Pulmonary Toxicity of Inhaled Aerosolized Prostacyclin Therapy—An Observational Study

Heerden, Peter Vernon van; Caterina, P.; Filion, Pierre; Spagnolo, Dominic V.; Gibbs, N. M.

doi:10.1177/0310057x0002800206

Cited by 27 publications

(9 citation statements)

References 38 publications

(58 reference statements)

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“…The primary concerns with aEPO revolve around inhibition of platelet aggregation and the localized effect of the highly alkaline glycine diluent (pH ~10.5) required for drug stability . A study in piglets investigated the effects of administration of aEPO in glycine diluent versus glycine diluent alone at a nebulization rate of 15 ml/hour (mean aEPO dose 200 ng/kg/min) for up to 8 hours . Mild acute tracheitis that involved the superficial layers of the trachea were observed after exposure to ~2‐fold the hourly dose of diluent and 4‐fold the hourly dose of aEPO commonly administered in humans .…”

Section: Aerosolized Epoprostenolmentioning

confidence: 99%

“…A study in piglets investigated the effects of administration of aEPO in glycine diluent versus glycine diluent alone at a nebulization rate of 15 ml/hour (mean aEPO dose 200 ng/kg/min) for up to 8 hours . Mild acute tracheitis that involved the superficial layers of the trachea were observed after exposure to ~2‐fold the hourly dose of diluent and 4‐fold the hourly dose of aEPO commonly administered in humans . Additionally, no supporting evidence of pulmonary toxicity was identified.…”

Section: Aerosolized Epoprostenolmentioning

confidence: 99%

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A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

et al. 2013

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Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are conditions associated with an estimated mortality of 40–50%. The use of inhaled vasodilators can help to improve oxygenation without hemodynamic effects. This article reviews relevant studies addressing the safety and efficacy of inhaled nitric oxide (iNO) and aerosolized epoprostenol (aEPO) in the treatment of life-threatening hypoxemia associated with ARDS and ALI. In addition, the article also provides a practicable guide to the clinical application of these therapies. Nine prospective randomized controlled trials were included for iNO reporting on changes in oxygenation or clinical outcomes. Seven reports of aEPO were examined for changes in oxygenation. Based on currently available data, the use of either iNO or aEPO is safe to use in patients with ALI or ARDS to transiently improve oxygenation. No differences have been observed in survival, ventilator-free days, or attenuation in disease severity. Further studies with consistent end points using standard delivery devices and standard modes of mechanical ventilation are needed to determine the overall benefit with iNO or aEPO.

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Section: Aerosolized Epoprostenolmentioning

confidence: 99%

Section: Aerosolized Epoprostenolmentioning

confidence: 99%

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

et al. 2013

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“…Aerosolized prostaglandins I 2 (PGI 2 ) and E 1 (PGE 1 ) have been reported to be effective selective pulmonary vasodilators in animals, adults, and preterm and term newborns [ 5 – 15 ]. Compared to PGI 2 , PGE 1 has a shorter half-life, lower acid dissociation constant (pKa, 6.3 versus 10.5), bronchodilator action, and anti-proliferative and anti-inflammatory effects on the alveolar, interstitial, and vascular spaces of the lung [ 10 , 16 – 20 ]. In addition, PGE 1 is readily available in pharmacies of hospitals with neonatal services and has a proven safety record from its intravenous use in ductal-dependent cardiac anomalies.…”

Section: Introductionmentioning

confidence: 99%

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

Sood

Keszler

Garg

et al. 2014

Trials

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BackgroundInhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.MethodsTwo pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.ResultsNo infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.ConclusionsThese two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.Trial registration: ClinicalTrials.govPilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011.Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.

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“…Further, it has been studied for its potential use in the treatment of PH and other respiratory disorders 21–24 . However, similar to commercially available prostacyclins, PGE 1 suffers from the disadvantage of short half-life of 3–5 minutes 25,26 . Although this drug is not commercially available for the treatment of PH, the biological and chemical properties of PGE 1 closely resemble those of currently available prostacyclin analogs.…”

Section: Introductionmentioning

confidence: 99%

Inhaled PLGA Particles of Prostaglandin E₁ Ameliorate Symptoms and Progression of Pulmonary Hypertension at a Reduced Dosing Frequency

Gupta

Shaik

et al. 2013

Mol. Pharmaceutics

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This study sought to investigate the efficacy of a noninvasive and long acting polymeric particle based formulation of prostaglandin E1 (PGE1), a potent pulmonary vasodilator, in alleviating the signs of pulmonary hypertension (PH) and reversing the biochemical changes that occur in the diseased lungs. PH rats, developed by a single subcutaneous injection of monocrotaline (MCT), were treated with two types of polymeric particles of PGE1, porous and nonporous, and intratracheal or intravenous plain PGE1. For chronic studies, rats received either intratracheal porous poly (lactic-co-glycolic acid) (PLGA) particles, once- or thrice-a-day, or plain PGE1 thrice-a-day for 10 days administered intratracheally or intravenously. The influence of formulations on disease progression was studied by measuring the mean pulmonary arterial pressure (MPAP), evaluating right ventricular hypertrophy and assessing various molecular and cellular makers including the degree of muscularization, platelet aggregation, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antigen (PCNA). Both plain PGE1 and large porous particles of PGE1 reduced MPAP and right ventricular hypertrophy (RVH) in rats that received the treatments for 10 days. Polymeric porous particles of PGE1 produced the same effects at a reduced dosing frequency compared to plain PGE1 and caused minimal off-target effects on systemic hemodynamics. Microscopic and immunohistochemical studies revealed that porous particles of PGE1 also reduced the degree of muscularization, von Willebrand factor (vWF) and PCNA expression in the lungs of PH rats. Overall, our study suggests that PGE1 loaded inhalable particulate formulations improve PH symptoms and arrest the progression of disease at a reduced dosing frequency compared to plain PGE1.

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Pulmonary Toxicity of Inhaled Aerosolized Prostacyclin Therapy—An Observational Study

Cited by 27 publications

References 38 publications

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

Inhaled PLGA Particles of Prostaglandin E₁ Ameliorate Symptoms and Progression of Pulmonary Hypertension at a Reduced Dosing Frequency

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Pulmonary Toxicity of Inhaled Aerosolized Prostacyclin Therapy—An Observational Study

Cited by 27 publications

References 38 publications

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

Inhaled PLGA Particles of Prostaglandin E1 Ameliorate Symptoms and Progression of Pulmonary Hypertension at a Reduced Dosing Frequency

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Product

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Inhaled PLGA Particles of Prostaglandin E₁ Ameliorate Symptoms and Progression of Pulmonary Hypertension at a Reduced Dosing Frequency