Persistent Pulmonary Hypertension of the Newborn - Mattel ...

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Phase I Trial: Adverse Effects:No exacerbation of hypotension, hyperthermia,dysrhythmias, or bleeding tendencyTestBefore IPGE 1Mean (SD)After IPGE 1Mean (SD)Alanine aminotransferase* 26.3 (10.2) 25.3 (14.1) NSAspartate aminotransferase* 74.7 (65.6) 47.2 (29.4) 0.04Alkaline phosphatase* 193.4 (272.5) 93.6 (54.9) NSBilirubin** 4.6 (2.9) 5.3 (4.3) NSBlood urea nitrogen** 7 (3.3) 9.9 (5.5) 0.011Creatinine** 0.7 (0.18) 0.7 (0.23) NSHematocrit (%) 46.8 (6.4) 40.1 (6.6) 0.001Platelets† 219.3 (116.7) 187 (77.5) NSTotal leukocyte count† 16.2 (6.8) 12.6 (6.4) 0.039* U/L, ** (mg/dL), † 10 3 /mm 3 Sood et al, Ped Res, 2004P
Animal Toxicity Studies:• Ten mechanically ventilated anesthetized piglets• High dose IPGE 1 (1200 ng/kg/min) or nebulized NS for 24 hNormal bronchus andadjacent alveoli in apiglet who receivedIPGE 1for 24 hFew neutrophils andred blood cells in thebronchus (arrow) andminimal alveolaredema (arrowhead)• No evidence of adverse cardio-respiratory respiratory effects,bronchial irritation or hypernatremia related to IPGE 1• No evidence of severe toxic injury:• Hyaline membranes• Diffuse/severe neutrophilic infiltration• Diffuse/severe ulceration• Distinct histologic findings in IPGE 1 animals:• Focal ulceration• Focal flattening of the bronchial epithelium• Focal loss of cilia of moderate to severe degreeSood et al, Pulm Pharm Ther, 2008
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Page 9 and 10: Off Label Drug Use• FDA regulates
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Page 16 and 17: Regulation of Pulmonary Vascular To
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Page 21 and 22: PO Sildenafil• 1 st dose - 1 mg/0
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Page 27 and 28: PDE-3 3 Inhibitor - Milrinone• Pr
Page 29 and 30: Milrinone Improves Oxygenationin Ne
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Page 38 and 39: In utero exposure to PGSynthetase i
Page 40 and 41: Non-selective action:• Systemic &
Page 42 and 43: PGE 1 - Metabolism70-95%PGE 115-OH
Page 44 and 45: Studies of Inhaled Prostaglandins i
Page 46 and 47: Studies of Inhaled Prostaglandins i
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Page 54 and 55: Effect on Ductus Arteriosus• Echo
Page 56 and 57: Stability and Emitted DoseModified
Page 58 and 59: ResultsLC-MS Chromatograms Followin
Page 60 and 61: Aerosol Particle Size DistributionA
Page 62 and 63: Pharmacokinetics of IPGE 1 ?
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Page 66 and 67: Aerosol Delivery Assessed by MRIExp
Page 68 and 69: Aerosol Delivery Assessed by MRI450
Page 70 and 71: Aerosol Delivery During HFOVSood et
Page 72 and 73: Preliminary Data - Conclusions• P
Page 74 and 75: Specific AimsPrimary Aims:‣ Evalu
Page 76: Challenges: RCTs in PPHN• Small n
Page 79 and 80: Thank YouDiscussion

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