The Function of Aviptadil Acetate on the Treatment of

Pulmonary Arterial Hypertension

Introduction

Aviptadil acetate, the nonproprietary or generic name for a vasoactive intestinal

peptide (VIP), is a synthetic 28-amino-acid VIP (Fig.1). In pulmonary arterial
hypertension (PAH), elevated pulmonary vascular resistance and pulmonary
arterial pressure are resulting from the progressive narrowing of the pulmonary
arterial lumens. Although an array of anti-PAH drugs are currently available, PAH
therapy still suffers from a number of limitations. Thus a series of small molecular
weight drugs and peptides have been evaluated for their anti-PAH effects.
Inhalation of aviptadil has been suggested as a novel approach for the treatment
of idiopathic PAH. Idiopathic PAH patients are deficient in VIP that triggers a
compensatory up regulation of receptor expression in the pulmonary vasculature
to counter-regulate VIP deficiency.

Fig. 1 The general structure of aviptadil acetate

Functional Study of Aviptadil Acetate on PAH

There were many experimental studies about the function of Aviptadil Acetate on
PAH. One trial described the acute effects on haemodynamics and blood gases, as
well as the tolerability, of a single 100-mg inhaled dose of aviptadil in a mixed
group of patients with moderate to severe PAH. Aviptadil was well tolerated, acted
as a weak pulmonary selective vasodilator and alleviated right heart strain. These
effects were comparable in the PAH and the non-PAH group. Additionally,
aviptadil tended to improve oxygenation in patients with chronic lung disease,
which suggested further studies were necessary to evaluate the role of aviptadil
as a new therapeutic option in the field of PAH. Another trial concluded that
patients with idiopathic PAH lack VIP and have a compensatory upregulation of
receptor expression in the pulmonary vasculature, as an attempt to counter-
regulate VIP deficiency. Subsequently, eight patients with idiopathic PAH were
treated and it also observed an acute and a chronic effect of aerosolised aviptadil.
In an acute challenge with a single 100 μg dose of aviptadil during right heart
catheterization, a P-pa reduction of 10 mmHg and an increase of cardiac output of
0.8 L/min were observed. Chronic treatment with aviptadil comprised four
inhalations per day, equaling a daily dose of 200 μg. After a period of 12 weeks a
significant improvement of the 6 min walk test was noted. Although the present
authors administered the same dose of aviptadil, comparable strong effects with
regard to pulmonary vasodilation were not seen. However, in the PAH group the
increase in cardiac output (~0.6 L/min ) was comparable. The modest
vasorelaxant effect of a single 100 μg aviptadil inhalation may not reflect the full
therapeutic potential of this drug. Additional study provided experimental
evidence that VIP is involved in the proliferation process of pulmonary vascular
smooth muscle. They were able to demonstrate that VIP deficiency leads to
moderately severe PAH in male mice lacking the VIP gene. This observation may
justify the speculation that chronic treatment with aviptadil positively influences
the remodeling process in the pulmonary vasculature in the context of PAH.

The Wide Acceptance

Biogen Idec, the drug producer in the United States, and Mondo Biotech AG, the
biotechnology company in Switzerland, have signed a sole transfer and
cooperation agreement, which coveres the development and production of
Aviptadil for the treatment of pulmonary hypertension. Aviptadil has been used
for pulmonary arterial hypertension in the United States and Europe as a rare drug.
Results in phase I trials showed that the patients’ athletic ability had improved
significantly since they undergone the treatment of Aviptadil for three to six
months.

References:

Petkov, V., Mosgoeller, W., Ziesche, R., Raderer, M., and Stiebellehner, L. (2003).
'Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary
hypertension’, Journal of Clinical Investigation, 111(9): 1339-1346.

Said, S.I., Hamidi. S.A., Dickman, K.G.,Szema, A. M., Lyubsky, S. (2007). 'Moderate
pulmonary arterial hypertension in male mice lacking the vasoactive intestinal
peptide gene’, Circulation, 115(10): 1260-1268.

Leuchte, H.H., Baezner, C., Baumgartner, R. A., Bevec, D. Bacher, G. (2008).

'Inhalation of vasoactive intestinal peptide in pulmonary hypertension’, European
Respiratory Journa, 32(5): 1289-1294.

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