ARA 290 and the ventilatory response to hypoxia and pain responses in healthy volunteers

Hypoxia may be defined as a relative deficiency in oxygen availability/delivery
for maintaining adequate physiological oxygen tensions and thus results from an
imbalance between oxygen demand and supply [1]. The peripheral chemoreceptors
in the carotid bodies are sensitive to changes in the tensions of oxygen and
carbon dioxide in the arterial blood and protect the body against hypoxia,
hyper- and hypocapnia and acidosis/alkalosis. The ventilatory response to
hypoxia (O2-chemoreflex) is initiated by a mechanism involving inhibition of
potassium channels in chemosensitive cells in the carotid bodies, followed by
membrane depolarisation, influx of Ca2+ ions and release of neurotransmitters.
Also the pulmonary vessel are sensitive to hypoxia responding with HPV or
Hypoxic Pulmonary Vasoconstriction. The mechanisms of hypoxic sensing at the
carotid bodies and within the pulmonary vasculature are still unknown but may
share important characteristics.

(1) To assess the effect of ARA 290 on the ventilatory response to hypoxia (and
compare the effects to Epo);
(2) To assess the effect of ARA 290 on the gradient over the tricuspid valve
during hypoxia (and compare the effects to Epo);
(3) To assess the effect of ARA 290 on pain responses.

We will perform a placebo-controlled, double blind, randomized, cross-over
study in healthy volunteers. In between study session there will at least 1
week.

IV injection of ARA or EPO or PLACEBO

Due to the venous lines some bruising may occur.

Hypoxia at the moderate levels we apply is without side effects although some
headache may occur during the isocapnic hypoxic studies. The headache responds
well to acetaminophen.

Side effects as described in the *Farmacotherapeutisch kompas 2009* related to
erythropoietin include: flu-like symptoms, headache, joint pain, dizziness and
tiredness. ARA 290 is well tolerated and save in administration. Some mild
headache can occur. It can cause some myalgia and irritation on the
administration site.