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Research: Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

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Research: Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

EBioMedicine

. 2022 Jun 29;81:104106.

 doi: 10.1016/j.ebiom.2022.104106. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/35779494/

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

Felix Rafael De Bie 1Christopher Gates Halline 2Travis Kotzur 2Kevin Hayes 2Christopher Copeland Rouse 2Jonathan Chang 2Abby Christine Larson 2Sameer Ahmad Khan 2Ashley Spina 2Samantha Tilden 2Francesca Maria Russo 3Holly Lee Hedrick 2Jan Deprest 4Emily Anne Partridge 5

Affiliations expand

Free PMC article

Abstract

Background: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH.

Methods: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied.

Findings: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure.

Interpretation: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH.

Funding: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Keywords: Congenital diaphragmatic hernia; Foetal therapy; Remodulin; Treprostinil.

EBioMedicine

. 2022 Jun 29;81:104106.

 doi: 10.1016/j.ebiom.2022.104106. Online ahead of print.

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

Felix Rafael De Bie 1Christopher Gates Halline 2Travis Kotzur 2Kevin Hayes 2Christopher Copeland Rouse 2Jonathan Chang 2Abby Christine Larson 2Sameer Ahmad Khan 2Ashley Spina 2Samantha Tilden 2Francesca Maria Russo 3Holly Lee Hedrick 2Jan Deprest 4Emily Anne Partridge 5

Affiliations expand

Free PMC article

Abstract

Background: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH.

Methods: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied.

Findings: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure.

Interpretation: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH.

Funding: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Keywords: Congenital diaphragmatic hernia; Foetal therapy; Remodulin; Treprostinil.

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