectives of other clinical and basic research investigations. THERAPIES WITH DEMONSTRATED CLINICAL EFFICACY: ALLOPURINOL: It blocks the production of free radicals following hypoxia-ischemia. In a recent study, infants with hypoplastic left heart syndrome treated with allopurinol, but not those with other congenital cardiopathies, had significantly less number of complications than controls, including death, seizures, coma or cardiac events.. In another recent study, newborns with HIE treated with morphine or phentanyl, had less severe brain damage on MRI and a better neurological outcome. HYPOTHERMIA: Both local (head cooling) or systemic (whole body) hypothermia have a neuroprotective effect in selected newborns with HIE.. ANTIEPILEPTIC DRUGS: They have multiple mechanisms of action that can block the biochemical cascade of neuronal damage in HIE. OTHER THERAPEUTIC MODALITIES: Among them the following should be emphasized: combined neuroprotective treatments, growth factors, genetic therapies, stem cell transplant, and neuroprotective immunization. In conclusion, a better knowledge of the molecular mechanisms of HIE pathogenesis and better clinical studies of neuroprotective therapies will open new possibilities aplicable to clinical practice. These advances will undoubtedly improve the prognosis of newborns with HIE.

Topics: Allopurinol; Animals; Anticonvulsants; Disease Models, Animal; Enzyme Inhibitors; Forecasting; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn

Perinatal hypoxia-ischemia (PHI) is a major cause of morbidity and mortality. A substantial part of PHI-related brain damage occurs upon reperfusion and reoxygenation by the excess production of excitatory amino acids, free (pro)radicals and the release of cytokines, triggering programmed cell death. In this respect, several neuroprotective agents have been investigated in neonatal animal models, providing evidence for their usefulness in PHI. Several agents have been shown to be neuroprotective in neonatal animal hypoxia-ischemia models, but only a few agents have been used in clinical studies on term newborns. Although some general information will be provided with respect to focal hypoxia-ischemia and neuroprotective agents, this paper focuses on the investigated neuroprotective agents for global PHI and reperfusion brain injury in the newborn, categorized by their mode of action. Future experimental and clinical trials with promising neuroprotective agents need to be performed, including long-term follow-up to monitor long-term consequences. Moreover, well-designed combinations of neuroprotective agents with or without other neuroprotective strategies such as brain hypothermia should be given consideration for producing the most promising results in reducing post-hypoxic-ischemic reperfusion injury of the newborn brain.

Topics: Apoptosis; Brain Diseases; Calcium Channel Blockers; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Growth Substances; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Inflammation Mediators; Iron Chelating Agents; Neuroprotective Agents; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Xanthine Oxidase

Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates.. The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated.. Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling.. The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Topics: Allopurinol; Biomarkers; Enzyme Inhibitors; Humans; Hypoxanthine; Hypoxia-Ischemia, Brain; Infant, Newborn; Oxypurinol; Uric Acid; Xanthine; Xanthine Oxidase

Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia.. This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion.. This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia.. NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

Topics: Allopurinol; Antimetabolites; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Double-Blind Method; Gestational Age; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Multicenter Studies as Topic; Neurodevelopmental Disorders; Randomized Controlled Trials as Topic

Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia.. We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007).. We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study.. Delivery rooms of 11 Dutch hospitals.. 500 mg allopurinol, intravenously to the mother, immediately prior to delivery.. Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events).. Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion.. A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects.. The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Topics: Adult; Allopurinol; Double-Blind Method; Female; Fetal Blood; Fetal Hypoxia; Fetus; Free Radical Scavengers; Free Radicals; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Labor, Obstetric; Maternal-Fetal Exchange; Neuroprotective Agents; Placenta; Pregnancy

Free-radical-induced reperfusion injury has been recognised as an important cause of brain tissue damage after birth asphyxia. Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia-reperfusion damage. In this study the long-term outcome of neonatal allopurinol treatment after birth asphyxia was examined.. Follow-up of 4 to 8 years of two earlier performed randomised controlled trials.. Leiden University Medical Center, University Medical Center Groningen and University Medical Center Utrecht, The Netherlands.. Fifty-four term infants were included when suffering from moderate-to-severe birth asphyxia in two previously performed trials.. Infants either received 40 mg/kg allopurinol (with an interval of 12 h) starting within 4 h after birth or served as controls.. Children, who survived, were assessed with the Wechsler Preschool and Primary Scales of Intelligence test or Wechsler Intelligence Scale for Children and underwent a neurological examination. The effect of allopurinol on severe adverse outcome (defined as mortality or severe disability at the age of 4-8 years) was examined in the total group of asphyxiated infants and in a predefined subgroup of moderately asphyxiated infants (based on the amplitude integrated electroencephalogram).. The mean age during follow-up (n=23) was 5 years and 5 months (SD 1 year and 2 months). There were no differences in long-term outcome between the allopurinol-treated infants and controls. However, subgroup analysis of the moderately asphyxiated group showed significantly less severe adverse outcome in the allopurinol-treated infants compared with controls (25% vs 65%; RR 0.40, 95%CI 0.17 to 0.94).. The reported data may suggest a (neuro)protective effect of neonatal allopurinol treatment in moderately asphyxiated infants.

Topics: Allopurinol; Asphyxia Neonatorum; Birth Weight; Developmental Disabilities; Female; Follow-Up Studies; Free Radical Scavengers; Gestational Age; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Intelligence; Male; Neuroprotective Agents; Neuropsychological Tests; Reperfusion Injury; Treatment Outcome

Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy.. The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis.. In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia.. Clinical Trials, protocol registration system: NCT00189007.

Topics: Allopurinol; Asphyxia Neonatorum; Biomarkers; Double-Blind Method; Female; Fetal Hypoxia; Free Radical Scavengers; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Multivariate Analysis; Nerve Growth Factors; Netherlands; Phosphopyruvate Hydratase; Pilot Projects; Pregnancy; Prenatal Care; Prospective Studies; Regression Analysis; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Xanthine Oxidase

Intrapartum hypoxia-ischemia leading to neonatal encephalopathy (NE) results in significant neonatal mortality and morbidity worldwide, with > 85% of cases occurring in low- and middle-income countries (LMIC). Therapeutic hypothermia (HT) is currently the only available safe and effective treatment of HIE in high-income countries (HIC); however, it has shown limited safety or efficacy in LMIC. Therefore, other therapies are urgently required. We aimed to compare the treatment effects of putative neuroprotective drug candidates following neonatal hypoxic-ischemic (HI) brain injury in an established P7 rat Vannucci model. We conducted the first multi-drug randomized controlled preclinical screening trial, investigating 25 potential therapeutic agents using a standardized experimental setting in which P7 rat pups were exposed to unilateral HI brain injury. The brains were analysed for unilateral hemispheric brain area loss after 7 days survival. Twenty animal experiments were performed. Eight of the 25 therapeutic agents significantly reduced brain area loss with the strongest treatment effect for Caffeine, Sonic Hedgehog Agonist (SAG) and Allopurinol, followed by Melatonin, Clemastine, ß-Hydroxybutyrate, Omegaven, and Iodide. The probability of efficacy was superior to that of HT for Caffeine, SAG, Allopurinol, Melatonin, Clemastine, ß-hydroxybutyrate, and Omegaven. We provide the results of the first systematic preclinical screening of potential neuroprotective treatments and present alternative single therapies that may be promising treatment options for HT in LMIC.

Topics: Allopurinol; Animals; Animals, Newborn; Asphyxia Neonatorum; Brain; Brain Injuries; Caffeine; Clemastine; Disease Models, Animal; Hedgehog Proteins; Humans; Hydroxybutyrates; Hypothermia, Induced; Hypoxia; Hypoxia-Ischemia, Brain; Infant, Newborn; Ischemia; Melatonin; Neuroprotective Agents; Rats

Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy.. Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM. In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33-0.77) and 0.2 1/h (95% confidence interval 0.09-0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48-0.92), suggesting full xanthine oxidoreductase inhibition during the period studied.. This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.

Topics: Allopurinol; Clinical Studies as Topic; Humans; Hypoxanthine; Hypoxia; Hypoxia-Ischemia, Brain; Infant, Newborn; Mannitol; Oxypurinol; Uric Acid; Xanthine; Xanthine Dehydrogenase

Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated.. P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment's neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life.. Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed.. Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender.

Topics: Allopurinol; Animals; Animals, Newborn; Antimetabolites; Combined Modality Therapy; Disease Models, Animal; Female; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Male; Neuroprotection; Neuroprotective Agents; Rats, Wistar

Xanthine oxidase (XO), an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid, is thought to contribute to hypoxic-ischemic brain injury by generating oxygen-free radicals during reperfusion. This is based largely on the observation that inhibition of XO reduces brain damage, but the precise mechanism by which the enzyme contributes to cerebral ischemic injury has not been specifically evaluated. We examined the role of XO in generating oxygen-free radicals that cause brain injury, hypothesizing that if XO generated a significant amount of free radicals during hypoxia-ischemia and reperfusion, providing additional substrate at the time of injury should increase brain damage. Anesthetized rabbits were first subjected to 8 min of cerebral hypoxia by breathing 3% oxygen and then to 8 min of ischemia by raising intracranial pressure equal to mean arterial pressure with an artificial CSF. In order to promote oxygen-free radical generation, hypoxanthine (n=9) or xanthine (n=9), XO substrates, or the vehicle (n=8) was infused intravenously beginning 30 min before and continuing until 30 min after the insult. Animals were sacrificed after 4 h of reperfusion. Neither hypoxanthine nor xanthine infusion increased brain damage. However, administration of hypoxanthine significantly improved somatosensory evoked potential recovery and preserved neurofilament 68 kDa protein, a neuronal structural protein. This study does not support free radical generation by XO as a major cause of damage in cerebral hypoxia-ischemia. Infusion of hypoxanthine reduced cerebral injury suggesting that another mechanism may explain why inhibition of XO reduces brain damage.

Topics: Analysis of Variance; Animals; Cerebral Cortex; Enzyme Activators; Evoked Potentials, Somatosensory; Free Radicals; Hypoxanthine; Hypoxia-Ischemia, Brain; Infusions, Intravenous; Male; Neurofilament Proteins; Rabbits; Random Allocation; Recovery of Function; Xanthine; Xanthine Oxidase

Early detection of delayed cerebral energy failure may be important in the prevention of reperfusion injury of the brain after severe perinatal hypoxia-ischaemia (HI). This study investigated whether monitoring of the redox state of cytochrome aa(3) (Cytaa(3)) with near infrared spectroscopy (NIRS) after severe perinatal asphyxia may allow us to detect early a compromised energy metabolism of the developing brain. We therefore correlated serial Cytaa(3) measurements (to estimate mitochondrial oxygenation) simultaneously with the (31)phosphorous-magnetic resonance spectroscopy ((31)P-MRS)-measured phosphocreatin/inorganic phosphate (PCr/Pi) ratio (to estimate cerebral energy reserve) in newborn piglets before and after severe hypoxia-ischaemia. The animals were treated upon reperfusion with either allopurinol, deferoxamine, or 2-iminobiotin or with a vehicle to reduce post-HI reperfusion injury of the brain. Four sham-operated piglets served as controls. Before HI, the individual Cytaa(3) values ranged between -0.02 and 0.71 micromol/L (mean value: -0.07) relative to baseline. The pattern over post-HI time of the vehicle-treated animals was remarkably different from the other groups in as far Cytaa(3) became more oxidised from 3 h after start of HI onwards (increase of Cytaa(3) as compared with baseline), whereas the other groups showed a significant reduction over time (decrease of Cytaa(3) as compared with baseline: allopurinol and deferoxamine) or hardly any change (2-iminobiotin and sham-operated piglets). Vehicle-treated piglets showed a significant reduction in PCr/Pi at 24 h after start of HI, but the cerebral energy state was preserved in 2-iminobiotin-, allopurinol- and deferoxamine-treated piglets. With severe reduction in PCr/Pi-ratio, major changes in the redox-state of Cytaa(3) also occurred: Cytaa(3) was mostly either in a reduced state (down to -6.45 micromol/L) or in an oxidised state (up to 6.84 micromol/L) at these low PCr/Pi ratios. The positive predictive value (PPV) of Cytaa(3) to predict severe reduction of the PCr/Pi ratio was 42%; the negative PPV was 87%. A similar relation was found for Cytaa(3) with histologically determined loss of neurons.

Topics: Allopurinol; Animals; Animals, Newborn; Biotin; Brain; Cell Survival; Deferoxamine; Disease Models, Animal; Disease Progression; Electron Transport Complex IV; Energy Metabolism; Free Radical Scavengers; Hypoxia-Ischemia, Brain; Iron Chelating Agents; Magnetic Resonance Spectroscopy; Neurons; Neuroprotective Agents; Oxidation-Reduction; Phosphates; Phosphocreatine; Predictive Value of Tests; Spectroscopy, Near-Infrared; Swine

The purpose of the present study was to determine whether oxypurinol, a xanthine oxidase inhibitor, reduces free radicals and brain injury in the rat pup hypoxic-ischemia (HI) model. Seven-day-old rat pups had right carotid arteries ligated followed by 2.5h of hypoxia (8% oxygen). Oxypurinol or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily for 3 days. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Oxypurinol treatments did not reduce weight loss in the right hemisphere. Brain weight loss in the right hemisphere were -26.2+/-3.6, -15.2+/-6.9, -21.7+/-4.4, -15.8+/-5.1, and -16.7+/-3.4% in vehicle (n=33), 10 (n=17), 20 (n=16), 40 (n=15), and 135 mg/kg (n=13) oxypurinol-treated groups (p>0.05), respectively. Brain thiobarbituric acid-reacting substances (TBARS) were assessed 3 and 6h after reoxygenation. Concentrations of TBARS rose 1.5-fold due to HI. Oxypurinol did not significantly reduce an HI-induced increase in brain TBARS. Thus, xanthine oxidase may not be the primary source of oxy-radicals in pup brain and as such oxypurinol does not prevent free radical-mediated lipid peroxidation or protect against brain injury in the neonatal rat HI model.

Topics: Animals; Animals, Newborn; Body Temperature; Cerebral Cortex; Enzyme Inhibitors; Female; Free Radicals; Hypoxia-Ischemia, Brain; Male; Oxypurinol; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

The hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n= 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.

Topics: Allopurinol; Animals; Animals, Newborn; Brain; Caspase 3; Caspases; Deferoxamine; Enzyme Inhibitors; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Iron; Iron Chelating Agents; Magnetic Resonance Imaging; Reperfusion Injury; Swine

The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

Topics: Allopurinol; Animals; Animals, Newborn; Biotin; Cerebral Cortex; Deferoxamine; Electroencephalography; Enzyme Inhibitors; Free Radical Scavengers; Hemoglobins; Hypoxia-Ischemia, Brain; Iron Chelating Agents; Magnetic Resonance Spectroscopy; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Phosphorus Radioisotopes; Spectrophotometry; Swine; Time Factors