Biology Reference
In-Depth Information
of iNO was a dramatic increase in PDE3 activity to levels similar to those observed
in normal 1-day lambs. Further, milrinone was found to significantly relax pulmo-
nary arteries isolated from PPHN lambs ventilated with iNO (Chen et al.
2009
). In
infants with PPHN, there have been two small case series of treatment with
milrinone. In both series, the infants were already receiving iNO at the time that
the milrinone was started, and significant improvements in oxygenation were
observed with milrinone treatment (Bassler et al.
2006
; McNamara et al.
2006
).
Similarly, in pediatric patients (
n
46, average age 5 years) undergoing a Fontan
procedure, postoperative use of milrinone in conjunction with iNO resulted in
greater improvements in the transpulmonary gradient and arterial oxygen saturation
versus those children treated with iNO alone or milrinone alone (Cai et al.
2008a
,
b
).
These clinical case series all support an interesting potential role for milrinone in
the treatment of neonatal pulmonary hypertension, especially when used in con-
junction with iNO. However, more study is needed to determine optimum dosing
and timing of therapy initiation for milrinone in these infants.
ΒΌ
2.3 PDE1 and PDE4 Inhibitors
To date, there have been no trials or case reports of PDE1 or PDE4 inhibitors in
neonates with pulmonary hypertension. However, data from adult patients and
animal models would suggest that this should be an area of investigation for future
potential therapies. For instance, zaprinast, initially thought to be a selective PDE5
inhibitor, has recently been described to have significant inhibitory activity against
PDE1. This agent was found to enhance relaxations to iNO in neonatal lambs with
PPHN (Thusu et al.
1995
). Increased PDE1C mRNA and protein have been
described in resistance pulmonary arteries and pulmonary artery smooth muscle
cells derived from lung specimens of human pulmonary arterial hypertension
patients (Murray et al.
2007
; Schermuly et al.
2007
). Thus, a PDE1C inhibitor
might have clinical utility across all of the different types of neonatal pulmonary
hypertension. Similarly, PDE4 inhibitors have reached clinical trials in adults with
asthma and chronic obstructive pulmonary disease (Fan Chung
2006
). In light of the
recent publications that PDE4 inhibition is beneficial in neonatal mice with BPD, it
is reasonable to hypothesize that PDE4 inhibitors might be clinically useful in the
patients with pulmonary hypertension due to BPD.
3 Conclusions
Neonatal pulmonary hypertension is a clinical syndrome that affects approximately
10% of all infants admitted to neonatal intensive care units. It has multiple
etiologies that involve complex alterations in multiple signaling pathways. As
such, no one therapy is likely to be appropriate or effective in every patient.
