Fundam Clin Pharrnacol(l991) 5 , 635-640
635
0 Elsevier. Paris
Rapid communication
Dose - response effects of atropine in human volunteers* J Boudet', W Qing', A Boyer-Chammard', G Del Franco', JL Bergougnan2, P Rosen2, P Meyer' 'Service de Pharmacologie Clinique, H6pital Necker, Paris 75015; 2SynthtYabo Recherche (LERS), Paris 75014, France
(Received 7 May 1991 ; accepted 7 May 1991)
Introduction
Antidepressor agents with a tricyclic structure can cause various side-effects and in particular central and peripheral cholinergic effects (Colonna et all 1988). New molecules possessing more specificity, acting on precise pharmacological pathways, are presently under investigation. Their study is aimed at eliminating the interference of a cholinergic effect, even if slight. We have therefore reinvestigated the effects of small doses of atropine sulfate iv in young volunteers who will subsequently receive the new antidepressor molecule(s). The results that are given in the present communication represent a dose - response curve of atropine effects useful for further clinical studies.
Methods Atropine is known to increase pupillary diameter, reduce sweat and salivary output, and increase heart rate. For the measurement of pupillary diameter and pupillary photo-reactivity, we have used the Pupilscan PC recorder (Fairville Medical Optics Inc, Amersham) connected to a Compaq Desk Pro 286e computer with a Fairville program. The method of Dollery et a/ (Dollery, 1976) was followed for determination of salivary flow, and dental cotton swabs were applied to gums for 2 min. Sweat production was determined with the use of a iontophoretic instillation of pilocarpine according to Shwachman et a/ (1981). Heart rate and arterial blood pressure were monitored with a Finapress recorder and heart rate variability was analysed with an Anapress program (Novocord, Paris) which allows Fourier transform and computes the
* Presented as an oral communication at the meeting of British and French Pharmacology, April 25-26, 1991, Lyon, France.
636
J Boudet et al
power spectral density of beat-by-beat RR variability (Akselrod et a/,1981). The study of vagal peak was conducted at a n imposed respiratory rate of 12 per min. A double-blind, placebocontrolled study of atropine sulfate given intravenously, at doses ranging between 0.125 and 0.750 mg, was performed in healthy volunteers aged 20-30 year. The study was approved by the Necker Ethical Committee. Atropine sulfate was provided by Chaix Dumaret Laboratory (Paris).The different above-described methods were applied during a control period and a 30-min experimental period 30 min following intravenous injection, the volunteers lying in a climatised and sound-proofed room.
Results Effects of low doses of atropine (0.125 and 0.250 mg) Heart rate was lowered (fig 1). The integral of the respiratory peak, measured at 200 mHz, increased in 2 subjects out of 3 (fig 2). Pupillary diameter did not vary. Sweat and salivary output diminished significantly (figs 4, 5 ) .
95
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0 0
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PLACEBO 0.125mg 0.250mg 0 . 5 0 0 mg 0 . 7 5 0 m0
I
0
I
1
0.125 0.250
I
1
0.500 0 . 1 5 0
ATROPINE SULFATE
(ma i v )
MEAN?.SD 4
Fig 1. Variations in heart rate with atropine administration. Mean is represented by a broken line.
Dose - response effects of atropine in human volunteers
0-
e-
-30
0
30
60
90
120
637
SSTUE lYALD
350
4 INJECTION
TIME ( M i n u t e s ) Fig 2. Variations in respiratory peak surface. Identification of subjects and atropine doses are given in the upper right-hand corner. Peak surface was measured between 1.75 and 2.26 mHz.
Effects of higher atropine dose (0.750 rng) The variations were clear. Heart rate was increased (fig 1). The vagal peak was reduced or suppressed (fig 2). Pupillary dilatation was apparent between 30 and 120 min after atropine administration (fig 3). The most apparent variation concerned the minimal diameter. Salivary and sweat output were reduced (figs 4, 5 ) .
Effects of 0.500 rng atropine The variations were intermediary. Vascular parameters were weak (figs 1,2). Increases in pupillary diameter were moderate and not constantly observed. Salivary and sweat output, conversely, were significantly diminished (figs 4, 5).
Discussion The present study indicates that a dose - effect curve can be obtained with small doses of atropine, and shows that the various effects of atropine d o not have a similar sensitivity. To assess the lack of any atropine effect of a new compound, it is therefore
J Boudet et a/
638
9 8 -
T
7 6
i
5 ; 4
4 i
-
n
E E v
a W c
=
635
0 Elsevier. Paris
Rapid communication
Dose - response effects of atropine in human volunteers* J Boudet', W Qing', A Boyer-Chammard', G Del Franco', JL Bergougnan2, P Rosen2, P Meyer' 'Service de Pharmacologie Clinique, H6pital Necker, Paris 75015; 2SynthtYabo Recherche (LERS), Paris 75014, France
(Received 7 May 1991 ; accepted 7 May 1991)
Introduction
Antidepressor agents with a tricyclic structure can cause various side-effects and in particular central and peripheral cholinergic effects (Colonna et all 1988). New molecules possessing more specificity, acting on precise pharmacological pathways, are presently under investigation. Their study is aimed at eliminating the interference of a cholinergic effect, even if slight. We have therefore reinvestigated the effects of small doses of atropine sulfate iv in young volunteers who will subsequently receive the new antidepressor molecule(s). The results that are given in the present communication represent a dose - response curve of atropine effects useful for further clinical studies.
Methods Atropine is known to increase pupillary diameter, reduce sweat and salivary output, and increase heart rate. For the measurement of pupillary diameter and pupillary photo-reactivity, we have used the Pupilscan PC recorder (Fairville Medical Optics Inc, Amersham) connected to a Compaq Desk Pro 286e computer with a Fairville program. The method of Dollery et a/ (Dollery, 1976) was followed for determination of salivary flow, and dental cotton swabs were applied to gums for 2 min. Sweat production was determined with the use of a iontophoretic instillation of pilocarpine according to Shwachman et a/ (1981). Heart rate and arterial blood pressure were monitored with a Finapress recorder and heart rate variability was analysed with an Anapress program (Novocord, Paris) which allows Fourier transform and computes the
* Presented as an oral communication at the meeting of British and French Pharmacology, April 25-26, 1991, Lyon, France.
636
J Boudet et al
power spectral density of beat-by-beat RR variability (Akselrod et a/,1981). The study of vagal peak was conducted at a n imposed respiratory rate of 12 per min. A double-blind, placebocontrolled study of atropine sulfate given intravenously, at doses ranging between 0.125 and 0.750 mg, was performed in healthy volunteers aged 20-30 year. The study was approved by the Necker Ethical Committee. Atropine sulfate was provided by Chaix Dumaret Laboratory (Paris).The different above-described methods were applied during a control period and a 30-min experimental period 30 min following intravenous injection, the volunteers lying in a climatised and sound-proofed room.
Results Effects of low doses of atropine (0.125 and 0.250 mg) Heart rate was lowered (fig 1). The integral of the respiratory peak, measured at 200 mHz, increased in 2 subjects out of 3 (fig 2). Pupillary diameter did not vary. Sweat and salivary output diminished significantly (figs 4, 5 ) .
95
I -
so
-
loo
85 r
I
E
80
-
n
w Ia
7 5 -
=I-
70
5I
65
. a
60
-
-
0 0
-
A
A 55
PLACEBO 0.125mg 0.250mg 0 . 5 0 0 mg 0 . 7 5 0 m0
I
0
I
1
0.125 0.250
I
1
0.500 0 . 1 5 0
ATROPINE SULFATE
(ma i v )
MEAN?.SD 4
Fig 1. Variations in heart rate with atropine administration. Mean is represented by a broken line.
Dose - response effects of atropine in human volunteers
0-
e-
-30
0
30
60
90
120
637
SSTUE lYALD
350
4 INJECTION
TIME ( M i n u t e s ) Fig 2. Variations in respiratory peak surface. Identification of subjects and atropine doses are given in the upper right-hand corner. Peak surface was measured between 1.75 and 2.26 mHz.
Effects of higher atropine dose (0.750 rng) The variations were clear. Heart rate was increased (fig 1). The vagal peak was reduced or suppressed (fig 2). Pupillary dilatation was apparent between 30 and 120 min after atropine administration (fig 3). The most apparent variation concerned the minimal diameter. Salivary and sweat output were reduced (figs 4, 5 ) .
Effects of 0.500 rng atropine The variations were intermediary. Vascular parameters were weak (figs 1,2). Increases in pupillary diameter were moderate and not constantly observed. Salivary and sweat output, conversely, were significantly diminished (figs 4, 5).
Discussion The present study indicates that a dose - effect curve can be obtained with small doses of atropine, and shows that the various effects of atropine d o not have a similar sensitivity. To assess the lack of any atropine effect of a new compound, it is therefore
J Boudet et a/
638
9 8 -
T
7 6
i
5 ; 4
4 i
-
n
E E v
a W c
=
