Sequential treatment with low dose ... hypoxaemic chronic obstructive airways disease in

Eur Resplr J
1992, 5 , 1054-1061
Sequential treatment with low dose almitrine bismesylate in
hypoxaemic chronic obstructive airways disease
P.A. Bardsley, P. Howard, 0. Tang, D. Empey, B. Harrison, M.D. Peake,
J. O'Reilly, J.F. Riordan, J. Wilkinson, F. Arnaud, J.A. Jarratt
Sequential treatment with low dose almitrine bismesylate in hypoxaemic chronic obstructive airways disease. P.A. Bards/ey, P. Howard, 0. Tang, D. Empey, B.
Harrison, M.D. Peake, J. O'Reilly, J.F. Riordan, J. Wilkinson, F. Arnaud, J.A.
Jarratt.
ABSTRACT: Dally dose schedules of 100-200 mg of almltrine bismesylate
improve arterial blood gases in patients with hypoxaemic chronic obstructive
airways disease (COPD) but dose related side effects are evident. In the present
study, daily doses approximately half of those previously used were employed
in a randomised double blind manner in 85 patients (age 35-79 years) with hypoxaemic COPD. After a one month period to check stability of arterial blood
gases, patients were allocated to almitrine (A) or placebo (P) using an unequal
code (60% A, 40% P). Tablets, 50-100 mg daily were stopped for one month
after 3, 6 and 9 months to counteract drug accumulation. SO patients in group
A and 35 in group P were comparable on entry; mean age 65 (sn=8) yrs., Pao
7.8 (0.7) kPa (58.3 (5.0) mmHg), Paco1 5.8 (0.8) kPa (43.2 (6.0) mmHg), forceJ
expiratory volume In one second • FEV1 0.89 (0.25) I and 6 minute walking distance 296 (97) metres. The improvement in baseline Pao1 values was the same
0.8-1.3 kPa (6-9.8 mmHg) as with previous higher dose therapy. Approximately
one third of patients did not respond, defined as Pao1 elevation >0.67 kPa (5
mmHg). The sequential dosing scheme stabllised blood levels of almitrine within
the therapeutic range of 280-300 ng·ml'1, After withdrawal of therapy arterial
blood gases and spirometry reverted to pre-treatment levels, suggesting no permanent reversal of pathophysiology. Dose related side effects of breathlessness,
indigestion and peripheral neuropathy were not observed. Nerve conduction
studies revealed no difference in peripheral nerve dysfunction in hypoxaemic
COPD between active and placebo therapy. Weight loss was still observed but
was less at lower doses.
Eur Respir J., 1992, 5, 1054- 1061.
Almitrine bismesylate (Vectarion) is a respiratory
drug which improves arterial blood gases through a
direct stimulatory action on the peripheral arterial
chemoreceptors [1]. The drug has no effect on the
central nervous system. In large doses minute ventilation increases but in smaller doses improvement of
blood gases is achieved by better ventilation/perfusion
matching in the lung resulting from either increased
alveolar ventilation and/or a direct action on small
pulmonary blood vessels [2]. In a recent large European Multicentre Study (Vectarion International
Multicentre Study • VIMS) [3] a dail-y dose of
almitrine of 100-200 mg significantly improved
arterial blood gas tension in patients with stable
hypoxaemic chronic obstructive airways disease
(COPD) when compared to placebo. After 12 months
therapy the mean rise in Paoz was in the order of 1
kPa (7.5 mmHg), the corresponding fall in Paco2 was
smaller but still significant. The treated group also
United Kingdom Multicentre Study
Group and Institut de Recherches
lnternationales Servier (I.R.I.S.)
92400 Courbevoie France.
Correspondence: P. Howard
University Department of Medicine
and Pharmacology
Royal Hallamshire Hospital
Sheffield SlO 2JF
U.K.
Keywords: Arterial blood gases
chronic airflow obstruction
peripheral neuropathy
plasma almitrine levels
weight loss
Received; July 10 1991
Accepted after revision April 6 1992
experienced a reduction in secondary polycythaemia,
a decrease in the number of hospital admissions and
a small but significant improvement in FEV1• The
changes in a smaller number of patients studied for
two years were still evident [4).
Almitrine bismesylate therapy was, however, associated with a number of side effects, enhanced dyspnoea, gastrointestinal upset and peripheral neuropathy.
The side effects were related to drug accumulation
found to be caused by an unexpectedly long half life.
Drug plasma levels were often well above the therapeutic range of 200-300 ng·ml·1 • One side effect, a
reversible peripheral neuropathy, has stimulated interest in the effects of hypoxaemia on peripheral nerve
function.
The excessive plasma levels suggested that daily
dosages of 100-200 mg almitrine were too high. The
aim of the present study was to investigate the clinical response and safety of approximately half these
INTERMITIENT LOW DOSE ALMITRINB IN HYPOXIC COPD
dosages (1 mg·kg·1 body weight daily) administered using a sequential dose technique. Peripheral nerve
function and clinical signs were subject to particular
scrutiny.
Patients and methods
The study was carried out simultaneously in several
centres in the United Kingdom. The admission criteria were: age between 35 and 79 years, weight
between 40 and 105 Kg, a clinical diagnosis of COPD
with spirometric evidence of airflow obstruction but
with an FEV1 above 0.6 litres, arterial oxygen tension
(PacoJ between 6.7 and 8.7 kPa (50-65 mmHg) and
carbon dioxide tension (Paco2) between 4.7 and 8.0
kPa (35-60 mm.Hg) whi lst breathing room air.
Patients currently treated with long term domiciliary
oxygen therapy were excluded.
Patients were studied during an initial period of 4
weeks when no trial tablets were administered, to test
stability of physiological parameters (T -1 - TO)
(Figure 1). If body weight (change of 2 Kg or 4%),
arterial blood gas tensions (>6 mmHg - 0.8 kPa), or
FEV1 (>0.3 litres) changed outside these limits of
stability then a further series of measurements
was conducted one week later. Patients who were still
unstable by the defined criteria were withdrawn.
LJ
Almitrine
f
Almitrine
Follow-up
'1,___~~-....1-..l
T-1 TO
Placebo
T6
T12
T18
Fig. 1. - Study design. Tablets were stopped for 1 month after
T3, T6 and T9 months to counteract any drug accumulation in the
blood. A stabilisation period of 1 month was followed by a 6
month double blind study, then a 6 month open study and finally
a 6 month follow-up period after treatment had ceased. T: time
in months (T-1 = one month before the onset of treatment (or
placebo)).
Following the stabilisation period (fig. 1) patients
were treated with oral almitrine or identical placebo
tablets using an unequal code of 60% almitrine and
40% placebo. None of the individual centres were
aware of the identity of active or placebo patients
as the prescriptions were arranged centrally through
IRIS, France. Patients were reviewed every three
months by full clinical examination and measurement
of arterial blood gas tensions, spirometry, six minute
walking test, visual analogue scales of breathlessness,
blood count, biochemistry and plasma almitrine estimations. The latter were measured using a gas chromatographic method at Servier Laboratories Ltd., UK.
A chest X-ray and ECG were also taken at the onset.
Neurologica l examinations, both clinical and
electrophysiological, were performed during the initial
stabilisation period and then at six monthly intervals
during the study. Nerve conduction studies were made
using surface recording electrodes. Limb temperature
was maintained about 30°C. The following motor and
1055
sensory nerves in the arm and leg were tested bilaterally: the median and peroneal motor and the median
and sural sensory nerves. Distal and F-wave latencies,
conduction velocities and amplitudes of evoked
potentials were measured [5].
The first six months of the study was placebo controlled and double blind (fig. 1) to test the response
of the smaller daily dose of almitrine on blood gases.
During the second six months all patients received active drug to investigate the effect of the sequential
dosage scheme on drug plasma levels. A number of
patients agreed to be studied for a further six months
after withdrawal of therapy.
Drug administration was intermittent with a window
of one month break in treatment after 3, 6 and 9
months. Patients took 25 mg tablets in doses which
varied according to their initial body weight. A daily
dose of 50 mg was given to patients weighing between
40 and 49 Kg; 75 mg between 50 and 64 Kg and
100 mg for those 65 Kg or more. The placebo group
in the double blind phase of the study received dummy
tablets of identical appearance with the same frequency. If patients lost weight (>5%) during the
course of the study the tablets were reduced by 25 mg
daily or placebo equivalent. Treatment was given in
addition to the patients usual therapy which, as far as
possible, was kept constant throughout the study.
All patients entering into the study gave their informed consent and approval was given by local Ethical Committees. Patients withdrawn from the study
for whatever reason were carefully analysed in addition to those who completed it. After six months the
randomised code was opened and an analysis made.
Further analyses were made at 12 and 18 months.
Statistical methods
Pre-treatment stability. Pre-treatment homogeneity
between T-1 and TO was tested by a two-way analysis of variance: Group (Almitrine, placebo) x Time
(T-1, TO) with repeated measures on time factor. In
case of non-significance of Group x Time interaction,
the evolution of the two groups between T-1 and
TO was compared. In case of non-significance of T1 and TO mean values (all groups together) and of
two groups mean values (all times together), the
stability and homogeneity of the groups were confirmed [6].
During the study. Comparison of the evolution of the
two groups was tested with a two-way analysis of
variance (Group x Time with repeated measures on
time factor). In case of a significant interaction
(Group x Time) the analysis was completed in order
to compare the means of the two groups at each time.
The within group evaluation was independently tested
by a two-way analysis of variance (Subject x Time)
for each group. A Chi-2 test was used for testing
qualitative data between groups at each time [6] .
Throughout the analysis, mean::t:lso is used.
P.A. BARDSLEY ET AL.
1056
Table 1.
-
Clinical data on admission to the study
Almitrine (A)
Placebo (P)
FVC I
6 minute walk• metres
Breathlessness (VAS) mm
50
44/6
64
72.6
58.3
7.8
43.2
5.8
0.90
2.13
299
21.5
(8)
(14.1)
(5.2)
(0.7)
(5.1)
(0.8)
(0.26)
(0.63)
(96)
(19.5)
35
24/11
66
65.5
58.3
7.8
43.2
5.8
0.87
2.12
292
20.4
Haematocrit %
49.0
(4.4)
47.2 (5.5)
n
Sex MJF
Age yr
Weight kg
Pao2 mmHg
kPa
Paco2 mmHg
kPa
FEVI
{
Total Group (A + P)
(8)
(13.3)
(4.0)
(0.5)
(7.1)
(0.9)
(0.24)
(0.73)
(99)
(20.2)
85
68/17
65
69.7
58.3
7.8
43.2
5.8
0.89
2.12
296
21.1
(8)
(14.2)
(5.0)
(0.7)
(6.0)
(0.8)
(0.25)
(0.67)
(97)
(20.4)
48.2 (4.9)
p
NS
<0.05
NS
NS
NS
NS
NS
NS
NS
NS
NS
Mean (so). Pao2 and Paco2 : arterial oxygen and carbon dioxide tensions; FEV 1 and FVC: forced expiratory volume in one second and forced vital capacity respectively; • : number of patients, 46 in the
almitrine group and 32 in the placebo group.
Table 2. - Initial daily dose of almitrine or placebo
equivalent according to body weight
Dose
Group A
mg·day·1
n
100
75
50
37
9
4
BW
kg
79.4 (9.3)
57.6 (5.2)
45.8 (2.6)
Group P
n
BW
kg
19
10
6
75.3 (10.0)
57.6 (4.0)
47.8 (1.7)
Mean (so). No active drug was present in placebo tablets but
their number and size were the same and were administered
in the same manner as for group A according to body weight.
Group A: almitrine group; Group P: placebo group.
Results
85 patients entered the study. All had COPD and
hypoxaemia (Pao 2 <65 mmHg or 8.7 kPa). After
randomisation, 50 patients were found to be in the
almitrine treated group (44 male and 6 female) and
35 in the placebo group (24 male and 11 female).
The details of the two groups of patients on entry are
given in table 1. There were no statistical differenc~s
between the two groups on entry for any parameter
except for body weight where the almitrine group were
somewhat heavier. The initial dose of almitrine and
tablet equivalents in the placebo group varied according to body weight and are given in table 2.
64 patients completed the placebo controlled part
of the study, 28 placebo and 36 almilrine treated.
During this period 14 patients (28%) withdrew in
the active group and 7 (20%) in the placebo
group. These figures are not significantly different.
The reasons for withdrawal were similar in both
groups, one death and one for non-compliance in each.
Other causes included dyspnoea, paraesthesiae,
gastrointestinal disturbances, depression and increasing
severity of chest disease. There were no differences
between groups. In particular, two in each group developed or aggravated paraesthesiae.
Changes of clinical and physiological parameters are
shown in table 3. There was a significant improvement of Pao2 from 7.8±0.7 kPa to 8.6±1.4 kPa without significant change of Paco 2 FEV 1 FVC and
haematocrit. Six minute walking dis'tance and
breathlessness judged by visual analogue scale (V AS)
were unchanged in the almitrine group (A) but deteriorated in the placebo patients (P) giving a significant
group x time interaction (p<0.05). Weight fell in the
almilrine group (A) but there was no correlation at 6
or 12 months between the weight lost and initial body
weight (r=0.126 and r=-0.183, respectively, at 6 and
12 months).
Responder status
A useful clinical response was considered to be a
rise of 5 mmHg (0.67 kPa) in Pao2 or more. Table 4
shows responder status on this basis. There were three
times as many responders in Group A compared to P.
Group A responders at 6 and 12 months had substantially higher Pao2 improvement than the mean values
for the whole group (Table 4). Non-responders
amounted to one third of patients in Group A.
Acute exacerbations
Three patients (6%) in the almitrine treated group
and 3 (9%) in the placebo group were admitted to
hospital with exacerbations of their chest condition in
the first six month period. 23 out of 50 (46%) group
A and 17 out of 35 (49%) Group P experienced at
1057
INTERMITTENT LOW DOSE ALMITRlNE IN HYPOXIC COPD
least one lower respiratory tract infection requiring
antibiotics in the same period. None of these differences were statistically significant.
Twenty seven patients completed 12 months on
almitrine treatment. Pao2 increased from 7.9 (0.8) kPa
(59.0 (6.0) mmHg) to 8.8 (1.3) kPa (66.3 (10.1) mmHg)
(p<0.001) during the period. Seventeen were followed
for a further six months after cessation of treatment. Figure 2 illustrates the change of Pao2 in these 17 patients
during the whole period of eighteen months. Pao2 rises
slowly to plateau at six months and achieves a maximal
mean increment of 8.2 mmHg (1.1 kPa). After cessation of treatment, Pao2 falls slowly towards pre-treatment
levels. Paco2 (fig 3) showed a reverse response of lesser
magnitude.
6-18 month study
Fifteen of the 28 patients in the former placebo
group completed 12 months after a high rate of withdrawal and showed a similar pattern of physiological
change as the former almitrine group.
Table 3. -
Physiological tests in almitrine and placebo groups during the double blind period of 6 months
n
TO
58.8 (5.5)
7.8
58.1 (4.2)
7.7
63.2 (7.5)
8.4
57.8 (6.3)
7.7
41.3 (5.4)
5.5
44.3 (6.9)
5.9
43.6 (6.7)
5.8
mmHg
kPa
mmHg
kPa
A
36
p
28
mmHg
kPa
mmHg
kPa
A
36
FVC
T3
T6
64.7
8.6
59.8
8.0
p
(10.4)
<0.01
(6.2)
p
27
42.6 (5.0)
5.7
44.6 (6.8)
5.9
41.5 (5.2)
A
p
31
29
0.91 (0.22)
0.85 (0.19)
0.98 (0.24)
0.87 (0.19)
0.97
0.83
(0.24)
(0.22)
NS
A
p
31
28
2.19 (0.68)
2.11 (0.70)
2.25 (0.63)
2.11 (0.72)
2.34
2.07
(0.74)
(0.71)
NS
301
292
305
279
(105)
(97)
<0.05
<0.05
5.5
NS
Walking distance
m
A
p
30
26
305
318
Breathlessness at rest
VAS
mm
mm
A
p
30
25
23.4 (18.4)
19.8 (21.2)
25.1 (19.4)
20.7 (21.8)
22.1 (18.9)
30.7 (24.2)
Haematocrit
%
%
A
p
33
26
48.3 (4.3)
46.4 (4.9)
48.3 (5.8)
48.3 (5.7)
48.5
48.6
Weight
kg
kg
A
36
28
74.2 (13.5)
64.3 (10.4)
71.6 (13.8)
64.4 (10.8)
70.6 (13.4)
63.7 (10.6)
p
(90)
(102)
(95)
(112)
(6.2)
(5.9)
NS
<0.001
Mean (so): significance applies to a time x group comparative interaction using ANOVA. Pao~ and Paco.2 between almitrine
and placebo patients: arterial oxygen and carbon dioxide tensions; FEV1 and FVC: forced expuatory volume in one second
and forced vital capacity. Breathlessness was measured with a 100 mm visual analogue scale (VAS). A: almitrine group;
P: placebo group.
Table 4 months
Comparison of Responders and non Responders in the active and placebo groups at six and twelve
T12
T6
Group
Responders
Total
n
n
%
6Pao2 •
mmHg
Non Responders
n
%
Responders
%
6Pao2
mmHg
n
n
27
19 70
A
36
23 64
10.6 (4.7)
(1.4 kPa)
13 36
-2.4 (5.2)
[-0.3 kPa)
p
28
6
8.8 (3.8)
(1.2 kPa)
22 79
-0.3 (3.5)
[-0.04 kPa)
21
Total
Non Responders
6Pao 2
mmHg
n
%
6Pao2
mmHg
11.5 (5.6)
[1.5 kPa]
8
30
-2.8 (4.7)
[-0.4 kPa)
•: mean (so) for 6Pao2• Mean kPa values are in [ ). A: Almitrine treated; P: Placebo; 6Pao2 : change in arterial oxygen
tension at six (T6) or 12 months (T 12) in mmHg. Responder status at T6 between almitrine and placebo was significant
p<0.005.
1058
P.A. BARDSLEY ET AL.
mmHg
kPa
80
10.7
70
9.3
60
8.0
(\j
0
<U
a..
p<0.001
p=0.01
1
TO
T3
T6
T9
1
T12
--1
T15
T18 months
Fig. 2. - Pa0 2 changes in 17 patients treated continuously with almitrine for 12 months followed by 6 months post-study evaluation
(mean values, bars indicate SD). See text for explanation.
mmHg
1
kPa
50
6.7
46
6.1
42
5.6
38
5.1
t - - - - - NS
TO
T3
T6
----+--
T9
!
T12
p<0.01
T15
--f
T18 months
Fig. 3. - PaC02 changes for 17 patients treated continuously with almitrine for 12 months followed by 6 months post-study evaluation
(mean values, bars indicate SD). See text for explanation. NS: not significant.
In the same 17 patients in Group A treated for 12
months body weight fell by a mean value of 4.5 Kg
to recover when the drug was withdrawn (fig 4).
for similar reasons (dyspnoea, paraesthesiae, gastrointestinal disturbance, etc) with no between group differences. There was one further death in the former
almitrine group and four in the former placebo group.
No death was considered therapy related.
Withdrawals 6 to 12 months
Neurological evaluation
Withdrawals between 6 and 12 months when all patients were actively treated were 8 in the former
almitrine group and 10 in the former placebo group
At entry 28 (38%) had normal peripheral nerves in
electrophysiological terms, and 11 (15%) had possible
or definite generalised peripheral neuropathy, 1 (1.6%)
Body weight
1059
INTERMITTENT LOW DOSE ALMITRINE IN HYPOXIC COPD
Almitrine plasma levels
mononeuritis multiplex and the remainder either
borderline abnormal measurements or evidence of
compression neuropathy. Thirty five (47.5%) were
considered normal on clinical assessment; only 3
(4.9%) bad a possible generalised peripheral neuropathy. The remainder had solitary signs of uncertain
significance or evidence of compressive lesions such
as carpal tunnel syndrome. No patient was withdrawn
for development of peripheral neuropathy and experience of paraesthesiae was similar in both almitrine and
placebo groups.
Figure 5 shows almitrine plasma levels for all patients
on whom measurements were available. Steady mean
plasma levels within the therapeutic range were realised
throughout the 12 month study period. At T3, T6, T9,
and T12 immediately before the windows of no therapy
plasma level values were, respectively, 287:t139,
309:t164, 309:t148 and 286:t155 ng·ml·1• The therapeutic windows of one month were associated with only minor falls of mean plasma drug levels and Pao2•
l
~
l:
C)
~
>-
"0
0
80
75
m
70
65
p<0.001
1
TO
T3
------....,1--- p<0.001 ~
T6
T9
t
T12
T15
T18
months
Fig. 4. - Body weight for 17 patients treated continuously with almitrine for 12 months followed by 6 months post-study evaluation
(values are means, bars indicate SO). Sec text for explanation.
1000
~
300
g>
<n
100
~
_g!
ea
E
~
Q.
C1>
c
10
·c
=E
<
Patients
Fig. 5. -
T3
38
T4
32
T6
33
T7
27
T9 T10
29 22
T12 T13 months
23 16
Mean and standard deviation of almitrine plasma levels for all studied patients during the first 13 months (mean:t:SD).
P.A. BARDSLEY ET AL.
1060
Discussion
All patients admitted to the study had hypoxaemic
COPD with physiological parameters very similar to
those of the high dose almitrine VIMS study (3). The
increase of Pao2 of 0.8-1.3 k.Pa according to subgroup
analysed was also the same, confirming that the lower
dose schedule is equally efficacious. It might yet be
possible to lower the daily dose still further without
loss of benefit. About one third of patients do not
respond to almitrine. If then patients are removed
from the calculations the improvement of Pao2 in the
'responders' is correspondingly raised and similar to the
elevation of Pao 2 achieved by long term domiciliary
oxygen therapy [7] with the added advantage of lowered Paco2 • The mortality of patients with hypoxaemic COPD is strongly related to the severity of arterial
hypoxaemia and pulmonary hypertension (8, 9]. It is
not yet possible to determine whether almitrine therapy
in those who respond will have the same survival benefits as supplemental oxygen. Clearly with lower dose
schedules this possibility should be explored in longer
term studies.
The high plasma half life of 28 days found in the
VIMS study (3] caused some surprise and probably
accounted for the high and increasing plasma levels of
the drug observed in some patients. Side effects,
particularly peripheral neuropathy, were correlated with
increasing serum drug levels. The sequential dosage
scheme tried in this study using therapeutic windows
every three months achieved steady mean plasma
levels in the therapeutic range with no evidence of a
rising plasma level in some patients. There is still
wide variance around the mean plasma levels but
the sequential technique achieved its purpose of
stabilising plasma concentration over the one year period.
Side effects
Evidence for clinical or electrophysiological neuropathic deterioration was carefully evaluated. The
occurrence of reversible peripheral neuropathy during
almitrine treatment in previous studies has focused
attention on the effect of tissue hypoxia, smoking,
alcohol and age on peripheral nerve function in
patients with COPD. There is a marked disparity
between the incidence of electrophysiological abnormality of peripheral nerve activity and clinical manifestations of peripheral neuropathy [10]. This study
demonstrates the importance of determining the
aetiology of peripheral neuropathy in hypoxaemic
patients when abnormalities are detected. Most are not
due to a generalised peripheral neuropathy, the
incidence of which is small, i.e. around 5%. There
was a slight reduction in peroneal motor conduction
velocity in the treated and control groups, the changes
being similar for both. Otherwise, no evidence was
found, at the doses used in this study for one year,
of either clinical or electrophysiological neuropathic
deterioration. Paraesthesiae and other clinical
neurological features were common but equally distributed between placebo and almitrine groups.
Other drug related side effects such as indigestion
and enhanced breathlessness were not observed with
the lower doses. In conclusion, during the period of
study no evidence for dose related side effects previously noted [10] were observed.
Airway function
Spirometric airway function declines steadily in severe hypoxaemic COPD. Previous investigations using almitrine have observed a slight improvement of
spirometry. Similar improvements were discovered at
the doses used in the current investigation but were
not statistically significant. The size of improvement
is probably not clinically relevant to patients with severe fixed airways disease but the results support the
concept that almitrine might stabilise airway disease
and possibly over a longer term, moderate decline of
airway function.
Body weight fell overall in the alniitrine group and
increased once therapy stopped. Weight drop was less
with the smaller doses and did not correlate with initial body weight. The reasons for loss of weight during almitrine therapy are not clear; appetite suppression
and catabolic metabolism have been suggested [11].
There is no evidence as yet that almitrine has such
effects. Should weight fall by more than 10% in
patients of less than 50 Kg, then the dose of the drug
should be reduced or therapy withdrawn.
Cessation of therapy
After treatment was stopped, arterial blood gases,
spirometry and body weight slowly returned over the
following six months to near pre-treatment levels, confirming pharmacological activity but no permanent reversal of these parameters. At low doses, minute
ventilation is not likely to be substantially increased
[3]. The drug is known to constrict pulmonary
arterioles (3] which would seem its most likely action
in improving ventilation/perfusion imbalance. Recent
experimental work suggests that very small doses of
almitrine in the rodent may augment natural hypoxic
pulmonary vasoconstriction without substantially elevating mean pulmonary artery pressure (12). Blood
gas benefit in the hypoxaemic COPD patient through
almitrine therapy should aim to utilise these pulmonary
vascular effects [12]. These, it seems, might be available with lower drug doses [11 ], less susceptible to
side effe.c ts than the higher doses needed to stimulate
the carotid body to increase minute ventilation.
References
1. Laubie M, Schmitt, H. - Long lasting hyperventilation induced by almitrine - Evidence for a specific effect
INTERM!TfENT LOW DOSE ALMITRINE IN HYPOXIC COPD
on carotid and thoracic chemoreceptors. Eur J Pharmacal,
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