RARE DISEASE
Premature closure of the arterial duct
Premature closure of the arterial duct
Premature closure of the arterial duct
Synonyms: Premature closure of the patent ductus arteriosus
Synonyms: Premature closure of the patent ductus arteriosus
Synonyms: Premature closure of the patent ductus arteriosus
Drug discovery
0
drugs
With orphan designations
Overview
Premature closure of the arterial duct is a rare prenatal event where the ductus arteriosus constricts or closes before birth, causing right ventricular hypertrophy, pulmonary hypertension, and compromised fetal circulation. Etiology includes idiopathic causes, maternal NSAID use, or polyphenol-rich food consumption. Clinical outcomes range from asymptomatic cases to severe respiratory failure, with mortality reported in up to 25% of severe cases [1][5][6].
Burden
Therapies
Prenatal: Close monitoring with echocardiography; early delivery if fetal distress occurs [1][6].
Postnatal: Oxygen therapy, pulmonary vasodilators (e.g., nitric oxide), mechanical ventilation, and ECMO for refractory pulmonary hypertension [1][6][11].
Long-term: Surveillance for right heart dysfunction and non-compaction cardiomyopathy [1][14].
Categories: rare cardiac malformations, rare circulatory system diseases, rare developmental anomalies during embryogenesis
Research Papers
1,326 drug discovery papers about Premature closure of the arterial duct, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,326 drug discovery papers about Premature closure of the arterial duct, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-09 | Pharmacologic treatment strategies and association with major neonatal outcomes for patent ductus arteriosus in preterm infants
Background Patent ductus arteriosus (PDA) is common in preterm infants. Although pharmacologic treatment promotes ductal closure, its impact on clinically meaningful outcomes remains uncertain. This study aimed to evaluate the association between different pharmacologic PDA treatment strategies and major neonatal outcomes. Methods This retrospective cohort study included preterm infants born at <32 weeks’ gestation who received pharmacologic treatment for clinically significant PDA following an integrated echocardiographic and clinical assessment in a tertiary-level neonatal intensive care unit between 2018 and 2024. Infants were categorized by treatment strategy (ibuprofen only, paracetamol only, or sequential therapy), treatment timing, and number of treatment courses. The primary outcome was a composite of bronchopulmonary dysplasia (BPD) and/or mortality. Secondary outcomes included intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, and sepsis. Results A total of 76 preterm infants were included, with a median gestational age of 28 weeks (IQR 26–30) and mean birth weight of 1,076 ± 343 g. Infants were treated with ibuprofen only ( n = 31, 40.8%), paracetamol only ( n = 27, 35.5%), or sequential therapy ( n = 18, 23.7%). The composite outcome occurred in 39 infants (51.3%) and did not differ significantly across treatment groups. In multivariate analysis, gestational age emerged as the strongest independent predictor of BPD and/or mortality (adjusted OR 0.54, 95% CI 0.38–0.77; p = 0.001), while treatment category was not independently associated with outcomes. Conclusion Pharmacologic PDA treatment strategies were not independently associated with BPD and/or mortality in this retrospective cohort. Gestational age showed the strongest association with the primary outcome; however, residual confounding and limited statistical power preclude causal or equivalence conclusions.
2026-07-03 | Acetaminophen versus Ibuprofen for the management of hemodynamically significant patent ductus arteriosus in very low birth weight infants: randomized trial.
The objective was to evaluate the efficacy and safety of Acetaminophen versus Ibuprofen in the treatment of hemodynamically significant patent ductus arteriosus. A randomized, partially blinded controlled study was conducted in very low birth weight infants. Diagnostic criteria included a ductal diameter of 1.5 millimeters or greater, left cavities dilation or a left atrium to aortic root ratio greater than 1.4, and retrograde flow. Preterm infants were randomized into intravenous Acetaminophen or Ibuprofen treatment groups. Ductal closure was evaluated at the end of the third treatment day. A blood count and renal and liver function tests were done before and after treatment. 120 preterm infants were enrolled; 60 were randomized to each treatment group. The average pre-treatment ductal diameter was similar between both groups. Mean weight and gestational age were 1145 grams and 28.3 weeks for Acetaminophen, and 1096 grams and 27.6 weeks for Ibuprofen. The ductal closure rate after the first treatment course was 66.7% in the Acetaminophen group and 63.3% in the Ibuprofen group (p = 0.70), increasing to 88.3% and 86.7%, respectively, after the second course (p = 0.78). In the Acetaminophen group, the need for surgical closure was 10% and in the Ibuprofen group 11.7% (p = 0.77). No significant differences were observed in laboratory tests before and after treatment. Acetaminophen may be considered a safe and effective alternative, with no differences in side effects, to ibuprofen for treating hemodynamically significant patent ductus arteriosus in very low birth weight premature infants.
2026-07-01 | Assessment of vital organ oxygenation by near-infrared spectroscopy in pharmacologic closure therapy for patent ductus arteriosus in preterm neonates.
Hemodynamically significant patent ductus arteriosus is a frequent problem in preterm neonates and may impair systemic and organ-specific oxygenation. Near-infrared spectroscopy provides a non-invasive tool to evaluate regional tissue oxygenation. The aim of this study was to investigate the effects of pharmacological closure therapy on cerebral, renal, and mesenteric tissue oxygenation in preterm neonates diagnosed with hemodynamically significant patent ductus arteriosus. This prospective observational study was conducted in a tertiary neonatal intensive care unit between September 2021 and November 2024. Twenty-four preterm infants (24-34 weeks' gestational age) with hemodynamically significant patent ductus arteriosus confirmed by transthoracic echocardiography were enrolled. Paracetamol treatment was given in cases where ibuprofen was contraindicated. Patients who underwent medical patent ductus arteriosus closure were divided into two groups: ibuprofen and paracetamol groups. Specific regional tissue oxygen saturation and fractional tissue oxygen extraction in three regions were monitored continuously using near-infrared spectroscopy for 72 h before and after medical treatment. Echocardiographic and hemodynamic parameters were recorded. While patent ductus arteriosus closure was achieved in 46% of cases with medical treatment, a significant reduction in patent ductus arteriosus diameter was achieved in 29% of cases. Ibuprofen was superior to paracetamol in reducing patent ductus arteriosus diameter. Mesenteric regional tissue oxygen saturation also improved significantly at 24-48 h in the ibuprofen group (p=0.01), while cerebral and renal oxygenation remained unchanged (p>0.05). Our findings revealed that ibuprofen therapy improved hemodynamic stability and mesenteric oxygenation in preterm neonates with hemodynamically significant patent ductus arteriosus. Although we showed in our study that there was no significant change in cerebral and renal oxygenation of hemodynamically significant patent ductus arteriosus with ibuprofen treatment, more comprehensive studies showing the changes with near-infrared spectroscopy are needed.
2026-05-19 | Efficacy of acetaminophen compared to ibuprofen for patent ductus arteriosus in preterm neonates: A systematic review and meta-analysis
BACKGROUND Patent ductus arteriosus (PDA) is prevalent in preterm neonates (< 37 weeks), often leading to respiratory distress and other complications. Ibuprofen, a nonsteroidal anti-inflammatory drug, achieves PDA closure in 70%-85% of cases but poses risks of renal impairment and gastrointestinal (GI) bleeding. Acetaminophen, with analgesic and antipyretic effects, is a potentially safer alternative. This study compares their efficacy and safety for PDA closure. AIM To assess the efficacy and safety of acetaminophen compared to ibuprofen for the treatment of PDA in preterm neonates. METHODS We conducted a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in PubMed, EMBASE, Scopus, Cochrane Library, and ScienceDirect for randomized controlled trials comparing ibuprofen and acetaminophen for PDA closure in preterm infants. Screening was done on Rayyan, and data on PDA closure and adverse effects were extracted into an Excel spreadsheet. Analysis was performed on Review Manager. A random-effects meta-analysis was performed, with risk ratios and 95%CI reported. RESULTS Total 18 randomized controlled trials were included, involving a total of 1946 preterm neonates with PDA. Acetaminophen was found to be just as effective as ibuprofen for closing a PDA in the first course of treatment [risk ratios (RR) = 0.99; 95%CI: 0.90-1.09; P = 0.86], in the second course of treatment (RR = 0.98, 95%CI: 0.89-1.09, P = 0.73), and overall (RR = 1.01, 95%CI: 0.97-1.06, P = 0.55). Rates of surgical ligation (RR = 0.72, 95%CI: 0.44-1.17, P = 0.86) and PDA reopening (RR = 1.23, 95%CI: 0.78-1.95, P = 0.38) did not differ. Both drugs were comparable in terms of safety outcomes, including necrotizing enterocolitis (RR = 1.10, 95%CI: 0.74-1.64, P = 0.64), intraventricular hemorrhage (RR = 0.96, 95%CI: 0.66-1.40, P = 0.84), hyperbilirubinemia (RR = 0.85, 95%CI: 0.50-1.43, P = 0.53), bronchopulmonary dysplasia (RR = 1.03, 95%CI: 0.58-1.82, P = 0.92), sepsis (RR = 0.88, 95%CI: 0.65-1.18, P = 0.40), pulmonary hemorrhage (RR = 0.71, 95%CI: 0.29-1.75, P = 0.46), retinopathy of prematurity (RR = 0.91, 95%CI: 0.65-1.18, P = 0.44). However, ibuprofen was associated with a higher risk of GI bleeding (RR = 0.32, 95%CI: 0.16-0.63, P = 0.001) and renal failure (RR = 0.37, 95%CI: 0.16-0.81, P = 0.01). CONCLUSION Acetaminophen is as effective as ibuprofen for PDA closure in preterm neonates, with a lower risk of GI bleeding and renal failure, making it a viable alternative.
2026-05-19 | Pharmacokinetics, dosing exposure and safety of oral ibuprofen in Chinese preterm neonates with patent ductus arteriosus: preliminary report.
The use of oral ibuprofen to treat haemodynamically significant patent ductus arteriosus (hsPDA) in premature neonates is common. However, among Chinese preterm neonates, the available pharmacokinetic (PK) findings for its enantiomers remain merely descriptive. This study aimed to characterise the PKs, dosing exposure and safety of oral ibuprofen in Chinese preterm infants treated with hsPDA. A pilot trial. Three perinatal centres across Southwest China. Preterm infants (≤35 weeks' gestational age, ≥48 hours postnatal age) with suspected hsPDA (August 2022-May 2023). Oral ibuprofen (10, 5 and 5 mg/kg at 24-hour intervals) was used and sparse sampling was performed. Plasma concentrations were analysed via ultrahigh-performance liquid chromatography-tandem mass spectrometry. The PK parameters were calculated via ADAPT 5 software. Adverse events and treatment efficacy were assessed. 14 neonates provided 42 plasma samples. The R-ibuprofen (R-IBU) concentrations were lower than the S-ibuprofen (S-IBU) concentrations. The clearance values for rac-ibuprofen (rac-IBU), R-IBU and S-IBU were 24.22±37.04, 206.1±143.1 and 12.67±26.53 mL/kg/hour, respectively. The area under the curve (AUC0-72h) values for rac-IBU, R-IBU and S-IBU were 799.8±392.8, 75.9±51.9 and 537±246.4 µg hour/mL, respectively. DA closure was achieved in 8 (57%) infants. The indirect bilirubin level increased significantly following the administration of oral ibuprofen (p<0.05). The recommended dosage regimen for Chinese preterm neonates with hsPDA may be insufficient to achieve targeted therapeutic exposure. Importantly, our study indicated that even at a relatively high dose, drug exposure might remain within the therapeutic window. Moreover, we observed a higher conversion ratio of R-IBU to S-IBU in these neonates than in adults. The use of ibuprofen may be associated with an elevated risk of jaundice in preterm infants. Chinese Clinical Trial Registry (ChiCTR2300067714).
gene therapies
2022-04-07 | Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA.
The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
2016-07-28 | Identification of differentially regulated genes in human patent ductus arteriosus
In order to identify differentially expressed genes that are specific to the ductus arteriosus, 18 candidate genes were evaluated in matched ductus arteriosus and aortic samples from infants with coarctation of the aorta. The cell specificity of the gene's promoters was assessed by performing transient transfection studies in primary cells derived from several patients. Segments of ductus arteriosus and aorta were isolated from infants requiring repair for coarctation of the aorta and used for mRNA quantitation and culturing of cells. Differences in expression were determined by quantitative PCR using the ΔΔCt method. Promoter regions of six of these genes were cloned into luciferase reporter plasmids for transient transfection studies in matched human ductus arteriosus and aorta cells. Transcription factor AP-2b and phospholipase A2 were significantly up-regulated in ductus arteriosus compared to aorta in whole tissues and cultured cells, respectively. In transient transfection experiments, Angiotensin II type 1 receptor and Prostaglandin E receptor 4 promoters consistently gave higher expression in matched ductus arteriosus versus aorta cells from multiple patients. Taken together, these results demonstrate that several genes are differentially expressed in ductus arteriosus and that their promoters may be used to drive ductus arteriosus-enriched transgene expression.
2004-09-08 | Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus
Oxygen (O2)-sensitive K+ channels mediate acute O2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O2 constriction in preterm DA is reduced expression and function of O2-sensitive, voltage-gated (Kv) channels.Preterm rabbit DA rings have reduced O2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O2 constriction in human DAs.These data demonstrate a central role for developmentally regulated DASMC O2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O2 responsiveness, including persistent DA.
small molecules
2026-07-09 | Pharmacologic treatment strategies and association with major neonatal outcomes for patent ductus arteriosus in preterm infants
Background Patent ductus arteriosus (PDA) is common in preterm infants. Although pharmacologic treatment promotes ductal closure, its impact on clinically meaningful outcomes remains uncertain. This study aimed to evaluate the association between different pharmacologic PDA treatment strategies and major neonatal outcomes. Methods This retrospective cohort study included preterm infants born at <32 weeks’ gestation who received pharmacologic treatment for clinically significant PDA following an integrated echocardiographic and clinical assessment in a tertiary-level neonatal intensive care unit between 2018 and 2024. Infants were categorized by treatment strategy (ibuprofen only, paracetamol only, or sequential therapy), treatment timing, and number of treatment courses. The primary outcome was a composite of bronchopulmonary dysplasia (BPD) and/or mortality. Secondary outcomes included intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, and sepsis. Results A total of 76 preterm infants were included, with a median gestational age of 28 weeks (IQR 26–30) and mean birth weight of 1,076 ± 343 g. Infants were treated with ibuprofen only ( n = 31, 40.8%), paracetamol only ( n = 27, 35.5%), or sequential therapy ( n = 18, 23.7%). The composite outcome occurred in 39 infants (51.3%) and did not differ significantly across treatment groups. In multivariate analysis, gestational age emerged as the strongest independent predictor of BPD and/or mortality (adjusted OR 0.54, 95% CI 0.38–0.77; p = 0.001), while treatment category was not independently associated with outcomes. Conclusion Pharmacologic PDA treatment strategies were not independently associated with BPD and/or mortality in this retrospective cohort. Gestational age showed the strongest association with the primary outcome; however, residual confounding and limited statistical power preclude causal or equivalence conclusions.
2026-07-03 | Acetaminophen versus Ibuprofen for the management of hemodynamically significant patent ductus arteriosus in very low birth weight infants: randomized trial.
The objective was to evaluate the efficacy and safety of Acetaminophen versus Ibuprofen in the treatment of hemodynamically significant patent ductus arteriosus. A randomized, partially blinded controlled study was conducted in very low birth weight infants. Diagnostic criteria included a ductal diameter of 1.5 millimeters or greater, left cavities dilation or a left atrium to aortic root ratio greater than 1.4, and retrograde flow. Preterm infants were randomized into intravenous Acetaminophen or Ibuprofen treatment groups. Ductal closure was evaluated at the end of the third treatment day. A blood count and renal and liver function tests were done before and after treatment. 120 preterm infants were enrolled; 60 were randomized to each treatment group. The average pre-treatment ductal diameter was similar between both groups. Mean weight and gestational age were 1145 grams and 28.3 weeks for Acetaminophen, and 1096 grams and 27.6 weeks for Ibuprofen. The ductal closure rate after the first treatment course was 66.7% in the Acetaminophen group and 63.3% in the Ibuprofen group (p = 0.70), increasing to 88.3% and 86.7%, respectively, after the second course (p = 0.78). In the Acetaminophen group, the need for surgical closure was 10% and in the Ibuprofen group 11.7% (p = 0.77). No significant differences were observed in laboratory tests before and after treatment. Acetaminophen may be considered a safe and effective alternative, with no differences in side effects, to ibuprofen for treating hemodynamically significant patent ductus arteriosus in very low birth weight premature infants.
2026-07-01 | Assessment of vital organ oxygenation by near-infrared spectroscopy in pharmacologic closure therapy for patent ductus arteriosus in preterm neonates.
Hemodynamically significant patent ductus arteriosus is a frequent problem in preterm neonates and may impair systemic and organ-specific oxygenation. Near-infrared spectroscopy provides a non-invasive tool to evaluate regional tissue oxygenation. The aim of this study was to investigate the effects of pharmacological closure therapy on cerebral, renal, and mesenteric tissue oxygenation in preterm neonates diagnosed with hemodynamically significant patent ductus arteriosus. This prospective observational study was conducted in a tertiary neonatal intensive care unit between September 2021 and November 2024. Twenty-four preterm infants (24-34 weeks' gestational age) with hemodynamically significant patent ductus arteriosus confirmed by transthoracic echocardiography were enrolled. Paracetamol treatment was given in cases where ibuprofen was contraindicated. Patients who underwent medical patent ductus arteriosus closure were divided into two groups: ibuprofen and paracetamol groups. Specific regional tissue oxygen saturation and fractional tissue oxygen extraction in three regions were monitored continuously using near-infrared spectroscopy for 72 h before and after medical treatment. Echocardiographic and hemodynamic parameters were recorded. While patent ductus arteriosus closure was achieved in 46% of cases with medical treatment, a significant reduction in patent ductus arteriosus diameter was achieved in 29% of cases. Ibuprofen was superior to paracetamol in reducing patent ductus arteriosus diameter. Mesenteric regional tissue oxygen saturation also improved significantly at 24-48 h in the ibuprofen group (p=0.01), while cerebral and renal oxygenation remained unchanged (p>0.05). Our findings revealed that ibuprofen therapy improved hemodynamic stability and mesenteric oxygenation in preterm neonates with hemodynamically significant patent ductus arteriosus. Although we showed in our study that there was no significant change in cerebral and renal oxygenation of hemodynamically significant patent ductus arteriosus with ibuprofen treatment, more comprehensive studies showing the changes with near-infrared spectroscopy are needed.
2026-05-19 | Efficacy of acetaminophen compared to ibuprofen for patent ductus arteriosus in preterm neonates: A systematic review and meta-analysis
BACKGROUND Patent ductus arteriosus (PDA) is prevalent in preterm neonates (< 37 weeks), often leading to respiratory distress and other complications. Ibuprofen, a nonsteroidal anti-inflammatory drug, achieves PDA closure in 70%-85% of cases but poses risks of renal impairment and gastrointestinal (GI) bleeding. Acetaminophen, with analgesic and antipyretic effects, is a potentially safer alternative. This study compares their efficacy and safety for PDA closure. AIM To assess the efficacy and safety of acetaminophen compared to ibuprofen for the treatment of PDA in preterm neonates. METHODS We conducted a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in PubMed, EMBASE, Scopus, Cochrane Library, and ScienceDirect for randomized controlled trials comparing ibuprofen and acetaminophen for PDA closure in preterm infants. Screening was done on Rayyan, and data on PDA closure and adverse effects were extracted into an Excel spreadsheet. Analysis was performed on Review Manager. A random-effects meta-analysis was performed, with risk ratios and 95%CI reported. RESULTS Total 18 randomized controlled trials were included, involving a total of 1946 preterm neonates with PDA. Acetaminophen was found to be just as effective as ibuprofen for closing a PDA in the first course of treatment [risk ratios (RR) = 0.99; 95%CI: 0.90-1.09; P = 0.86], in the second course of treatment (RR = 0.98, 95%CI: 0.89-1.09, P = 0.73), and overall (RR = 1.01, 95%CI: 0.97-1.06, P = 0.55). Rates of surgical ligation (RR = 0.72, 95%CI: 0.44-1.17, P = 0.86) and PDA reopening (RR = 1.23, 95%CI: 0.78-1.95, P = 0.38) did not differ. Both drugs were comparable in terms of safety outcomes, including necrotizing enterocolitis (RR = 1.10, 95%CI: 0.74-1.64, P = 0.64), intraventricular hemorrhage (RR = 0.96, 95%CI: 0.66-1.40, P = 0.84), hyperbilirubinemia (RR = 0.85, 95%CI: 0.50-1.43, P = 0.53), bronchopulmonary dysplasia (RR = 1.03, 95%CI: 0.58-1.82, P = 0.92), sepsis (RR = 0.88, 95%CI: 0.65-1.18, P = 0.40), pulmonary hemorrhage (RR = 0.71, 95%CI: 0.29-1.75, P = 0.46), retinopathy of prematurity (RR = 0.91, 95%CI: 0.65-1.18, P = 0.44). However, ibuprofen was associated with a higher risk of GI bleeding (RR = 0.32, 95%CI: 0.16-0.63, P = 0.001) and renal failure (RR = 0.37, 95%CI: 0.16-0.81, P = 0.01). CONCLUSION Acetaminophen is as effective as ibuprofen for PDA closure in preterm neonates, with a lower risk of GI bleeding and renal failure, making it a viable alternative.
2026-05-19 | Pharmacokinetics, dosing exposure and safety of oral ibuprofen in Chinese preterm neonates with patent ductus arteriosus: preliminary report.
The use of oral ibuprofen to treat haemodynamically significant patent ductus arteriosus (hsPDA) in premature neonates is common. However, among Chinese preterm neonates, the available pharmacokinetic (PK) findings for its enantiomers remain merely descriptive. This study aimed to characterise the PKs, dosing exposure and safety of oral ibuprofen in Chinese preterm infants treated with hsPDA. A pilot trial. Three perinatal centres across Southwest China. Preterm infants (≤35 weeks' gestational age, ≥48 hours postnatal age) with suspected hsPDA (August 2022-May 2023). Oral ibuprofen (10, 5 and 5 mg/kg at 24-hour intervals) was used and sparse sampling was performed. Plasma concentrations were analysed via ultrahigh-performance liquid chromatography-tandem mass spectrometry. The PK parameters were calculated via ADAPT 5 software. Adverse events and treatment efficacy were assessed. 14 neonates provided 42 plasma samples. The R-ibuprofen (R-IBU) concentrations were lower than the S-ibuprofen (S-IBU) concentrations. The clearance values for rac-ibuprofen (rac-IBU), R-IBU and S-IBU were 24.22±37.04, 206.1±143.1 and 12.67±26.53 mL/kg/hour, respectively. The area under the curve (AUC0-72h) values for rac-IBU, R-IBU and S-IBU were 799.8±392.8, 75.9±51.9 and 537±246.4 µg hour/mL, respectively. DA closure was achieved in 8 (57%) infants. The indirect bilirubin level increased significantly following the administration of oral ibuprofen (p<0.05). The recommended dosage regimen for Chinese preterm neonates with hsPDA may be insufficient to achieve targeted therapeutic exposure. Importantly, our study indicated that even at a relatively high dose, drug exposure might remain within the therapeutic window. Moreover, we observed a higher conversion ratio of R-IBU to S-IBU in these neonates than in adults. The use of ibuprofen may be associated with an elevated risk of jaundice in preterm infants. Chinese Clinical Trial Registry (ChiCTR2300067714).
gene therapies
2022-04-07 | Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA.
The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
2016-07-28 | Identification of differentially regulated genes in human patent ductus arteriosus
In order to identify differentially expressed genes that are specific to the ductus arteriosus, 18 candidate genes were evaluated in matched ductus arteriosus and aortic samples from infants with coarctation of the aorta. The cell specificity of the gene's promoters was assessed by performing transient transfection studies in primary cells derived from several patients. Segments of ductus arteriosus and aorta were isolated from infants requiring repair for coarctation of the aorta and used for mRNA quantitation and culturing of cells. Differences in expression were determined by quantitative PCR using the ΔΔCt method. Promoter regions of six of these genes were cloned into luciferase reporter plasmids for transient transfection studies in matched human ductus arteriosus and aorta cells. Transcription factor AP-2b and phospholipase A2 were significantly up-regulated in ductus arteriosus compared to aorta in whole tissues and cultured cells, respectively. In transient transfection experiments, Angiotensin II type 1 receptor and Prostaglandin E receptor 4 promoters consistently gave higher expression in matched ductus arteriosus versus aorta cells from multiple patients. Taken together, these results demonstrate that several genes are differentially expressed in ductus arteriosus and that their promoters may be used to drive ductus arteriosus-enriched transgene expression.
2004-09-08 | Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus
Oxygen (O2)-sensitive K+ channels mediate acute O2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O2 constriction in preterm DA is reduced expression and function of O2-sensitive, voltage-gated (Kv) channels.Preterm rabbit DA rings have reduced O2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O2 constriction in human DAs.These data demonstrate a central role for developmentally regulated DASMC O2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O2 responsiveness, including persistent DA.
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