The effect of P-glycoprotein transport inhibition on brainmechanisms of sedation and cognitive impairment following antihistamines in healthy volunteers.

One of the most prominent side effects of antihistamines is sedation. Due to
this sedation there is a decrease in in workproductivity, an increased
absenteeism from work or school, and an increased risk for traffic accidents.
Antihistamines are divided into first and second generation antihistamines.
First generation antihistamines cause sedation, whereas second generation
antihistamines have been found to be mildly sedative, or even mildly
stimulating.
First generation antihistamines are lipophilic. Therefore, they can easily
cross the blood-brain barrier (BBB) and block histamine H1-receptors in the
central nervous system, which causes the sedation. Because second generation
antihistamines are more lipophobic they cause less sedation. However, other
factors, such as P-glycoprotein (Pgp) mediated efflux of the BBB may also
determine the presence, absence and/or magnitude of sedation.

This Pgp transporter can pump drugs out of the brain, resulting in a reduction
of undesired effects in the central nervous system.

It is hypothesized that the behavioral effect (i.e. slower RT and impaired
attention) of a non-sedative antihistamine will be apparent in combination with
a Pgp-blocker, but will not be apparent when administered alone. When a
non-sedative antihistamine is not pumped out of the brain by the Pgp
transporter, the antihistamine is able to bind at the histamine 1 receptor and
will cause cognitive side effects, comparable with sedative antihistamines.

The objective of the study is to test the effects of the p-glycoproteine
transporter on cognitive test in healthy volunteers and to explore the effects
of the p-glycoproteine transporter on functional Magnetic Resonance Imaging
(fMRI).

Double blind, placebo-controlled, 2-way cross over design

During the study, all volunteers will experience the following testconditions:
1. placebo and verapamil (120 mg)
2. cetirizine (15 mg) and verapamil (120 mg)

Volunteers will visit the study centre and will be monitored by one of the
investigators for examination during medical screening (45 minutes); for
training of cognitive tests and habituation to the scanner (2 hours), and 2
treatment periodes of 6 hours each (total time: 14,75 hours).

Blood samples are drawn during screening and twice during the testperiods
(5mL). During treatment periods subjects perform cognitive tests and resting
state and BOLD signal will be measured.

Both, verapamil and cetirizine are already registered medication for a long
time, Intake of both medications can cause posible side effect. However, those
effects are normally mild.

This study is relevant in order to get better insights about the mechanisms of
H1-antagonists. With more insights in these mechanisms, the administration of
antihistamines can be adjusted in order to be more effective and less sedative.