The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Matthew W. Kemp - One of the best experts on this subject based on the ideXlab platform.
-
the duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation
American Journal of Obstetrics and Gynecology, 2019Co-Authors: Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Augusto F Schmidt, Masatoshi Saito, Shinichi Sato, Takushi HanitaAbstract:ABSTRACT Objective Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. ACS dosing remains un-optimized, and there is little understanding of how different treatment to delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with ACS do not deliver within the widely accepted 1-7 day window of treatment efficacy. We used a sheep model to test duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. Methods For infusion studies, ewes with single fetuses were randomised to receive an intravenous bolus and maintenance infusion of Betamethasone phosphate to target 1-4ng/mL fetal plasma Betamethasone for 36 hours, with delivery at either 2, 4 or 7 days-post treatment or sterile saline as control. Animals receiving the clinical treatment were randomised to receive either:i) a single injection of 0.25mg/kg with a 1:1 mixture of Betamethasone phosphate + Betamethasone Acetate with delivery at either 1 or 7 days post treatment; or ii) two treatments of 0.25 mg/kg Betamethasone phosphate + Betamethasone Acetate spaced at 24 hours (giving approximately 48 hours of fetal steroid exposure) with delivery at 2, 5, 7 or 10 days post-treatment. Negative control animals were treated with saline. All lambs were delivered at 121±3 days gestational age and ventilated for 30 minutes to assess lung function. Results Preterm lambs delivered at 1 or 2 days post-ACS treatment had significant improvements in lung maturation for both intravenous and single dose intramuscular treatments. After 2 days the efficacy of 36 hour Betamethasone phosphate infusions was lost. The single dose of 1:1 Betamethasone phosphate + Betamethasone Acetate also was ineffective at 7 days. In contrast, animals treated with two doses had significant improvements in lung maturation at 2, 5 and 7 days, with treatment efficacy reduced by 10 days. Conclusion In preterm lambs, the durability of ACS treatment depends on the duration of fetal exposure and is independent of the IV or IM maternal route of administration. For acute 24-48 hour post-treatment deliveries, a 24 hour fetal ACS exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single dose ACS treatment should be sufficient for women delivering within
-
the efficacy of antenatal steroid therapy is dependent on the duration of low concentration fetal exposure evidence from a sheep model of pregnancy
American Journal of Obstetrics and Gynecology, 2018Co-Authors: Shimpei Watanabe, Yusaku Kumagai, Takushi Hanita, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Shinichi Sato, Timothy J MolloyAbstract:Background Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. Objective The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. Study Design Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of Betamethasone phosphate to target 12-hour fetal plasma Betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma Betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (Betamethasone phosphate + Betamethasone Acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma Betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. Results The loading and maintenance doses were achieved and maintained the desired fetal plasma Betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma Betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL Betamethasone infusion group. Lambs from the 12-hour 2-ng/mL Betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL Betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. Conclusion In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma Betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose Betamethasone phosphate infusion to achieve a fetal plasma Betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.
-
Low-dose Betamethasone-Acetate for fetal lung maturation in preterm sheep.
American journal of obstetrics and gynecology, 2017Co-Authors: Augusto F Schmidt, Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Judith Rittenschober-böhm, Paranthaman S. Kannan, Lucy L. Furfaro, Sarah J. Stock, Boris W. KramerAbstract:Background Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with Betamethasone-Acetate+Betamethasone-phosphate is more effective than 2 doses of Betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released Betamethasone-Acetate component induces similar lung maturation to Betamethasone-phosphate+Betamethasone-Acetate with decreased dose and fetal exposure. Objective The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal Betamethasone-Acetate in preterm fetal sheep. Study Design Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of Betamethasone-phosphate+Betamethasone-Acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of Betamethasone-Acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of Betamethasone-phosphate 0.125 mg/kg, Betamethasone-Acetate 0.125 mg/kg, or Betamethasone-Acetate 0.5 mg/kg. Maternal and fetal Betamethasone concentrations in plasma were measured for 24 hours. Results All Betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular Betamethasone-Acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of Betamethasone-Acetate+Betamethasone-phosphate. Betamethasone-Acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to Betamethasone compared with Betamethasone-phosphate 0.125 mg/kg. Conclusion A single dose of Betamethasone-Acetate results in similar fetal lung maturation as the 2-dose clinical formulation of Betamethasone-phosphate+Betamethasone-Acetate with decreased fetal exposure to Betamethasone. A lower dose of Betamethasone-Acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.
-
Antenatal dexamethasone vs. Betamethasone dosing for lung maturation in fetal sheep
Pediatric Research, 2017Co-Authors: Augusto F Schmidt, Matthew W. Kemp, Paranthaman S. Kannan, Boris W. Kramer, Suhas G Kallapur, John P Newnham, Alan H. JobeAbstract:Background: Dexamethasone-phosphate (Dex-PO_4) and the combination Betamethasone-phosphate (Beta-PO_4) + Betamethasone-Acetate (Beta-Ac) are the most used antenatal corticosteroids to promote fetal lung maturation. We compared fetal lung maturation induced by Beta-Ac+Beta-PO_4, Dex-PO_4, or Beta-PO_4 alone. Methods: Pregnant ewes received two intramuscular doses 24 h apart of 0.25 mg/kg/dose of Beta-Ac+Beta-PO_4, Dex-PO4 or Beta-PO_4; or 2 doses of 0.125 mg/kg/dose of Beta-PO_4 at 6, 12, or 24 h intervals. Fetuses were delivered 48 h after the first dose and ventilated for 30 min. We assessed ventilatory variables, vital signs, and blood gas. After ventilation pressure-volume curves were measured and lungs were sampled for analysis. Results: All treatments improved lung compliance and ventilation efficiency. Only Beta-Ac + Beta-PO_4 required lower positive inspiratory pressure compared with control. Beta-Ac + Beta-PO_4 and Beta-PO_4 alone, but not Dex-PO_4, increased the mRNA of surfactant proteins compared with control. Low-dose Beta-PO_4 did not increase mRNA of surfactant proteins. There were no differences among Beta-PO_4 treatment intervals. Conclusion: Beta-Ac + Beta-PO_4 given as two doses 24 h apart was more effective in promoting fetal lung maturation than Dex-PO_4 or Beta-PO_4 alone, consistent with a prolonged exposure provided by the Beta-Ac + Beta-PO_4. These results support the clinical use of combined Beta-Ac + Beta-PO_4 preparations over phosphate corticosteroids alone for fetal lung maturation.
-
Antenatal dexamethasone vs. Betamethasone dosing for lung maturation in fetal sheep.
Pediatric research, 2016Co-Authors: Augusto F Schmidt, Matthew W. Kemp, Paranthaman S. Kannan, Boris W. Kramer, Suhas G Kallapur, John P Newnham, Alan H. JobeAbstract:Dexamethasone-phosphate (Dex-PO4) and the combination Betamethasone-phosphate (Beta-PO4) + Betamethasone-Acetate (Beta-Ac) are the most used antenatal corticosteroids to promote fetal lung maturation. We compared fetal lung maturation induced by Beta-Ac+Beta-PO4, Dex-PO4, or Beta-PO4 alone. Pregnant ewes received two intramuscular doses 24 h apart of 0.25 mg/kg/dose of Beta-Ac+Beta-PO4, Dex-PO4 or Beta-PO4; or 2 doses of 0.125 mg/kg/dose of Beta-PO4 at 6, 12, or 24 h intervals. Fetuses were delivered 48 h after the first dose and ventilated for 30 min. We assessed ventilatory variables, vital signs, and blood gas. After ventilation pressure-volume curves were measured and lungs were sampled for analysis. All treatments improved lung compliance and ventilation efficiency. Only Beta-Ac + Beta-PO4 required lower positive inspiratory pressure compared with control. Beta-Ac + Beta-PO4 and Beta-PO4 alone, but not Dex-PO4, increased the mRNA of surfactant proteins compared with control. Low-dose Beta-PO4 did not increase mRNA of surfactant proteins. There were no differences among Beta-PO4 treatment intervals. Beta-Ac + Beta-PO4 given as two doses 24 h apart was more effective in promoting fetal lung maturation than Dex-PO4 or Beta-PO4 alone, consistent with a prolonged exposure provided by the Beta-Ac + Beta-PO4. These results support the clinical use of combined Beta-Ac + Beta-PO4 preparations over phosphate corticosteroids alone for fetal lung maturation.
Masatoshi Saito - One of the best experts on this subject based on the ideXlab platform.
-
Oral antenatal corticosteroids evaluated in fetal sheep
Pediatric Research, 2019Co-Authors: Augusto F Schmidt, Yusaku Kumagai, Haruo Usuda, Masatoshi Saito, Alan H. Jobe, Paranthaman S. Kannan, John P Newnham, James P. Bridges, Erin L. Fee, Michael ClarkeAbstract:Background The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model. Methods We measured pharmacokinetics of oral Betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and Betamethasone-Acetate at 2, 5, and 7 days after initiation of ACS. Results Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability. Conclusion Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.
-
the duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation
American Journal of Obstetrics and Gynecology, 2019Co-Authors: Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Augusto F Schmidt, Masatoshi Saito, Shinichi Sato, Takushi HanitaAbstract:ABSTRACT Objective Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. ACS dosing remains un-optimized, and there is little understanding of how different treatment to delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with ACS do not deliver within the widely accepted 1-7 day window of treatment efficacy. We used a sheep model to test duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. Methods For infusion studies, ewes with single fetuses were randomised to receive an intravenous bolus and maintenance infusion of Betamethasone phosphate to target 1-4ng/mL fetal plasma Betamethasone for 36 hours, with delivery at either 2, 4 or 7 days-post treatment or sterile saline as control. Animals receiving the clinical treatment were randomised to receive either:i) a single injection of 0.25mg/kg with a 1:1 mixture of Betamethasone phosphate + Betamethasone Acetate with delivery at either 1 or 7 days post treatment; or ii) two treatments of 0.25 mg/kg Betamethasone phosphate + Betamethasone Acetate spaced at 24 hours (giving approximately 48 hours of fetal steroid exposure) with delivery at 2, 5, 7 or 10 days post-treatment. Negative control animals were treated with saline. All lambs were delivered at 121±3 days gestational age and ventilated for 30 minutes to assess lung function. Results Preterm lambs delivered at 1 or 2 days post-ACS treatment had significant improvements in lung maturation for both intravenous and single dose intramuscular treatments. After 2 days the efficacy of 36 hour Betamethasone phosphate infusions was lost. The single dose of 1:1 Betamethasone phosphate + Betamethasone Acetate also was ineffective at 7 days. In contrast, animals treated with two doses had significant improvements in lung maturation at 2, 5 and 7 days, with treatment efficacy reduced by 10 days. Conclusion In preterm lambs, the durability of ACS treatment depends on the duration of fetal exposure and is independent of the IV or IM maternal route of administration. For acute 24-48 hour post-treatment deliveries, a 24 hour fetal ACS exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single dose ACS treatment should be sufficient for women delivering within
-
the efficacy of antenatal steroid therapy is dependent on the duration of low concentration fetal exposure evidence from a sheep model of pregnancy
American Journal of Obstetrics and Gynecology, 2018Co-Authors: Shimpei Watanabe, Yusaku Kumagai, Takushi Hanita, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Shinichi Sato, Timothy J MolloyAbstract:Background Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. Objective The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. Study Design Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of Betamethasone phosphate to target 12-hour fetal plasma Betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma Betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (Betamethasone phosphate + Betamethasone Acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma Betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. Results The loading and maintenance doses were achieved and maintained the desired fetal plasma Betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma Betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL Betamethasone infusion group. Lambs from the 12-hour 2-ng/mL Betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL Betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. Conclusion In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma Betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose Betamethasone phosphate infusion to achieve a fetal plasma Betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.
-
Low-dose Betamethasone-Acetate for fetal lung maturation in preterm sheep.
American journal of obstetrics and gynecology, 2017Co-Authors: Augusto F Schmidt, Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Judith Rittenschober-böhm, Paranthaman S. Kannan, Lucy L. Furfaro, Sarah J. Stock, Boris W. KramerAbstract:Background Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with Betamethasone-Acetate+Betamethasone-phosphate is more effective than 2 doses of Betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released Betamethasone-Acetate component induces similar lung maturation to Betamethasone-phosphate+Betamethasone-Acetate with decreased dose and fetal exposure. Objective The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal Betamethasone-Acetate in preterm fetal sheep. Study Design Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of Betamethasone-phosphate+Betamethasone-Acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of Betamethasone-Acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of Betamethasone-phosphate 0.125 mg/kg, Betamethasone-Acetate 0.125 mg/kg, or Betamethasone-Acetate 0.5 mg/kg. Maternal and fetal Betamethasone concentrations in plasma were measured for 24 hours. Results All Betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular Betamethasone-Acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of Betamethasone-Acetate+Betamethasone-phosphate. Betamethasone-Acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to Betamethasone compared with Betamethasone-phosphate 0.125 mg/kg. Conclusion A single dose of Betamethasone-Acetate results in similar fetal lung maturation as the 2-dose clinical formulation of Betamethasone-phosphate+Betamethasone-Acetate with decreased fetal exposure to Betamethasone. A lower dose of Betamethasone-Acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.
Haruo Usuda - One of the best experts on this subject based on the ideXlab platform.
-
Oral antenatal corticosteroids evaluated in fetal sheep
Pediatric Research, 2019Co-Authors: Augusto F Schmidt, Yusaku Kumagai, Haruo Usuda, Masatoshi Saito, Alan H. Jobe, Paranthaman S. Kannan, John P Newnham, James P. Bridges, Erin L. Fee, Michael ClarkeAbstract:Background The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model. Methods We measured pharmacokinetics of oral Betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and Betamethasone-Acetate at 2, 5, and 7 days after initiation of ACS. Results Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability. Conclusion Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.
-
the duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation
American Journal of Obstetrics and Gynecology, 2019Co-Authors: Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Augusto F Schmidt, Masatoshi Saito, Shinichi Sato, Takushi HanitaAbstract:ABSTRACT Objective Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. ACS dosing remains un-optimized, and there is little understanding of how different treatment to delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with ACS do not deliver within the widely accepted 1-7 day window of treatment efficacy. We used a sheep model to test duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. Methods For infusion studies, ewes with single fetuses were randomised to receive an intravenous bolus and maintenance infusion of Betamethasone phosphate to target 1-4ng/mL fetal plasma Betamethasone for 36 hours, with delivery at either 2, 4 or 7 days-post treatment or sterile saline as control. Animals receiving the clinical treatment were randomised to receive either:i) a single injection of 0.25mg/kg with a 1:1 mixture of Betamethasone phosphate + Betamethasone Acetate with delivery at either 1 or 7 days post treatment; or ii) two treatments of 0.25 mg/kg Betamethasone phosphate + Betamethasone Acetate spaced at 24 hours (giving approximately 48 hours of fetal steroid exposure) with delivery at 2, 5, 7 or 10 days post-treatment. Negative control animals were treated with saline. All lambs were delivered at 121±3 days gestational age and ventilated for 30 minutes to assess lung function. Results Preterm lambs delivered at 1 or 2 days post-ACS treatment had significant improvements in lung maturation for both intravenous and single dose intramuscular treatments. After 2 days the efficacy of 36 hour Betamethasone phosphate infusions was lost. The single dose of 1:1 Betamethasone phosphate + Betamethasone Acetate also was ineffective at 7 days. In contrast, animals treated with two doses had significant improvements in lung maturation at 2, 5 and 7 days, with treatment efficacy reduced by 10 days. Conclusion In preterm lambs, the durability of ACS treatment depends on the duration of fetal exposure and is independent of the IV or IM maternal route of administration. For acute 24-48 hour post-treatment deliveries, a 24 hour fetal ACS exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single dose ACS treatment should be sufficient for women delivering within
-
the efficacy of antenatal steroid therapy is dependent on the duration of low concentration fetal exposure evidence from a sheep model of pregnancy
American Journal of Obstetrics and Gynecology, 2018Co-Authors: Shimpei Watanabe, Yusaku Kumagai, Takushi Hanita, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Shinichi Sato, Timothy J MolloyAbstract:Background Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. Objective The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. Study Design Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of Betamethasone phosphate to target 12-hour fetal plasma Betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma Betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (Betamethasone phosphate + Betamethasone Acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma Betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. Results The loading and maintenance doses were achieved and maintained the desired fetal plasma Betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma Betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL Betamethasone infusion group. Lambs from the 12-hour 2-ng/mL Betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL Betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. Conclusion In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma Betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose Betamethasone phosphate infusion to achieve a fetal plasma Betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.
-
Low-dose Betamethasone-Acetate for fetal lung maturation in preterm sheep.
American journal of obstetrics and gynecology, 2017Co-Authors: Augusto F Schmidt, Shimpei Watanabe, Haruo Usuda, Matthew W. Kemp, Masatoshi Saito, Judith Rittenschober-böhm, Paranthaman S. Kannan, Lucy L. Furfaro, Sarah J. Stock, Boris W. KramerAbstract:Background Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with Betamethasone-Acetate+Betamethasone-phosphate is more effective than 2 doses of Betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released Betamethasone-Acetate component induces similar lung maturation to Betamethasone-phosphate+Betamethasone-Acetate with decreased dose and fetal exposure. Objective The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal Betamethasone-Acetate in preterm fetal sheep. Study Design Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of Betamethasone-phosphate+Betamethasone-Acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of Betamethasone-Acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of Betamethasone-phosphate 0.125 mg/kg, Betamethasone-Acetate 0.125 mg/kg, or Betamethasone-Acetate 0.5 mg/kg. Maternal and fetal Betamethasone concentrations in plasma were measured for 24 hours. Results All Betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular Betamethasone-Acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of Betamethasone-Acetate+Betamethasone-phosphate. Betamethasone-Acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to Betamethasone compared with Betamethasone-phosphate 0.125 mg/kg. Conclusion A single dose of Betamethasone-Acetate results in similar fetal lung maturation as the 2-dose clinical formulation of Betamethasone-phosphate+Betamethasone-Acetate with decreased fetal exposure to Betamethasone. A lower dose of Betamethasone-Acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.
Alan H. Jobe - One of the best experts on this subject based on the ideXlab platform.
-
Antenatal corticosteroids: a reappraisal of the drug formulation and dose
Pediatric Research, 2020Co-Authors: Alan H. Jobe, Matthew Kemp, Augusto Schmidt, Tsukasa Takahashi, John Newnham, Mark MiladAbstract:We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials. The treatment used in the United States is two intramuscular doses of a mixture of 6 mg Betamethasone phosphate (Beta P) and 6 mg Betamethasone Acetate (Beta Ac). To optimize outcomes with ACS, the goal should be to minimize fetal drug exposure. We have determined that the minimum exposure needed for fetal lung maturation in sheep, monkeys, and humans (based on published cord blood corticosteroid concentrations) is about 1 ng/ml for a 48-h continuous exposure, far lower than the concentration reached by the current dosing. Because the slowly released Beta Ac results in prolonged fetal exposure, a drug containing Beta Ac is not ideal for ACS use. Impact Using sheep and monkey models, we have defined the minimum corticosteroid exposure for a fetal lung maturation. These results should generate new clinical trials of antenatal corticosteroids (ACS) at much lower fetal exposures to ACS, possibly given orally, with fewer risks for the fetus.
-
Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India.
Clinical and translational science, 2019Co-Authors: Alan H. Jobe, Mark A. Milad, Thomas Peppard, William J. JuskoAbstract:High-dose Betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, Betamethasone phosphate, or a 1:1 mixture of Betamethasone phosphate and Betamethasone Acetate in reproductive age South Asian women. Intramuscular or oral Betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of Betamethasone phosphate and Betamethasone Acetate shows an immediate release of Betamethasone followed by a slow release where plasma Betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the Acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for Betamethasone and dexamethasone, but with longer times to return to baseline for Betamethasone. The 1:1 mixture of Betamethasone phosphate and Betamethasone Acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.
-
Oral antenatal corticosteroids evaluated in fetal sheep
Pediatric Research, 2019Co-Authors: Augusto F Schmidt, Yusaku Kumagai, Haruo Usuda, Masatoshi Saito, Alan H. Jobe, Paranthaman S. Kannan, John P Newnham, James P. Bridges, Erin L. Fee, Michael ClarkeAbstract:Background The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model. Methods We measured pharmacokinetics of oral Betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and Betamethasone-Acetate at 2, 5, and 7 days after initiation of ACS. Results Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability. Conclusion Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.
-
Antenatal dexamethasone vs. Betamethasone dosing for lung maturation in fetal sheep
Pediatric Research, 2017Co-Authors: Augusto F Schmidt, Matthew W. Kemp, Paranthaman S. Kannan, Boris W. Kramer, Suhas G Kallapur, John P Newnham, Alan H. JobeAbstract:Background: Dexamethasone-phosphate (Dex-PO_4) and the combination Betamethasone-phosphate (Beta-PO_4) + Betamethasone-Acetate (Beta-Ac) are the most used antenatal corticosteroids to promote fetal lung maturation. We compared fetal lung maturation induced by Beta-Ac+Beta-PO_4, Dex-PO_4, or Beta-PO_4 alone. Methods: Pregnant ewes received two intramuscular doses 24 h apart of 0.25 mg/kg/dose of Beta-Ac+Beta-PO_4, Dex-PO4 or Beta-PO_4; or 2 doses of 0.125 mg/kg/dose of Beta-PO_4 at 6, 12, or 24 h intervals. Fetuses were delivered 48 h after the first dose and ventilated for 30 min. We assessed ventilatory variables, vital signs, and blood gas. After ventilation pressure-volume curves were measured and lungs were sampled for analysis. Results: All treatments improved lung compliance and ventilation efficiency. Only Beta-Ac + Beta-PO_4 required lower positive inspiratory pressure compared with control. Beta-Ac + Beta-PO_4 and Beta-PO_4 alone, but not Dex-PO_4, increased the mRNA of surfactant proteins compared with control. Low-dose Beta-PO_4 did not increase mRNA of surfactant proteins. There were no differences among Beta-PO_4 treatment intervals. Conclusion: Beta-Ac + Beta-PO_4 given as two doses 24 h apart was more effective in promoting fetal lung maturation than Dex-PO_4 or Beta-PO_4 alone, consistent with a prolonged exposure provided by the Beta-Ac + Beta-PO_4. These results support the clinical use of combined Beta-Ac + Beta-PO_4 preparations over phosphate corticosteroids alone for fetal lung maturation.
-
Antenatal dexamethasone vs. Betamethasone dosing for lung maturation in fetal sheep.
Pediatric research, 2016Co-Authors: Augusto F Schmidt, Matthew W. Kemp, Paranthaman S. Kannan, Boris W. Kramer, Suhas G Kallapur, John P Newnham, Alan H. JobeAbstract:Dexamethasone-phosphate (Dex-PO4) and the combination Betamethasone-phosphate (Beta-PO4) + Betamethasone-Acetate (Beta-Ac) are the most used antenatal corticosteroids to promote fetal lung maturation. We compared fetal lung maturation induced by Beta-Ac+Beta-PO4, Dex-PO4, or Beta-PO4 alone. Pregnant ewes received two intramuscular doses 24 h apart of 0.25 mg/kg/dose of Beta-Ac+Beta-PO4, Dex-PO4 or Beta-PO4; or 2 doses of 0.125 mg/kg/dose of Beta-PO4 at 6, 12, or 24 h intervals. Fetuses were delivered 48 h after the first dose and ventilated for 30 min. We assessed ventilatory variables, vital signs, and blood gas. After ventilation pressure-volume curves were measured and lungs were sampled for analysis. All treatments improved lung compliance and ventilation efficiency. Only Beta-Ac + Beta-PO4 required lower positive inspiratory pressure compared with control. Beta-Ac + Beta-PO4 and Beta-PO4 alone, but not Dex-PO4, increased the mRNA of surfactant proteins compared with control. Low-dose Beta-PO4 did not increase mRNA of surfactant proteins. There were no differences among Beta-PO4 treatment intervals. Beta-Ac + Beta-PO4 given as two doses 24 h apart was more effective in promoting fetal lung maturation than Dex-PO4 or Beta-PO4 alone, consistent with a prolonged exposure provided by the Beta-Ac + Beta-PO4. These results support the clinical use of combined Beta-Ac + Beta-PO4 preparations over phosphate corticosteroids alone for fetal lung maturation.
H R Schumacher - One of the best experts on this subject based on the ideXlab platform.
-
intra articular corticosteroid preparations different characteristics and their effect during inflammation induced by monosodium urate crystals in the rat subcutaneous air pouch
Rheumatology, 2003Co-Authors: M Rull, Gilda Clayburne, Marie Sieck, H R SchumacherAbstract:Objective. To examine the effects of three commonly used intra-articular depot corticosteroid preparations tested in a rat air pouch model and their effect against monosodium urate (MSU) crystal-induced inflammation. Rheumatologists use intra-articular corticosteroid preparations to relieve pain and inflammation of acute monoarthritis without really knowing their effects on the synovial fluid and membrane or the differences between distinct preparations. This work compares the effect of three commonly used corticosteroid preparations in vivo, showing that they behave differently. Methods. A subcutaneous air pouch was formed in male Sprague-Dawley rats. A first group of 6-day-old air pouches were injected with 10 ml of 6 mg/ml normal saline solution, 6 mg/ml Betamethasone containing both depot Betamethasone Acetate and soluble Betamethasone phosphate (Celestone) in 9 ml of normal saline solution, 20 mg/ml of prednisolone tebutate (Hydeltra) in 9 ml of normal saline solution or 20 mg/ml of triamcinolone hexacetonide (Aristospan) in 9 ml of normal saline solution. A second group (group 2) of air pouches were injected with 15 mg of synthetic MSU crystals and 24 h later they were reinjected with 1 ml of the same three corticosteroid suspensions. For each condition four rats were killed at 6, 24, 48 h and 7 days. Pouch fluid and tissue were analysed. Results. In the first 6 h after normal saline solution or corticosteroid injection into the air pouch there were mildly increased leucocyte counts in the air pouch fluid. Betamethasone-injected pouches showed no cells in the fluid after 6 h and no crystals after 24 h, triamcinolone-injected pouches still showed rare cells at 7 days. Both triamcinolone and prednisolone crystals persisted in higher numbers and lasted longer in the fluid than did Betamethasone (P < 0.05). In group 2 MSU crystal phagocytosis in the fluid was decreased in the Betamethasone- (P < 0.01), prednisolone- (P < 0.003) and triamcinolone- (P < 0.006) injected pouches when compared with the MSU crystal-injected pouches alone. Pouches injected with MSU crystals alone showed the most intense tissue inflammation at all times. After MSU, Betamethasone-injected pouches had a rapid but mild decrease in the number of lining cells and inflammation. In contrast, triamcinolone- and prednisolone-injected pouches showed a very thin tissue with few or no vessels and almost no inflammation at 7 days. The pouches injected with MSU crystals and any of the corticoid preparations had three times more tophus-like structures and persistent crystals identified than the ones injected with MSU crystals alone. Conclusion. Each of the corticosteroid preparations by themselves produced very mild transient inflammation. The Betamethasone preparation with a soluble steroid component had a quicker but milder anti-inflammatory effect on MSU crystal-induced inflammation. In contrast to the doses used, prednisolone tebutate and triamcinolone hexacetonide preparations dramatically suppressed urate crystal-induced inflammation at 7 days, but both produced atrophy and necrosis of the membrane, yielding a very thin membrane with almost no vessels. When used for MSU crystal-induced inflammation these corticosteroid preparations suppressed some aspects of inflammation but may actually promote the persistence of MSU crystals and the formation of tophi.
-
Intra‐articular corticosteroid preparations: different characteristics and their effect during inflammation induced by monosodium urate crystals in the rat subcutaneous air pouch
Rheumatology (Oxford England), 2003Co-Authors: M Rull, Marie Sieck, Clayburne G, H R SchumacherAbstract:Objective. To examine the effects of three commonly used intra-articular depot corticosteroid preparations tested in a rat air pouch model and their effect against monosodium urate (MSU) crystal-induced inflammation. Rheumatologists use intra-articular corticosteroid preparations to relieve pain and inflammation of acute monoarthritis without really knowing their effects on the synovial fluid and membrane or the differences between distinct preparations. This work compares the effect of three commonly used corticosteroid preparations in vivo, showing that they behave differently. Methods. A subcutaneous air pouch was formed in male Sprague-Dawley rats. A first group of 6-day-old air pouches were injected with 10 ml of 6 mg/ml normal saline solution, 6 mg/ml Betamethasone containing both depot Betamethasone Acetate and soluble Betamethasone phosphate (Celestone) in 9 ml of normal saline solution, 20 mg/ml of prednisolone tebutate (Hydeltra) in 9 ml of normal saline solution or 20 mg/ml of triamcinolone hexacetonide (Aristospan) in 9 ml of normal saline solution. A second group (group 2) of air pouches were injected with 15 mg of synthetic MSU crystals and 24 h later they were reinjected with 1 ml of the same three corticosteroid suspensions. For each condition four rats were killed at 6, 24, 48 h and 7 days. Pouch fluid and tissue were analysed. Results. In the first 6 h after normal saline solution or corticosteroid injection into the air pouch there were mildly increased leucocyte counts in the air pouch fluid. Betamethasone-injected pouches showed no cells in the fluid after 6 h and no crystals after 24 h, triamcinolone-injected pouches still showed rare cells at 7 days. Both triamcinolone and prednisolone crystals persisted in higher numbers and lasted longer in the fluid than did Betamethasone (P < 0.05). In group 2 MSU crystal phagocytosis in the fluid was decreased in the Betamethasone- (P < 0.01), prednisolone- (P < 0.003) and triamcinolone- (P < 0.006) injected pouches when compared with the MSU crystal-injected pouches alone. Pouches injected with MSU crystals alone showed the most intense tissue inflammation at all times. After MSU, Betamethasone-injected pouches had a rapid but mild decrease in the number of lining cells and inflammation. In contrast, triamcinolone- and prednisolone-injected pouches showed a very thin tissue with few or no vessels and almost no inflammation at 7 days. The pouches injected with MSU crystals and any of the corticoid preparations had three times more tophus-like structures and persistent crystals identified than the ones injected with MSU crystals alone. Conclusion. Each of the corticosteroid preparations by themselves produced very mild transient inflammation. The Betamethasone preparation with a soluble steroid component had a quicker but milder anti-inflammatory effect on MSU crystal-induced inflammation. In contrast to the doses used, prednisolone tebutate and triamcinolone hexacetonide preparations dramatically suppressed urate crystal-induced inflammation at 7 days, but both produced atrophy and necrosis of the membrane, yielding a very thin membrane with almost no vessels. When used for MSU crystal-induced inflammation these corticosteroid preparations suppressed some aspects of inflammation but may actually promote the persistence of MSU crystals and the formation of tophi.