Oral drugs used to treat persistent pulmonary hypertension of the newborn.

Introduction:Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects. Areas covered: We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics. Expert opinion: Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.

The effects of bosentan on hyperoxia-induced lung injury in neonatal rats.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important cause of morbidity and mortality in premature infants. There is currently no proven effective treatment modality for BPD, and inflammation and oxidative injury play an important role in the pathogenesis of this disease. This study investigated the histopathological and biochemical effects of bosentan, which is a non-specific endothelin receptor antagonist with known antioxidant and anti-inflammatory properties, on hyperoxia-induced lung injury (HILI) in neonatal rats. METHODS: The experiment was performed on newborn rats from the 3rd to the 13th postnatal day. The rats were randomly divided into six groups: Group 1 (air-exposed + saline, n = 6); Group 2 (HILI, n = 8); Group 3 (air-exposed + bosentan, n = 7); Group 4 (HILI + saline, n = 7); Group 5 (HILI + early bosentan-treated group, n = 6), and Group 6 (HILI + late bosentan-treated group, n = 7). Bosentan was administered (30 mg/kg/day) intraperitoneally. The histopathological effects of bosentan on lung tissue were assessed by their alveolar surface area, fibrosis, and smooth muscle actin (SMA) scores, and the biochemical effects on lung tissue were assessed by interleukin-1 beta (IL-1ß), IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α). RESULTS: The alveolar surface area and fibrosis scores were found to be significantly higher in HILI groups compared with Group 1 (P < 0.01). The SMA scores in HILI groups were also significantly higher than Group 1 (P < 0.01). Bosentan treatment, especially late therapy, reduced all of these histopathological scores and the levels of IL-6 and TNF-α in the hyperoxia groups (P < 0.01). CONCLUSION: This experimental study showed that bosentan had a protective effect on hyperoxic lung injury through its anti-inflammatory properties.

Involvement of Endothelin 1 in Remote Preconditioning-Induced Cardioprotection through connexin 43 and Akt/GSK-3ß Signaling Pathway.

The present study was aimed to explore the role of endothelins in remote preconditioning (RP)-induced myocardial protection in ischemia-reperfusion (IR) injury. RP stimulus was given by subjecting hind limb to four cycles of ischemia and reperfuion (5 minutes each) using blood pressure cuff in male rats. Following RP, hearts were isolated and subjected to 30 minutes of ischemia and 120 minutes of reperfusion on Langendorff apparatus. The extent of myocardial injury was determined by measuring the levels of LDH-1, CK-MB and cardiac troponin T (cTnT) in coronary effluent; caspase-3 activity and Bcl 2 expression in heart (apoptosis); infarct size by triphenyl tetrazolium chloride and contractility parameters including left ventricular developed pressure, dp/dtmax dp/dtmin and heart rate. RP reduced ischemia reperfusion-induced myocardial injury, increased the levels of endothelin 1 (in blood), Akt-P, GSK-3ß-P and P-connexin 43 (in hearts). Pretreatment with ETA receptor antagonist, BQ 123 (1 and 2 mg/kg), ETB receptor antagonist, BQ 788 (1 and 3 mg/kg) and dual inhibitor of ETA and ETB receptor, bonsentan (25 and 50 mg/kg) abolished these effects of RP. However, the effects of bonsentan were more pronounced in comparison to BQ 123 and BQ 788. It is concluded that RP stimulus may release endothelin 1 in the blood, which may activate myocardial ETA and ETB receptors to trigger cardioprotection through connexin 43 and Akt/GSK-3ß pathway.