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Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial.
[cadasil]
Cerebral
autosomal-dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
(
CADASIL
)
,
a
rare
autosomal
dominant
disorder
caused
by
NOTCH
3
mutations
,
is
characterized
by
vascular
smooth
muscle
and
endothelial
cells
abnormalities
,
altered
vasoreactivity
,
and
recurrent
lacunar
infarcts
.
Vasomotor
function
may
represent
a
key
factor
for
disease
progression
.
Tetrahydrobiopterin
,
essential
cofactor
for
nitric
oxide
synthesis
in
endothelial
cells
,
ameliorates
endothelial
function
.
We
assessed
whether
supplementation
with
sapropterin
,
a
synthetic
tetrahydrobiopterin
analog
,
improves
endothelium-dependent
vasodilation
in
CADASIL
patients
.
In
a
24
-
month
,
multicenter
randomized
,
double
-blind
,
placebo-controlled
trial
,
CADASIL
patients
aged
30
to
65
years
were
randomly
assigned
to
receive
placebo
or
sapropterin
200
to
400
mg
BID
.
The
primary
end
point
was
change
in
the
reactive
hyperemia
index
by
peripheral
arterial
tonometry
at
24
months
.
We
also
assessed
the
safety
and
tolerability
of
sapropterin
.
Analysis
was
done
by
intention-
to
-treat
.
The
intention-
to
-treat
population
included
61
patients
.
We
found
no
significant
difference
between
sapropterin
(
n
=
32
)
and
placebo
(
n
=
29
)
in
the
primary
end
point
(
mean
difference
in
reactive
hyperemia
index
by
peripheral
arterial
tonometry
changes
0
.
19
[
95
%
confidence
interval
,
-
0
.
18
,
0
.
56
]
)
.
Reactive
hyperemia
index
by
peripheral
arterial
tonometry
increased
after
24
months
in
37
%
of
patients
on
sapropterin
and
in
28
%
on
placebo
;
however
,
after
adjustment
for
age
,
sex
,
and
clinical
characteristics
,
improvement
was
not
associated
with
treatment
arm
.
The
proportion
of
patients
with
adverse
events
was
similar
on
sapropterin
and
on
placebo
(
50
%
versus
48
.
3
%
)
;
serious
adverse
events
occurred
in
6
.
3
%
versus
13
.
8
%
,
respectively
.
Sapropterin
was
safe
and
well-tolerated
at
the
average
dose
of
5
mg
/
kg
/
day
,
but
did
not
affect
endothelium-dependent
vasodilation
in
CADASIL
patients
.
https
:
/
/
www
.
clinicaltrialsregister
.
eu
.
Unique
identifier
:
2007
-
004370
-
55
.
Diseases
Validation
Diseases presenting
"peripheral arterial tonometry changes"
symptom
cadasil
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