1. health and fitness
2. disease

Low-dose
Almitrine Bismesylate
in the
Treatment
of Hypoxemia
due to Chronic
Obstructive
Pulmonary
Disease*
Bernhard
Dieter
R. Winkelmann,
G.
Hartmut
Kneissi,
M.D.;
M.D.;
Thomas
Dietmar
Kronenberger,
H. Kullmer,
and
Trenk,
M.D.
Study
objective:
Assessment
of acute
and chronic
effects
of low-dose
almitrine
bismesylate
(AB) in stable
chronic
obstructive
pulmonary
disease
(COPD).
Study
design:
Oral administration
of AB, 25 mg three
times
a day, for 6 months
in all patients.
Pulmonary
function,
blood gases, and peripheral
nerve conduction
velocity
were measured
at baseline
and after long-term
administration
of AB. In addition,
oral pharmacokinetics and effects
on pulmonary
circulation
at rest were
studied
in half of the patients.
Intravenous
pharmacokinetics
were measured
after a single intravenous
dose
of 60 mg of AB 3 months
before
the start of oral AB
treatment
in the other seven patients.
Setting:
Outpatient
clinic of a community
hospital
in a
coal mining
district
in southwest
Germany.
Patients:
Fourteen
patients
with clinically
stable COPD
and hypoxemia.
Results:
Acute effects
of AB were as follows:
a significant increase
in arterial
oxygen
tension
(Pa02)
from
61 ±7 mm Hg to 74±8
mm Hg (p<O.OO1), a decrease
in
arterial
carbon dioxide
tension
(PaCO)
from 41 ± 8 mm
Hg to 38±7
mm Hg (p<O.Oi),
a rise of pH from
7.45 ± 0.04 to 7.48 ± 0M4 (p<0.Oi),
and a transient
increase in mean pulmonary
artery pressure
from 26 ± 7 to
29 ± 6 mm Hg (not significant).
After long-term
treatment, once tissues
were saturated
with almitrine,
improvement
in gas exchange
persisted
with a Pa02 of
P
atients
with
ease
arterial
by an
(PaCO2).
The
survival.2
that has
‘From
and
long-term
prognosis
especially
after
Long-term
only
pu!monary
have
treatment
of patients
the
onset
domiciliary
that
has
been
the Division
of Cardiology
Medicine
(Drs.
Kullmer
and
with
therapy
is a new drug
chemorecep-
Germany.
study
was
Recherches
Manuscript
supported
Internationales
received
July
by
a
grant
Servier,
Paris.
21, i993; revision
Reprint
requests:
Dr. Winkelmann,
gang Goethe
University,
Theodor
Germany
from
and Kneissi
Kronenberger,
the
accepted
Institut
remained
unchanged
with
long-term
treatment
de-
spite
persistent
improvement
of pulmonary
gas exchange.
Monitoring
of AB plasma
levels is advisable
in
select patients
during long-term
administration
to avoid
neuropathy,
even with such a low daily dose.
(Chest
1994; 105:1383-91)
I Clconfldence
ton
interval;
agonist
of
dose
of 100
the
mg.4
are common,
of the drug.
Johann
Wolfgang
Goethe-University
Medical
Center,
Frankturt, Germany;
and the Department
of Clinical
Pharmacology
(Dr. Trenk),
Benedikt
Kreutz Rehabilitation
Center,
Bad Krozingen,
This
it
ABalmitrine
carotid
and
bimesylate
aortic
bodies.3
The
In contrast
to oxygen
therapy,
the
drug also reduces
hypercapnia.58
However,
at doses
of 100 to 200 mg/d
for 6 to i2 months,
side effects
such as increased
dyspnea
and peripheral
paresthesia
to improve
(Drs Winkelmann
70 ± iO mm Hg (p<O.OO1) and a PaCO2 of 39 ± 6 mm Hg
(not significant)
without
elevation
of pH (7.45 ± 0.04) or
of pulmonary
artery
pressure
(26 ± 8 mm Hg). The
terminal
half-life
of AB was 56 ± 45 days after a single
intravenous
administration,
and 55 ± 16 days after longterm oral dosing.
None of the patients
developed
clinically manifest
peripheral
neuropathy.
Impaired
asymptomatic
peripheral
motor nerve function
was prevalent
in 4(29 percent)
of the patients
and remained
unchanged
during
long-term
AB administration.
However,
asymptomatic
impairment
of motor nerve conduction
velocity
developed
in two patients
with
inadequate
high AB
plasma
levels
despite
low-dose
therapy.
Both patients
were known to have additional
conditions
predisposing
for neuropathy.
Conclusions:
Low-dose
AB therapy,
75 mg daily,
resulted in sustained
elevation
of arterial
oxygen
tension
in hypoxemic
patients
with COPD.
Although
pulmonary
artery
pressure
increased
transiently
after the first dose,
compound
induces
a significant
and
persistent
increase
in arterial
oxygen
tension
of 5 to 10 mm Hg
in most
hypoxemic
patients
with
COPD
at a daily
of severe
oxygen
shown
Almitnine
bismesylate
(AB)
been classified
as a peripheral
Pulmonary
dis-
a reduced
tension
(PaO2),
often
accompanied
in arterial
carbon
dioxide
tension
is poor,
hypoxemia.’
obstructive
characteristically
oxygen
increase
COPD
is the
chronic
(COPD)
M.D.;
Ph.D.;
almost
Therefore,
ate whether
was tolerated
effective
certain
Cardiology,
Johann
WolfStern-Kai
7, 60590
Frankfurt,
to an accumulation
the purpose
of this study
was to evalulow-dose
AB, 25 mg three
times
a day,
better
and whether
the agent
was still
in the
treatment
of hypoxemia.
METHODS
de
November
due
Subjects
Fourteen
lung
disease
ten
informed
patients
were
with
enrolled
consent.
hypoxemia
in the
The
selection
due
study
to chronic
after
criteria
having
for
CHEST/105/5/MAY,1994
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
obstructive
given
entry
into
writthe
1383
study were the same as in the VIMS stud?
and included
the following: (1) no previous
oxygen treatment;
(2) PaOa 65
mm Hg
with a variation
6
mm Hg in three measurements
during
the
previous
3 weeks;
(3) PaCO2>35
mm Hg; (4) age between
35 and
using a blood gas analyzer
(CORNING
Medfield,
Mass). The samples
were
of the radial
artery.
75
administration
years;
(5)
FEV170
variation
FEV1/FVC
percent
in weight
Exclusion
ratio
25
and
65
percent
and
of the predicted
value; and (6) less than
within
the previous
3 weeks.
criteria
chronic
between
were
bronchitis
and
as
follows:
(1)
clinically
2 kg
unstable
eg, occurrence
of
the past year or one ex-
emphysema
(CBE),
of the disease
within
the previous
6 weeks;
(2) clinically
unstable
right or left heart failure; (3) a history of pulmonary
embolism;
(4) unstable
angina or myocardial
infarction
within the previous
S months;
(5) renal failure (creatinine>180
mol/L);
and (6) abnormal
results of liver function
tests. Almitrine
bismesylate
was
administered
in addition
to the usual long-term
medication.
The
three
acerbation
exacerbations
within
concomitant
drug
regimen
was
kept
constant,
as much
as possi-
ble,
throughout
the study. The study was performed
in the outclinic of the Department
of Medicine,
St. Elisabeth
Clinic,
Saarlouis
(former
affiliation
of first author).
The 500-bed
clinic
serves
as a community
hospital
for the region,
which
has been
patient
dominated,
untilnow,
by the
six of the patients
active
duty;
the
hairdresser
(two),
worker
Study
steeland
coalmining
industry.
(one).
Design
samples-the
latter
catheterization-were
syringes
drawn
maintained
performed
were
obtained
in duplicate
5 min
temperature.
at 37#{176}C.Blood
n
n
-
Single dose
IV almitrine
I
into
at room
within
=
during
I
25
period
n
=6
patients
‘I
therapyOraI
mg t.i.d.
washouL
period
/7
I
FIGURE
travenous
studied
1 80
I
360
0
i. Outline
and
oral
of the study
almitrine
solely after oral almitrine.
all patients
were
restudied
Days
plan.
treatment.
after
elimination
tiont0
Seven
Seven
patients
With exception
long-term
received
more
patients
inwere
of one dropout,
treatment.
1384
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
were
in seven
drawn
during
of the patients
intravenous
and
during
oral
kinetics
in seven
patients
after
single
(1 through
intravenous
7) and
after
administra-
multiple
oral
dos-
ing in six of the seven
other patients
(one dropout).
were monitored
carefully
for side effects throughOn entry, all patients
were subjected
to a thorough
The patients
out the study.
clinical
examination,
including
a neurologic
evaluation
of
the
sensory and motor nerve fibers, since relevant
side effects of the
drug
had been
reported
earlier.”2
Electromyography
with
measurement
of the median
nerve sensory
conduction
velocity
and the peroneal
nerve motor conduction
velocity
was performed
at baseline,
before
after
AB
administration
in all
6 months
of long-term
presented
as means
patients,
treatment
and
in ii
it was
patients.
Statistics
Results
are
and
long-term
Student’s
paired
er’s
test.
exact
effects
t
All
±
standard
of almitrine
test. Discrete
p values
were
variables
are
were
reported
deviation.
The
using the
tested with Fish-
assessed
for
a two-tailed
test.
RESULTh
Baseline
summarized
clinical
characteristics
in Table
i. There
was
of the patients
no difference
tween
the seven patients
who were
oral therapy
and those who received
and
oral
almitrine.
In
contrast
treatment
group,
the combined
cluded
two female
patients
and
weight
was
difference
concomitant
Function
are
be-
treated
only with
both intravenous
to
the
“oral
treatment
the group
lower
(not significant
[NS]).
in exposure
to cigarette
medication.
Pulmonary
only”
group
mean
There
smoking
infor
was
no
and
Testing
Short-term
administration
itnine
in seven
patients
of
not
did
intravenous
almalter
pu!monany
function,
despite
high
plasma
levels
of almitnine
Repeated
body
plethysmography
and
spirometry
after
long-term
oral treatment
in all patients
revealed
no significant
difference
in pulmonary volumes
with the exception
of a slight increase
in
almitrine
Study
drug’s
(Table
Last oral dose
90
-90
heparinized
7 patients
=
7 patients
Chronic
2-ml
samples
heart
Measurements
were
gases
were determined
First oral dose
Iv washout
right
blood
of the drug
treatment
in all patients
for determination
of almitrine
plasma
levels. The drug concentration
was measured
using high pressure
liquid chromatography
(detection
limit, 5 ng/ml
of AB).9
The rate of decline
was fitted to a multiexponential
model by
weighted
nonlinear
regression
analysis
for determination
of the
short-
Figure
1 depicts
the study design. Short- and long-term
effects
of AB on arterial
blood gases and pulmonary
function
(Bodytest
plethysmograph,
J#{228}ger,
H#{246}chberg, Germany)
were assessed
before, 2 hours after the first dose, and after 6 months
treatment
in
14 patients.
Patients
1 through
7 received
a single intravenous
infusion
of 60 mg of AB 3 months
before oral treatment
to assess
intravenous
pharmacokinetics
and its short-term
effects on pulmonary
function
and on blood gas values. The other seven patients
starteddirectly
with oraltreatment.
In six of thelatter,
pulmonary
hemodynamics
were investigated after the first dose and, with the
exception of one dropout, again 6 months later after the last dose.
One patient was studied without
right heart catheterization,
because access from the brachial vein was impossible.
In those patients, the total daily dose of 75 mg of AB was administered
as a
single oral dose in the morning
of the first and last study day to
maximize
effects for measurements.
Arterial
and mixed venous
blood
venous
repeated
Thus,
were coal miners
with more than 30 years of
occupation
of the remaining
patients
was
locksmith
(two), floor tiler (one), white collar
(two), and housewife
Multiple
160, Corning
Medical
Inc.
obtained
by direct puncture
2).
vita!
capacity
(p<O.O5).
However,
decrease
in airway
term AB treatment
resistance
was
despite
constant
chodilator
throughout
therapy
the
a significant
seen
after
continuous
study.
Even
longbronwhile
under
medication,
patients
were still responsive
to an
inhaled
f32-mimetic
(two metered
doses of fenoterol)
as shown
by a significant
and constant
decrease
of the
group
lation
means
at any
Blood
Gas
After
of airways
resistance
time throughout
the
bronchodi(Table
1).
Analyses
infusion
Low-dose
after
study
AImitrke
of 60 mg
Bismesylate
of almitnine
for
Hypoxemia
over
a period
(Winke!mann
etaO
Table
1-Clinical
Characteristics
of Patients
at Study
Entry
(Mean
± SD)
Intravenous
and
Parameter
Oral
Treatment
Patient,
No.
Age,yr
Weight,
kg
Sex, M/F
Historyof
Oral
Group
Only
Treatment
Total
Group
Group
14
7
7
62±3
64 ± 14
5/2
62±8
72 ± 8
7/0
7±5
62±6
68 ± 12
12/2
11±4
9±5
respiratory
complaints,
History of
yr
6 (86)
7 (100)
13 (93)
44±25
40±22
6 (86)
7 (100)
13 (93)
4 (57)
4
(57)
8 (57)
2 (29)
3
(43)
5 (36)
4 (57)
5 (71)
3 (43)
5
4
4
(71)
(57)
(57)
9 (64)
9 (64)
7 (50)
cigarette
smoking’
No.
(%)
Pack-years
36±19
of smoking,
yr
Concomitant
medication
Theophylline,
No.
(%)
fi2-adrenergic
agonist, No. (%)
(oral + inhaled)
Corticosteroid,
No.
(%)
(oral + inhaled)
Digitalis,
No. (%)
Diuretics,
(%)
No.
Vasodilators,
No. (%)
(Ca-antagonists,
nitrates,
(Ca-antagonists,
nitrates,
ACE-inhibitors)f
‘Four
patients
were
still active
tACEangiotensin-converting
of 2 h, the
from
mean
64.0±5.9
smokers
despite
knowledge
and
warnings
arterial
mm
Hg
oxygen
tension
to 76.7±3.7
increased
mm
Hg
Hg (difference
p<O.Oi).
The
values
are
illustrated
-3.7 ± 2.5;
individual
in Figure
95 percent
changes
2. Also
response
to long-term
oral almitrine
three
times a day, starting
3 months
seven
values
from
patients.
The
was maintained
61.6±6.7
mm
percent
(p<O.OO1).
in arterial
8.5
to 18.2)
to
A 9 percent
decrease
carbon
dioxide
tension
± 4.8 mm
almitnine
was not statistically
to -7.5; p<O.ii).
The
mean
Hg was
treatment,
CI, -1.3 to
and mean
shown
is the
therapy,
25 mg
later in the same
beneficial
effect
with an increase
Hg by 13.4±5.3
CI,
Hg to 35.2
months
of
(95 percent
adverse
effects
of smoking
(two
in each
group).
blood
gas
of the PaO2
mm Hg (95
75.0±9.9
mm
Hg
by -3.3 ± 4.5 mm Hg
from 38.5 ± 6.1 mm
also
recorded
after
but the difference
significant
(95
of arterial
blood
percent
CI,
gases
CI, 4.7 to
mm
I
P<0.001
I
significant
short-
in PaO2 is reflected
in hemoglobin
oxpercent
to 95.0 ± i.6
I
P<0.001
-
c,1
0
0
o_
40
‘4
cJ
LP<o.oi
20
0
6
Co
af-
Oral
Intravenous
0
Baseline
+0.9
for all pa-
Hg; p<0.OOi)
This
I
E80
E
FIGURE
values
administration.
and long-term
persistent
increase
by a corresponding
improvement
ygen saturation
from 90.9 ± 3.9
6O
on
tients before
and after almitnine
treatment
are summarized
in Table
3. The mean
increase
in PaO2 was
i3.2±4.0
mm Hg (95 percent
CI, iO.9 to i5.5 mm
Hg; (p<0.OOi)
after the first dose and 9.3 ± 77 mm
Hg
the
ten long-term
(dif-
ference,
12.7 ± 3.5 mm Hg; 95% confidence
interval
[CI], 9.4 to 15.9; p<O.OO1).
Arterial
carbon
dioxide
tension
decreased
from 37. i ± 4.5 mm Hg toSS.4
± 3.7
mm
-6.0,
about
enzyme.
2.
Acute
Individual
changes
Baseline
of
Pa02
Chronic
(solid
repeated,
initiated,
treatment
mean
oral
almitrine
and
long-term
(before
± SD for PaOa
the
therapy,
effects
morning
(solid)
25
were
mg
dose).
and
three
measured
PaCO2
The
times
after
crosses
and
a day
6 months
indicate
was
of
the
(open).
CHEST/105/5/MAY,1994
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
triangles)
PaCO2 (open triangles)
in seven patients
with COPD after shortand long-term
almitrine
administration.
Short-term
effects were
measured
at the end of a single 2-h intravenous
infusion
of 60 mg
of almitrine.
Three
months
later, baseline
measurements
were
1385
Table
2-Pulmonary
Function
Data
Short-
BLQ
Almitrine
plasma
FVC, L
level,
and
Long-term
Short
Termf
Intravenous
(n7)
Baseline
(n7)
‘
Parameter
After
Therapy
With
Bismesylate
BLQ*
(Mean
p Value
Long Term (
Oral Administration
(n13)
Baselinet
(n13)
632 ± 295
Almitrine
± SD)
v s Baseline
.
‘
Short
302 ± 137
Term
Long
Term
<0.001
<0.001
ng/ml
2.9±0.6
2.8±0.6
2.8±0.6
3.2±0.7
(%pred)
80±10
76±12
80±10
82±19
FEy1, L
(%FEV1/VC)
TLC, L
1.4±0.5
49±7
7.4±2.0
1.3±0.5
45±8
7.0± 1.9
1.3±0.3
44±10
7.6±2.6
1.5±0.5
7.8±2.3
(%pred)
127±21
162±23
124±35
128±30
RV, L
(%RV/TLC)
FRC, L
(%pred)
Raw before
4.5±1.5
63±12
5.5±1.4
161±25
4.2±1.1
62±6
5.0±1.4
4.8±2.4
4.6±1.9
60±13
57±10
5.7±2.6
5.6±2.1
143±22
153±53
150±45
bronchodilator,
cm
H2O/L/s
11.1
(%pred)
± 6.4
<0.05
NS
NS
NS
NS
NS
NS
NS
NS
NS
<0.05
NS
<0.05
NS
NS
47±11
10.7 ± 6.7
10.7 ± 6.4
357±243
357±218
428±262
NS
6.7 ± 3.1
235±94
Raw after
bronchodilator,
cm
8.1 ±4.0
H20/L/s
(% prod)
8.1 ±4.3
307 ± 164
262±
2.9±3.8
(p<O.05)
2.6±2.7
(p<O.05)
8.3±4.5
147
5.0±
1.8
278 ± 150
167 ± 61
2.3±2.2
(p<O.O2)
1.7±2.0
(p<O.O2)
Difference
Raw before-after,
(p value)
‘FVCforced
vital
capacity;
fBefore
cm H20/L/s
capacity;
Rawairways
and
FEV1forced
resistance.
directly
after
expiratory
Pulmonary
a single
intravenous
volume
volumes
2-hr
in 1
FVC,
infusion
effects measured
in the morning
before almitrine
was taken in the evening
before the measurements.
BLQbelow
percent
highly
limit
of quantification
short term,
and
significant
degree
(<5
TLC,
of almitrine
ILong-term
dose
TLCtotal
5;
FEy1,
intake
(60
after
3-Arterial
Gases,
RVresidual
and
measured
FRC
are
volume;
after
FRCfunctional
Hemoglobin,
mg).
of almitrine
body
therapy,
25 mg three
times a day; the last 25-mg
weight
remained
unchanged
(Table
Short-term
oral administration
of the
dose of almitrine
resulted
in a transient
and
Body
Bismesylate
(Mean
Weight
± SD)
at Baseline
and
After
Almitrine
plasma level, ng/ml
PaO2, mm Hg
PaCOt,
mm Hg
pH, -log[H+]
SO2,
%
P(A-a)O,
mm Hg
Hb, g/dl
Hematocrit,
%
Weight,
kg
‘PaOaarterial
oxygen
tension;
(PAO-PaO2);
PAO2alveolar
tTwo hours after administration
fusion of 60 mg of almitrine)
Long-term
effects
were
Short
termf
(n14)
(n14)
BLQ
405 ±327
Long
termj
(n13)
302 ± 137
v s Baseline
Short
Long
term
term
<0.001
<0.001
<0.001
60.8±7.2
74.0±7.3
70.0±9.7
<0.001
41.2±7.5
7.45±0.04
37.6±6.8
7.48±0.04
38.9±6.0
7.45±0.04
<0.01
<0.01
NS
90.9±3.9
95.0±1.6
93.6±2.6
<0.001
<0.001
40.8±2.1
14.6 ± 1.5
44.7 ±5.4
68.2 ± 12.5
31.8±6.6
33.8±5.0
<0.001
<0.002
PaCO2arterial
...
...
...
carbon
dioxide
44.2 ± 5.8
67.2 ± 13.1
tension;
Hbhemoglobin;
in the
morning
before
the last dose was taken in the evening before
BLQbelow
limit of quantification
(<5 mg/mI).
. . . =not done; -not
applicable.
patients;
1386
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
almitrine
intake
after
of almitrine
NS
NS
NS
-
P(A-a)O2alveolar
6 months
NS
-
14.9 ± 2.0
oxygen tension.
of the first dose of almitrine;
either after intravenous
administration
or after oral administration
of 75 mg of almitrine
in the other seven
measured
first 75-mg
increase
in
Administration
p Value
Baseline
3).
Hemodynamics
Hematocrit,
of Almitrine
Parameter’
residual
bronchodilation.
ng/ml).
to a slightly
lessen,
but still
of 93.6 ± 2.6 percent
!ong
Blood
lung capacity;
6 months
term (p<0.OOi).
However,
pH remained
unchanged
long term, despite
the persistent
increase
in PaO2 and
decrease
in PaCO2.
Hemoglobin,
hematocrit,
and
Table
RV,
arterial
in seven
patients.
therapy,
oxygen
patients
25 mg
tension
(directly
three
difference
after
times
a 2-h in-
a day
in 13
(Wnke!mann
etaO
the measurements.
Low-dose Almitrine
Bismesylate
for
Hypoxemia
only
spite
during
wakefulness
continued
increase
It was
postulated
and not during
in PaO2.16
that
almitnine
sleep,
de-
improves
Pa02
even without
increase
in ventilation,
especially
when
smaller
doses are administered.’7
The most important
mechanism
seems
to be an improvement
of ventila-
/Q)
tion/perfusion
ratio
hypoxic
vasoconstniction.
(V
explain
the transient
again
this hypothesis
rise in pulmonary
does not explain
effects
ment
on gas
without
after
artery
pressure
percapnia.25
of
also
pressure.
But
why beneficial
long-term
treatartery
pressure,
as
study,
as well as by other
authors.’8”9
are other
mechanisms
such as a direct
effect
regulating
by enhancement
mechanism
would
This
exchange
persist
a rise in pulmonary
found
in this
Possibly
there
vasoactive
A
the
via
the
vascular
pulmonary
tone.
endothelium
Laboratory
studies
have
shown
that-depending
on a number
of pre-existing
conditions
before
almitnine
therapy,
eg, the pulmonary
vascular
tone,
hypoxia,
on normoxia
and a low
or hight almitnine
and induces
either
dosage-the
vasocilation
drug has a dual
on vasoconstruction
ten long-term
treatment
have been
reported
in two
earlier
trials.’8”9
An explanation
for these contnadictony findings
could
be the fact that
in studies
with
intravenous
almitnine,
a significant
rise in pulmonary
effect
There
are also
plaints
of weight
treatment.
reported
like
seen
only
conflicting
loss during
in our
study.
parameters
during
derivatives
in the lung.2’
does not affect
short-
and
long-term
or
spinometnic
almitnine.
the
heart
of the
failure
loss
versa
weight
loss
with
respect
a worsening
weight
loss
was
weight
If vice
for
(FVC)
which
after
long-term
was not accompanied
needs
further
Almitrine
FEV,
and
total
lung
capacity.
Interestingly,
these
authors6
also noted
a small
but significant
improvement
in small airways’
function
in both the low- and
high-dose
group
in comparison
to the placebo
group.
This finding
is supported
by the results
of this study
showing
an improvement
in airways
resistance
(Tab!e 2). As stated
by those
an explanation
for this
Patients
with stable
pulmonary
that the
authors,6
we also do not
observation.
COPD
usually
exhibit
seen
with
ions are correlated
with the increase
artery
pressure
and
right
ventricular
in
this
disease.22’23
and of the concentration
Our
results
imply
that
treatment
with a low daily dose of 75 mg of AB does
not induce
unfavorable
hemodynamic
changes
with
respect
to the pulmonary
circulation
during
both
shortand
long-term
administration
of almitnine.
While
Macnee
and colleagues24
found
a slight,
but
significant
five patients
increase
after
100 mg three
times
in pulmonary
artery
pressure
in
3 months
of oral almitnine
therapy,
a day,
no significant
changes
af-
receiving
is taken
as an
of well
might
indicate
the downhill
course
of
survival.
However,
in
100 to 200 mg daily,
in 43 almitnine-treated
paplacebo-treated
patients.31
being:
studies.
is extensively
patients
more
of
conclua stable
loose
weight
active
life
with
this phenomenon
bound
in
peripheral
sites,
as demonstrated
of more than a 1,000
bound
terminal
(>99
percent).32-34
In
half-life
of almitnine
li-
by a
L, which
after both
long-term
single
oral
respectively
ranging
intravenous
treatment
. Steady-state
reached
only after
even
with
75 mg
several
daily,
from
our study,
the
was prolonged
concentrations
186
to 544
ng/ml,
itnine
that almitnine
according
to
plasma
doses
current
levels
were
of 100 and
knowledge.
double
the
55
were
months
of treatment
the almitnine
trough
a recommended
upper
therapeutic
limit
m135 in all but one patient.
The results
of the 2-year
multicenter
show
high
mean
and
administration
with
56 and
was
and
at 6
above
of 200
ng/
trial
also
200 mg are
Mean
too
a!m-
recommended
therapeutic
level of 200 to 300 ng/ml
in this study.
A high incidence
of clinical
peripheral
neuropathy
was reported,
14 percent
in the a!mitnine-treated
group,
4 percent
in the placebo-treated
group.
It is
common
consent
that
almitnine-associated
CHEST/105/5/MAY,1994
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
in-
to prognosis,22
also seems
to indicate
that there
exists an enterohepatic
recirculation
and
the drug
is highly
protein
months,
in
as a con-
group
just as well draw the opposite
weight
loss in patients
with
compartment
of distribution
days,
of hypercapnia,
failure
pophilic
volume
mild
hypoxemia,
49
in the
almitnine
they
can
lead
a
Thus,
clarification
identical
and after
of hydrogen
pulmonary
unchanged
with
is a sign
because
almitnine.
have
arterial
hypertension
at nest. It is known
severity
of COPD,
as well as the degree
of
for this
explained
of right
condition
in
be given
isodes
sequence
tion. Nevertheless,
we found,
similarly
to Bell and
colleagues6
and Watanabe
and coworkers4
a significant
increase
in forced
inspinatony
vital
capacity
almitnine
administration,
by significant
changes
can
weight
was
in others’6
the volume
overCOPD.3#{176} Actually,
reduction
of ep-
But one might
sion, such that
administra-
of body
but not
effect28’29
and might
thus connect
load seen in many
patients
with
in the VIMS
study,5
the significant
survival
was
tientscompared
of pnostacyclin
substances
almitnine
hy-
potential
mechato have
a diuretic
to induce
release
with
data concerning
comlong-term
almitnine
No explanation
that the agent
could accelerate
the disease
and thus decrease
a 2-year
trial with
almitnine,
the
patients
phenomenon,
but there are several
nisms.
Almitnine
has been
found
the capillary
level.2#{176}There
is experimental
evidence
de-emphasizing
the role of the carotid
bodies
in favor of a direct
humora!
mechanism.
The drug seems
other
mediator
In general,
in
A significant
decrease
in most
studies,4’5’26’27
dicaton
at
was
neuropa1389
condition
had
his underlying
hi!! course
worsened
almitnine
treatment
second
patient,
nerve
rapidly
pulmonary
accelerated
and
In this
from
patient,
who
old women
weighing
a!mitrine
dose was
already
objective
velocity
only
obviously
complained
about
signs of impaired
before
inclusion
sony findings
persisted
throughout
the
highest
long-term
maxima!
drug
between
nerve
impairment
regression
line
the
of the
motor
correlation
patients
levels
deterioration
showed
the
of all subjects
A significant
level
and
found
the
conduction
the
patients
after
come-
degree
This
long-term
a!m-
13 patients
and
of the sensory
during
low-dose
trough
the conof the
were
results
of their
nerve
function
a!mitnine
them-
effective
study,
placebo-controlled
in improving
arterial
almitnine
blood
gas
was
values
in
to
The
gas
trials,
.
mechanisms
cally,
acting
carotid
bodies,
bodies.
The
however,
patients’
long-term,
beneficial
changes
were
not
or were
found
small,
in the
and,
in
patients,
not
signifi-
poorly
with
understood.
respect
to
Pharmacologi-
and
to a lesser
increase
in
extend
alveolar
in the
aortic
ventilation
is me-
in PaCO2
and a concomitant
rise in pH by 0.04 was seen
in our
the
study
only
after
first
dose,
increase
in mean
not any more
after
persistent
reported
treatment,
elevation
together
(V
with
pulmonary
long-term
of Pa02.
a
artery
therapy
Other
authors
a significant
increase
in pH after long-term
as well, but only after a high dose of 200
Several
mechanisms
are discussed
to explain
these
discrepancies.
poxemia.
alveolar
defects
in lung
unable
to achieve
volume,
tidal
volume,
in the
anatomy,
normal
or mean
litema-
patients
increases
inspiratory
/T I ) in response
to hypercapnia
It was suggested
that
almitrine
ventilation
by a change
in breathing
and hyimproves
pattern:
T
a slight
increase
in VT without
rate coupled
with an increased
change
in respiratory
inspiratory
flow mate
(V T /t I ) and decreased
inspiratory
duty
cycle.’3
There
are conflicting
data
from
several
placebocontrolled
studies
concerning
the clinical
evidence.
No alteration
of ventilatory
time
constants
were
E
4
2
Change
imal
the
flected
by the decrease
rise in pH. A significant
flow
FIGURE
a
almitnine
is classified
as a respiratory
stimulant
on peripheral
chemomeceptors
located
in the
in minute
00
show
were found
to
a daily dose
of improvement
are
Due to structural
with COPD
are
A
0)
that
of 5 to 1 1 mm Hg
a reduction
in Pa-
improved
In other
almitrine-treated
exchange
mg.6
tune
1,400
in-
4,6
despite
low-dose
studies
period
of the trial
to some
extent.
contrast
between
mean
of 100 mg and 200 mg concurrently.6
Since our study
was
done in an open,
nonplacebo-contro!led
manner,
we cannot
rule out that intensified
clinical
care taken
velocity
is signif-
The
The effects
investigating
on arterial
oxygen
tension
group
without
active
drug57
DISCUSSION
present
previous
CO2 of 1 to 4 mm Hg.47
be dose related
in a study
slight
transient
pressure,
but
the
hypoxemia.
(Fig 4) . The slope
almitnine
plasma
apy.
In
and
confirms
during
the
hypoxemia
of
COPD
persistent
rise in Pa02
in a range
after
doses of 100 to 200 mg and
(least squares
regression,
p<O.O2).
A similar
sig-
existed
with
crease
in Pa02
after
the first dose by 13 mm Hg was
maintained
after
long-term
treatment
with a pemsistent rise in PaO2
by 9 mm Hg. A slight reduction
of
2 mm
Hg in PaCO2,
which
had decreased
significantly
by 4 mm Hg after the first dose, was noted
long
term.
kg, the daily
75-mg
a high
dose.
She had
Both
zero
r0.7,
by the other
examination
unchanged
was
62-year-
itnine trough
levels or the difference
between
levels
and the maximal
concentration
and
duction
velocity.
Concerning
the evaluation
sensory
nerve
function,
no new
paraesthesias
reported
neurologic
remained
motor
m/s
a graci!e
further
was
between
nerve
In the
to 43.5
without
plasma
icant!y
different
from
correlation
coefficient
nificant
later.
drop
was
39
almitrine
administration.
motor
of the
and
1 year
49.5
of
clinical
downnot receiving
paresthesias
and had shown
sensory
nerve
conduction
into the study.
These
sen-
study.
lation
level
he died
velocity
to progression
The
was
an asymptomatic
conduction
measured.
due
disease.
once
he
4.
level
Correlation
measured
0
of Motor
between
-2
-4
Nerve
-6
Conduction
the
2 to 3 h after
almitrine
drug
-8
-10
plasma
14
-12
Velocity
(mis)
level
administration)
(max-
and
the
change
of peroneal
motor
nerve
conduction
velocity
after
longterm
almitrine
treatment,
25 mg three
times
a day. The shaded
area
represents
the normal
range
of variation
( ± 1 SD) of an
age-matched
control
population
with
COPD
(n78).3’
1388
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
found
term
tients,4
in a crossover
effects
of a high
neither
did
study
investigating
oral dose (3 mg/kg)
external
another
placebo-controlled
the same dose.’5
In two
1-year
increase
trials
of 50
in minute
Low-dose
Almitrine
mg
the shortin ten pa-
ventilation
change
parallel
group
study
reports
of placebo-controlled
of almitrine
ventilation
Bismesylate
was
twice
daily,
described,4”6
for Hypoxemia
(Winkelmann
in
with
an
but
et a!)
only
spite
during
wakefulness
continued
increase
It was
postulated
and not during
in PaO2.16
that
almitnine
sleep,
de-
improves
Pa02
even without
increase
in ventilation,
especially
when
smaller
doses are administered.’7
The most important
mechanism
seems
to be an improvement
of ventila-
/Q)
tion/perfusion
ratio
hypoxic
vasoconstniction.
(V
explain
the transient
again
this hypothesis
rise in pulmonary
does not explain
effects
ment
on gas
without
after
artery
pressure
percapnia.25
of
also
pressure.
But
why beneficial
long-term
treatartery
pressure,
as
study,
as well as by other
authors.’8”9
are other
mechanisms
such as a direct
effect
regulating
by enhancement
mechanism
would
This
exchange
persist
a rise in pulmonary
found
in this
Possibly
there
vasoactive
A
the
via
the
vascular
pulmonary
tone.
endothelium
Laboratory
studies
have
shown
that-depending
on a number
of pre-existing
conditions
before
almitnine
therapy,
eg, the pulmonary
vascular
tone,
hypoxia,
on normoxia
and a low
or hight almitnine
and induces
either
dosage-the
vasocilation
drug has a dual
on vasoconstruction
ten long-term
treatment
have been
reported
in two
earlier
trials.’8”9
An explanation
for these contnadictony findings
could
be the fact that
in studies
with
intravenous
almitnine,
a significant
rise in pulmonary
effect
There
are also
plaints
of weight
treatment.
reported
like
seen
only
conflicting
loss during
in our
study.
parameters
during
derivatives
in the lung.2’
does not affect
short-
and
long-term
or
spinometnic
almitnine.
the
heart
of the
failure
loss
versa
weight
loss
with
respect
a worsening
weight
loss
was
weight
If vice
for
(FVC)
which
after
long-term
was not accompanied
needs
further
Almitrine
FEV,
and
total
lung
capacity.
Interestingly,
these
authors6
also noted
a small
but significant
improvement
in small airways’
function
in both the low- and
high-dose
group
in comparison
to the placebo
group.
This finding
is supported
by the results
of this study
showing
an improvement
in airways
resistance
(Tab!e 2). As stated
by those
an explanation
for this
Patients
with stable
pulmonary
that the
authors,6
we also do not
observation.
COPD
usually
exhibit
seen
with
ions are correlated
with the increase
artery
pressure
and
right
ventricular
in
this
disease.22’23
and of the concentration
Our
results
imply
that
treatment
with a low daily dose of 75 mg of AB does
not induce
unfavorable
hemodynamic
changes
with
respect
to the pulmonary
circulation
during
both
shortand
long-term
administration
of almitnine.
While
Macnee
and colleagues24
found
a slight,
but
significant
five patients
increase
after
100 mg three
times
in pulmonary
artery
pressure
in
3 months
of oral almitnine
therapy,
a day,
no significant
changes
af-
receiving
is taken
as an
of well
might
indicate
the downhill
course
of
survival.
However,
in
100 to 200 mg daily,
in 43 almitnine-treated
paplacebo-treated
patients.31
being:
studies.
is extensively
patients
more
of
conclua stable
loose
weight
active
life
with
this phenomenon
bound
in
peripheral
sites,
as demonstrated
of more than a 1,000
bound
terminal
(>99
percent).32-34
In
half-life
of almitnine
li-
by a
L, which
after both
long-term
single
oral
respectively
ranging
intravenous
treatment
. Steady-state
reached
only after
even
with
75 mg
several
daily,
from
our study,
the
was prolonged
concentrations
186
to 544
ng/ml,
itnine
that almitnine
according
to
plasma
doses
current
levels
were
of 100 and
knowledge.
double
the
55
were
months
of treatment
the almitnine
trough
a recommended
upper
therapeutic
limit
m135 in all but one patient.
The results
of the 2-year
multicenter
show
high
mean
and
administration
with
56 and
was
and
at 6
above
of 200
ng/
trial
also
200 mg are
Mean
too
a!m-
recommended
therapeutic
level of 200 to 300 ng/ml
in this study.
A high incidence
of clinical
peripheral
neuropathy
was reported,
14 percent
in the a!mitnine-treated
group,
4 percent
in the placebo-treated
group.
It is
common
consent
that
almitnine-associated
CHEST/105/5/MAY,1994
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
in-
to prognosis,22
also seems
to indicate
that there
exists an enterohepatic
recirculation
and
the drug
is highly
protein
months,
in
as a con-
group
just as well draw the opposite
weight
loss in patients
with
compartment
of distribution
days,
of hypercapnia,
failure
pophilic
volume
mild
hypoxemia,
49
in the
almitnine
they
can
lead
a
Thus,
clarification
identical
and after
of hydrogen
pulmonary
unchanged
with
is a sign
because
almitnine.
have
arterial
hypertension
at nest. It is known
severity
of COPD,
as well as the degree
of
for this
explained
of right
condition
in
be given
isodes
sequence
tion. Nevertheless,
we found,
similarly
to Bell and
colleagues6
and Watanabe
and coworkers4
a significant
increase
in forced
inspinatony
vital
capacity
almitnine
administration,
by significant
changes
can
weight
was
in others’6
the volume
overCOPD.3#{176} Actually,
reduction
of ep-
But one might
sion, such that
administra-
of body
but not
effect28’29
and might
thus connect
load seen in many
patients
with
in the VIMS
study,5
the significant
survival
was
tientscompared
of pnostacyclin
substances
almitnine
hy-
potential
mechato have
a diuretic
to induce
release
with
data concerning
comlong-term
almitnine
No explanation
that the agent
could accelerate
the disease
and thus decrease
a 2-year
trial with
almitnine,
the
patients
phenomenon,
but there are several
nisms.
Almitnine
has been
found
the capillary
level.2#{176}There
is experimental
evidence
de-emphasizing
the role of the carotid
bodies
in favor of a direct
humora!
mechanism.
The drug seems
other
mediator
In general,
in
A significant
decrease
in most
studies,4’5’26’27
dicaton
at
was
neuropa1389
thy is dose related.
will take several
drug’s
long
peripheral
Since
high
who
Nevertheless,
causes
never
took
agent
clinical
with
reports
on
in
plasma
instances
almost
levels.
always
in
Therefore,
clinical
neunopathy.
Two
patients
with the highest
plasma
levels,
however,
showed
asymptomatic
impainment
of motor nerve conduction
velocity.
One of
those
patients
had a very low body weight
(39 kg),
remained
high plasma
of
10
kg
COPD,
previously
unchanged;
levels
were
within
in
the
associated
6 months
thus
probably
tissue-bound
other
with
due
to
loss
when
administered
intravenous
6-month
or oral
therapy.
gas exchange,
with daily
could
daily
short
dose,
This
which
doses
of
but
term
also
persistent
using
after
of
that
doses,
seems
such as half
warranted.
the
daily
dose,
I, Vrhovac
et al. Double-blind
bismesylate
J
a sample
371:1309-14
2 Timms
Group.
Bull
Eur
Ann
Intern
Med
1986;
B, Stangi B, Tabori D, Ivicevic
A, Todic V.
placebo controlled
clinical trial of almitrine
with
JJ,
both
chronic
1990;
respiratory
NJ,
Morgan
AD,
N, et al. Almitrine
awake
and
insufficiency.
38:249-53
Douglas
JA, Pauly
when
asleep
Shapiro
improves
in patients
with
CM,
oxygenation
hypoxia
and
car-
ben dioxide
retention
caused
by chronic
bronchitis
and emphysema.
Am Rev Respir Dis 1985; 132:206-10
9 Luitjen
W, Damien
G, Marchand
B, Capart
J. Analysis of
almitrine
and
its metabolites
bombardement
Biomed
in plasma
liquid
Mass
10 Heinzel
Spectrom
and
1988;
MB,
chronic
Gustav
Prowse
Fischer
atom
2.0-pharma-
analysis
Verlag,
system
for
the
1993
nervefunction
receiving
fast
spectrometry.
P. TopFit
data
K. Peripheral
bronchitis
on-line
16:93-7
R, Thomann
pharmacodynamic
PC. Stuttgart:
using
chromatography/mass
C, Woloszczak
cokinetic
Chedru
F, Nodzenski
almitrine
in patients
or placebo.
of
R, DunandJF,
with
Thorax
almitrine.
JR.
NB.
Amarenco
C, et al. Peripheral
with
Stradling
Pride
BMJ
Nicholl
The
1989;
and
gas
D,
Dacies
almitrine
exchange
pulmonary
disease.
during
in
Clin
EE,
Hughes
bismesylate
on
patients
Sci
gas
chronic
mg,
exchange
air-flow
during
obstruction.
exercise
Am
chronic
66:435-42
in
Rev
JMB,
pattern
with
1984;
14 Escourrou
P. Simonneau
C, Ansquer
JC, Duroux
A. A single orally administered
dose
of almitrine
pulmonary
R,
treat-
290:896
Cover
of oral
G, Ghnassia
neuropathy
1985;
CG,
effects
breathing
obstructive
P, Lockhart
improves
patients
Respir
with
Dis
1986;
133:562-67
15
JW,
Traver
of different
forms
from the general
R, Fareed
a
in COAD-
1 1):169-82
disease.
Pharmacol
Critchley
Simonneau
Prost
itrine
16
GA,
C,
at rest
Clime
MG.
The
course
and
and
M,
obstruction.
Gothe
B, Cherniack
KA. Long-term
during
Denjean
effects
on exercise
airflow
Chest
wakefulness
in patients
1986;
NS,
effects
Bachand
sleep
B, Had
oral
with
dose
hypoxic
A,
of almchronic
89:174-79
RT,
of almitrine
and
A, Raffestin
of a single
Szalkowski
bismesylate
in chronic
Am J Med 1988; 84:436-44
17 Melot
C, Dechamps
P. Hallemans
Enhancement
of hypoxic
pulmonary
MB,
Bianco
on oxygenation
obstructive
pulmonary
disease.
almitrine
Dis 1989;
of chronic
population.
Meignan
JF. Cardiopulmonary
dose
B, Bloom
study
West LG, Bachand
RT, Johanson
WG.
bismesylate
on hypoxemia
in chronic
in patients
Clin
8 Connaughton
REFERENCES
prognosis
obstructive
140:1269-73
bismesylate:
Study
23(suppl
pulmonary
7 Bakran
ment
ACKNOWLEDGMENTS:
The authors
would like to thank the
patients
and the medical
staff involved
in thepatient
care. We are
also indebted
to Prof. Dr. W. Rapp, head of the Department
of
Internal
Medicine
of the St. Elisabeth-Klinik,
Saarlouis,
Germany,
for support
and cooperation,
and Mr. J. P. Jeanniot
(Biologie
Servier
Orleans,
France)
for the measurement
of the almitrine
plasma levels and parts of the pharmacokinetic
analysis.
Finally,
we are very grateful
for the many valuable
contributions
of Dr.
J. C. Ansquer,
Servier Research,
Paris, France,
while performing
the study and later during
analysis
of the results.
1 Burrows
chronic
105:342-46
13
high
lower
37.5
R.
RL, Bachand
of almitrine
Dis 1989;
Almitrine
double-blind
1987;
RC, Mullins RC,
effect of almitrine
Ciaudo-Lacroix
dyspnea
or paresthesia
dose,
but
asymptomatic
motor
nerve
function
was
current
hypoxemic
Multicenter
Respir
obstructive
12
in this study
using
a reduced
of AB. No clinical
overt
adverse
documented
in two patients
with inadequately
plasma
levels.
Further
research
studying
even
E, VanMaele
after bilateral
carotid
obstruction.
Bull Eur
44:292-97
already
been demonstrated
100 and 200 mg of almitnine,
effect,
such
as increased
occurred
with
this
low
impairment
of peripheral
International
The
on
had
be confirmed
dose of 75 mg
with
Am Rev Respir
P, Ansquer
JC.
Vectarion
1 1 Allen
effect
E, Janssens
21:427-32
patients
placebo-controlled,
6 Bell
a single
a long-term
beneficial
1985;
long-term,
Physiopathol
of
low-dose
almitnine
therapy,
75 mg daily,
prevents
neuropathy
unless
there
are conditions
that lead to
high
plasma
levels
despite
a low daily
drug
intake.
In conclusion,
AB therapy
improves
pulmonary
gas exchange
in hypoxemic
patients
with COPD,
not
only
in
disease.
Howard
Eur
progression
releasing
large
amounts
drug.
Our study
shows
P, Bogaert
Respir
pulmonary
5 Voisin
C,
subject,
a weight
Vermeire
bismesylate
there
exists
a considerable
clinical
interest
whether
lowdose almitnine
therapy
could
prevent
these
adverse
effects.
In our study,
none of the patients
developed
which
W,
4 Watanabe
5, Kanner
RE, Cutillo AG, Menlove
RT, Szalkowski
MB, et al. Long-term
effect
subclin-
some
102:29-35
DeBacker
Physiopathol
patients
to enhance
and
response
to oxygen
disease.
Ann Intern
Almitrine
has no effect
on gas exchange
body
resection
in severe chronic
airflow
almitnine.36
seems
1985;
Med
3
it has
been
asymptomatic
of
neunopathy,
high
first
ygen Therapy
Trial Group. Hemodynamic
therapy
in chronic
obstructive
pulmonary
but it
of the
in hypoxemic
neunopathy
overt
association
exists
the
peripheral
the
neuropathy,”27
prevalence
neunopathy
COPD
ical
disorder
is reversible,
to resolve
because
half-life.4”0’26
almitnine-associated
shown
that
a
with
The
months
18
airways
obstruction
in
N Engl J Med 1987;
bismesylate
in normal
humans.
Am
Rev
Respir
139:111-19
Paramelle
B,
pulmonary
arterial
by
R, Decroly
P. Mols P.
vasoconstriction
by low
almitrine
Levy
P.
Pirotte
pressure
bismesylate.
C.
Long
evolution
Eur
J
term
of COPD
Respir
Dis
follow-up
patients
1983;
of
treated
64(suppl
126):333-36
UK,
Williams
GW,
and
the
Nocturnal
1390
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
Ox-
19
Prefaut
CH,
Low-dose
Bourgouin-Karaouni
Almitrine
Bismesylate
D,
Ramonataxo
for Hypoxemia
M,
Michel
(Winkelmann
et a
J. One year double
FB, Macabies
tensions
Eur
20
and
J
Respir
Nakanashi
in low
hypoxia.
Respir
Douget
D, Zelter
an increase
Vandenberg
Am
23
Physiol
1973;
Kawakami
W,
gins
Muir
NJ,
25
J Med
AL,
on
Clin
Bouche
1983;
almitrine:
Dis
1987;
induces
carotid
30
body
Sadoul
report
PA,
of
Valloton
K. Relation
and
obstructive
MB.
Diuresis,
Biomed
31
Hayhurst
of the
artery
Bardsley
of
late
32
PA,
in
a result
of arterial
Biochim
Acta
1987;
patients
and
bronchitis
with
Chaunu
neuropathies
of 46 cases.
J
ef-
Acta
1987;
right
and
haemodynamic
chronic
hypercapnia.
Neurol
MP,
during
1989;
Ratinahirana
treatment
236:29-33
27 Gherardi
R, Louarn
F, Benevenuti
C, Perrier
M, Lejonc
JL,
Schaeffer
A, et al. Peripheral
neuropathy
in patients
treated
with almitrine
dimesylate.
Lancet
1985; 1:1247-50
36
1983;
Winkelrnann
hypoxic
Drug
BR,
with
P, Mairesse
almitrine
chronic
M,
bismesy-
obstructive
Taylor
AR,
bismesylate
64(suppl
airways
J. The
Williams
in man:
Eur J
a review.
126):337-48
JT,
MacLeod
CM,
One
year
bismesylate
(Vectarion)
to chronic
disease
patients:
pharmacokinetic
Dispos
1989;
Hertrich
adminis-
obstrucanalysis.
10:247-55
F, Trenk
D, Jeanniot
JP,
Ansquer
JC. Pharmacokinetics
and pharmacodynamics
of almitrine
in
man following
single and repeated
administrations
[abstract].
Eur Respir J 1988; 1(suppl
1):148
Evans
TW,
Tweney
J, Waterhouse
JC, Nichol
J, Suggett AJ,
Howard
P. Almitrine
bismesylate
and oxygen
therapy
in
hypoxic
cor pulmonale.
Thorax
1990; 45:16-21
Lerebours
G, Moore
N, Senant
J, David P, Arnaud F, Nouvet
G. A prospective
study of almitrine
bismesylate
on the peripheral
nerve
ease
patients[abstract].
function
of hypoxemic
Am
Rev
chronic
Respir
CHEST
Downloaded From: http://journal.publications.chestnet.org/ on 09/09/2014
Atem-
4:308-10
BH,
5, Doluisio
pulmonary
therapy
[abstract
W, Vermeire
treatment
1991;
Gordon
of almitrmne
Biopharm
34
years
J
H. Rational
3:138
of almitrmne
Stavchansky
tive
134:559-65
pulmonary
JM,
Biochim
of diuretics
P, DeBacker
with
Respir
DB,
Dis
tration
of almitrine
pressure
Campbell
Respir
35
L, Leger
and natriuresis:
body
Biomed
F, Leinberger
1987;
Howard
Eur
pulmonary
Dou-
Hertrich
C, et al. Two
biodisposition
MD,
effects
chronic
Dis 1986;
in men
carotid
in COPD-value
Lungenkrank
Ledent
33
GB,
in hypoxic
P. The
AJ. The
bismesylate.
BR,
pulmonary
308:1045-49
Rhind
Suggett
almitrine
Winkelmann
weg
64:25-31
P, et al. Peripheral
RE,
stimulation?
of hypoxemia
135:514
H, Miyamoto
pulmonary
infusion
P, Lacomblez
H, Brunet
with
JM,
of almitrine
Sci
after
in chronic
Am Rev Respir
Polu
sheep
oxygenation,
et al. A comparison
fraction
Lang
Bardsley
feet
disease.
JJ,
ejection
WL,
to
KP. Course and
chronic
obstructive
pulby means of functional
indices.
1983;
breathing
EA,
46:1017-22
bismesylate
Respir
venous
ventricular
effects
26
Rev
F, Yamamoto
or oxygen
Dull
29
vessels
advanced
Connaughton
emphysema.
Y. Almitrine
74:139-50
to prognosis
N EngI
Koller
chemoreceptor
J, van de Woestinjne
mixed
Macnee
28
55:736-46
Y, Fishi
disease.
Nishimoto
of pulmonary
Almitrine
Am
with
delivery,
hemodynamics
N,
in the anesthetized
E, Clement
Med
oxygen
24
1988;
M, CholletJM.
disease-evaluation
J
gas
therapy.
46:1051-54
T, Ahmed
of patients
monary
of blood
bismesylate
the reactivity
[abstract].
prognosis
follow-up
1:41-50
dose
in PaO2
denervation
22
1988;
blind
in almitrine
S, Hiramoto
enhances
21
haemodynamics
obstructive
Dis
I 105 I
1987;
5
I MAY,
lung
dis-
135(suppl):277
1994
1391