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Assessment of erectogenic drugs by numeric plethysmography
Assessment of Erectogenic Drugs by Numeric Plethysmography
P. DANJOU,
A method
L. LACOMBLEZ,
of assessment
D. WAROT,
of the erection
AND A. J. PUECH
in man,
using
numeric
penile
plethys-
The data concerning the sensor, the electronic circuit, and the computer interfacing with an IBM PC are described. As a validation of this method, apomorphine (0.009 mg/kg) was tested in a double-blind, placebocontrolled study, carried out in healthy volunteers. Apomorphine induced an erection starting, as a mean, at the fourth minute postinjection. The treatment increased the penis volume without any other stimulation (p = O.ooOS)and potentiated the physiologic response induced by visual erotic stimulation (p = 0.0012). The limits of plethysmography are discussed in reference to rigidimetry. mography,
is presented.
Key Words:
Penile tumescence; unteer, Plethysmography
Erection; Drugs; Apomorphine;
Healthy vol-
INTRODUCTION When one studies the physiologic reactions following the administration of potentially erectogenic drugs, penile tumescence is usually assessed by analogic strip chart plethysmographs during acute administration or by self-ratings when longterm treatments are used. We have developed a low-cost, easy-to-build plethysmographic interface using a mercury strain gauge and delivering a signal digitalized by an analog to digital (A/ D) converter, allowing the continuous integration of data, and making data vectors manipulations such as averaging or zero interpolation, possible. Simultaneous to the treatment of the digitalized signal, analogic recording on paper strips was performed (Figure 1). Dopamine receptors seem to be implicated in the physiology of erection and specific agonists induce erections in animals (Ferrari et al., 1985; Foreman et al., 1987) as well as in healthy volunteers (La1 et al., 1984) and patients (La1 et al., 1987). This technique was therefore tested in a study carried out in IO healthy volunteers assessing the effects of 0.009 mg/kg of apomorphine HCI injected subcutaneously using a double-blind, placebo-controlled design.
From the Departement de Pharmacologic, Hopital de la Pitie-Salpetriere 47 Bld. de I’Hopital, 75651 Paris Cedex 13, France. Address reprint requests to: Dr. P. Danjou, Departement de Pharmacologic, Hopital de la PitieSalpetri&e, 47 Bid. de I’Hbpital, 75651 Paris Cedex 13, France. Received May 1988; revised and accepted July 1988.
61 Journal of Pharmacological Methods Q 1989 Elsevier Science Publishing
21, 61-69 (1989) Co., Inc., 6.55 Avenue of the Americas, New York, NY 1OLTlO
@l6n-~ls3.SO
~~1~
s/c FIGURE 1.
'%WL
EROTICSTIMILATION
Paper strip recording no. 3, following apomorphine
administration.
Etectogenic Drugs and Plethysmography
METHODS Erectometer Circuit and Sensor Our purpose was to build an instrument of primary screening, sensitive enough to detect small changes in the penis size, with no concern for the level of rigidity. The sensor we used was a mercury strain gauge (SEGA, France) with an internal diameter ranging from 28 to 36 mm, adapted individually to each subject. The impedance of the mercury column was about 1 &2 increasing of IO-’ fz mm-’ with the diameter changes. The circuit is shown in Figure 2. Computer tnterfacing The output of the circuit was connected to one of the 16 inputs of a 12 bits DA converter. (U-Limited, Stanford, CT). Signal was read at an approximate sampling frequency of 15 Hz. The area under curve was calculated every second (using 15 measurements) and stored on disk. The area under curve of three 20-min phases were used as dependent variable in the analysis. The SEM used in the analysis was the between-subjects SEM. Subjects Subjects were 10 male volunteers, aged 19-27 yr (mean = 23.6 yr) who were heterosexual and considered as healthy according to the medical examination, EKG, biological data (inclusive of HIV), Cattell anxiety scale, and Eysenck personality inventory. The subjects‘ sexual habits were considered to be in the normal range. Their monthly mean number of occurrences of sexual intercourse was between 2 and 20 (mean = 7.3), and their number of different sexual partners was between one and six (mean = 2.7). Subjects were fully informed of the protocol and were paid $200 for their participation. The study was approved by the local ethics committee.
PI R3
R4 FIGURE 2.
Erectometer:
schematic diagram.
63
64
P. Danjou et al. Study Design A cross-over design was used to control random variations in subject reactivity. A dose of apomorphine was compared to a placebo during two separate sessions at a l-week interval. The order of administration was balanced: five subjects received apomorphine first, and five subjects were started on placebo. All sessions were conducted between 1 P.M. and 4 P.M. Subjects were instructed to abstain from having sex the evening and the night preceding the experimental day. Apomorp~ine
Solution
A dose of 0.009 mglkg of apomorphine HCI was prepared extemporaneously and injected subcutaneously under a volume of 1 ml. The placebo was a NaCl 9% solution equally unpainful as apomorphine when injected subcutaneously. Procedure At the beginning of the session, subjects were installed in a sound proof, climatecontrolled experiment room. The subjects were recumbent and under the observation of a video camera. The plethysmographic strain gauge was placed at the base of the penis and a zero calibration was made. Subjects were instructed to remain quiet for 30 min whiJe baseline recording was initiated. Usually a decrease of penis volume was noted after the initial manipulation; if a complete detumescence was not obtained after 30 min, a IO-min mental calculation sequence was used, followed by 15 min of a new baseline recording. The baseline used for calculations was the lowest level reached by subjects. Apomorphine or placebo were then injected subcutaneously at the level of the deltoid muscle, followed by three different 20-min phases: during phase 1, subjects were resting; during phase 2, subjects underwent visual erotic stimulation. The stimuiation was composed of a series of 50 slides extracted from pornographic magazines; both series were standardized and the stimulation was equilibrated between periods. During phase 3, subjects were again left quiet. At the end of each phase, subjects were asked to give their impression (ranging zero-5) assessing penile tumescence and rigidity. Concerning penile stiffness, “2” was considered stiff enough to allow penetration with the help of a hand, and “3” without help. Subjects were asked not to touch their penis to check the stiffness, and they could not see it neither, as their pelvic area was covered with a sheet in order to allow observation of subjects through a TV camera. Statistical Analysis The area under curve was analyzed by a three-way ANOVA (subject, period, treatment) with time as a repetition factor (three levels). The overall effect of apomorphine was deducted from the treatment effect and the repetition by treatment interaction, Orthogonal decomposition of the interaction term was calculated in order to check the time-course of the effect. Between-treatment comparisons were done using t-tests for each phase when an overall effect existed. The individual vectors were averaged and plotted but not analyzed (see Figure 3). Correlations between
Erectogenic Drugs and Plethysmography
VOLTS (x10-2) 30-
5min
262624 222018 16 14 12 10 (I(I42-
phase
1
2
3
FIGURE 3. Mean erectile response following placebo (P) and apo~~hine (A). Erotic stimulation (ERS) was administered during the second of the ZO-min lasting phases.
objective (AUC) and subjective (their impression) were examined through Spearman rank correlation. RESULTS Apomorphine induced an erection in phase 1 (no stimulation) in all subjects (lo/ IO), starting as a mean at the end of the fourth minute. Plethysmographic AUC was significantly, increased in phase 1 (p = 0.~8) and in phase 2 (p = 0.0012) (Figure 4). Under both treatments, the AUC was greatly increased by the visual stimulation. The time by treatment interaction was of the first order (p = 0.0196), confirming the observation that the effect was maximum during phase 1. Self-assessed penile stiffness was increased during phase 1 (placebo: 0 Z!Z0, apomorphine: 2.44 + 0.603, p = 0.0041, phase 2 (placebo: 1.30 + 0.448, apomorphine: 3.700 rt 0.395,~ = 0.0008), and during phase 3 (placebo: 0.3 + 0.152, apomorphine: 1.5 z!z 0.477, p = 0.035). Seif-assessed penile tumescence followed the same changes and was increased during phase I (placebo: 0.2 rf: 0.113, apomorphine: 2.778 +- 0.618, p = 0.003) and
65
66
P. Danjou et al.
AUC (volt 8. seconds) xl00 300
*
T * p(O-01
250
200
* * 150
100
i
50
-
0
phase
1
FIGURE 4. Area under curve of plethysmographic subjects SEM, during the three phases.
2
3 data, expressed in mean and between-
phase 2 (placebo: 2.6 + 0.452, apomorphine: 3.80 2 0.388, p = 0.059) but was not modified during phase 3 (placebo: 1.1 2 0.314, apomorphine: 1.9 s 0.504, p = 0.198). During phase 1, when the greatest changes were observed, self-assessed tumescence and self-assessed stiffness were highly correlated (r = 0.948, p = 0.004; see Figure 5). Both penile tumescence and penile stiffness showed a trend to be correlated to the AUC (respectively, r = 0.59, p = 0.073, and r = 0.62, p = 0.064) but failed to reach the 5*X, significance threshold.
--
.
-.
_
TUMESCENCE
. . -. ... -
- -
r
C
/-
l-
--
- - --
A.U.C.
8
68
P. Danjou et al.
DISCUSSION The results demonstrate that numeric plethysmography allows one to quantify precisely data for which analogic paper recorders would have either required a manual planimetric integration or an electronic capacitor integrating device. The major problem using a size-adapted strain gauge was the variability intergauge that was statistically included in the subject effect, as the same gauge was used during the two periods of each subjects. In case of parallel groups, an individual calibration session would be recommended in order to express results as a function of the maximal vacuum (Nadig et al., 1986) or vibrator-induced erection (Riley et al., 1982). The estimation of an erection level by the volume changes of the penis is possible as long as the erection is submaximal. At high levels of erection, volume changes would be negligible and only rigidity would progress. In the case of our data, it was obvious that without mechanical maneuvers the subjects could not distinguish stiffness from tumescence as both parameters were intercorrelated. Subjects seem unaware of their penile stiffness level at low or medium level of sexual arousal, and a rigidimeter could be helpful to study that parameter. The major obstacle using a rigidimeter (Bradley et al., 1985) is not only the high cost of this device, but also the fact that a mechanical stimulation might interfere with the observed data. The results obtained are consistent with those of Lal et al. (1984) and confirm the erectogenic activity of apomorphine in humans. COMPONENTS
LIST
Resistors (t/4 w):
Rl : 2.2 K fz R4: 1 fz R7: 10 K Q
R2: 1OOKfZ R5: 2.2 K Sz R8: 10 K fz
RZ%:-IKft R6: I KfZ
Capacitors Wv) Cl:
500 *F
C2: 50 *F
Integrated Circuits lC1 = tC2 = 114 (LM 358)
fC3: 7812 ~regulator~
REFERENCES Bradley WE, Timm CW, Gallagher J/vi, Johnson BK (1985) New method for continuous measurement of nocturnal penile tumescence. Urology XXXVL:4-9. Ferrari F, Biaggio C, Mangiafico V (1985) The dopamine autoreceptor agonist B-HT 928 mark~ly stimulated sexuai behavior in male rats. Experientia 41: 636-533.
Foreman MM, Hall IL (1987) Effects of D2 dopaminergic receptor stimulation on male rat sexual behavior. 1 Neural Transm 68:153-170. Lal 5, Ackman D, Thavundayil IX, Kiely ME, Etienne P (1984) Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects, Frog Ne~#~s~c~o~~arrnacol Bio! Psychiatry 11:235-242.
Erectogenic Drugs and Plethysmography Lal S, Larya E, Thavundayil JX, Vasavan Nair NP, Negrete J, Ackman D, Blundell P, Gardiner RJ (1987) Apomorphine-induced penile tumescence in impotent patients-preliminary finding. Prog Neoropsychopharmacol Biol Psychiatry 11:235242. Nadig PW, Ware JC, Blumoff R (1986) Non-invasive
device to produce and maintain an erection-like state. Urology XXVII :126-131. Riley Al, Riley EJ, Davies HJ (1982) A method for monitoring drug effect on male sexual response: The effect of a single dose of labetalol. Br] C/in Pharmacol14:695-700.
69
P. DANJOU,
A method
L. LACOMBLEZ,
of assessment
D. WAROT,
of the erection
AND A. J. PUECH
in man,
using
numeric
penile
plethys-
The data concerning the sensor, the electronic circuit, and the computer interfacing with an IBM PC are described. As a validation of this method, apomorphine (0.009 mg/kg) was tested in a double-blind, placebocontrolled study, carried out in healthy volunteers. Apomorphine induced an erection starting, as a mean, at the fourth minute postinjection. The treatment increased the penis volume without any other stimulation (p = O.ooOS)and potentiated the physiologic response induced by visual erotic stimulation (p = 0.0012). The limits of plethysmography are discussed in reference to rigidimetry. mography,
is presented.
Key Words:
Penile tumescence; unteer, Plethysmography
Erection; Drugs; Apomorphine;
Healthy vol-
INTRODUCTION When one studies the physiologic reactions following the administration of potentially erectogenic drugs, penile tumescence is usually assessed by analogic strip chart plethysmographs during acute administration or by self-ratings when longterm treatments are used. We have developed a low-cost, easy-to-build plethysmographic interface using a mercury strain gauge and delivering a signal digitalized by an analog to digital (A/ D) converter, allowing the continuous integration of data, and making data vectors manipulations such as averaging or zero interpolation, possible. Simultaneous to the treatment of the digitalized signal, analogic recording on paper strips was performed (Figure 1). Dopamine receptors seem to be implicated in the physiology of erection and specific agonists induce erections in animals (Ferrari et al., 1985; Foreman et al., 1987) as well as in healthy volunteers (La1 et al., 1984) and patients (La1 et al., 1987). This technique was therefore tested in a study carried out in IO healthy volunteers assessing the effects of 0.009 mg/kg of apomorphine HCI injected subcutaneously using a double-blind, placebo-controlled design.
From the Departement de Pharmacologic, Hopital de la Pitie-Salpetriere 47 Bld. de I’Hopital, 75651 Paris Cedex 13, France. Address reprint requests to: Dr. P. Danjou, Departement de Pharmacologic, Hopital de la PitieSalpetri&e, 47 Bid. de I’Hbpital, 75651 Paris Cedex 13, France. Received May 1988; revised and accepted July 1988.
61 Journal of Pharmacological Methods Q 1989 Elsevier Science Publishing
21, 61-69 (1989) Co., Inc., 6.55 Avenue of the Americas, New York, NY 1OLTlO
@l6n-~ls3.SO
~~1~
s/c FIGURE 1.
'%WL
EROTICSTIMILATION
Paper strip recording no. 3, following apomorphine
administration.
Etectogenic Drugs and Plethysmography
METHODS Erectometer Circuit and Sensor Our purpose was to build an instrument of primary screening, sensitive enough to detect small changes in the penis size, with no concern for the level of rigidity. The sensor we used was a mercury strain gauge (SEGA, France) with an internal diameter ranging from 28 to 36 mm, adapted individually to each subject. The impedance of the mercury column was about 1 &2 increasing of IO-’ fz mm-’ with the diameter changes. The circuit is shown in Figure 2. Computer tnterfacing The output of the circuit was connected to one of the 16 inputs of a 12 bits DA converter. (U-Limited, Stanford, CT). Signal was read at an approximate sampling frequency of 15 Hz. The area under curve was calculated every second (using 15 measurements) and stored on disk. The area under curve of three 20-min phases were used as dependent variable in the analysis. The SEM used in the analysis was the between-subjects SEM. Subjects Subjects were 10 male volunteers, aged 19-27 yr (mean = 23.6 yr) who were heterosexual and considered as healthy according to the medical examination, EKG, biological data (inclusive of HIV), Cattell anxiety scale, and Eysenck personality inventory. The subjects‘ sexual habits were considered to be in the normal range. Their monthly mean number of occurrences of sexual intercourse was between 2 and 20 (mean = 7.3), and their number of different sexual partners was between one and six (mean = 2.7). Subjects were fully informed of the protocol and were paid $200 for their participation. The study was approved by the local ethics committee.
PI R3
R4 FIGURE 2.
Erectometer:
schematic diagram.
63
64
P. Danjou et al. Study Design A cross-over design was used to control random variations in subject reactivity. A dose of apomorphine was compared to a placebo during two separate sessions at a l-week interval. The order of administration was balanced: five subjects received apomorphine first, and five subjects were started on placebo. All sessions were conducted between 1 P.M. and 4 P.M. Subjects were instructed to abstain from having sex the evening and the night preceding the experimental day. Apomorp~ine
Solution
A dose of 0.009 mglkg of apomorphine HCI was prepared extemporaneously and injected subcutaneously under a volume of 1 ml. The placebo was a NaCl 9% solution equally unpainful as apomorphine when injected subcutaneously. Procedure At the beginning of the session, subjects were installed in a sound proof, climatecontrolled experiment room. The subjects were recumbent and under the observation of a video camera. The plethysmographic strain gauge was placed at the base of the penis and a zero calibration was made. Subjects were instructed to remain quiet for 30 min whiJe baseline recording was initiated. Usually a decrease of penis volume was noted after the initial manipulation; if a complete detumescence was not obtained after 30 min, a IO-min mental calculation sequence was used, followed by 15 min of a new baseline recording. The baseline used for calculations was the lowest level reached by subjects. Apomorphine or placebo were then injected subcutaneously at the level of the deltoid muscle, followed by three different 20-min phases: during phase 1, subjects were resting; during phase 2, subjects underwent visual erotic stimulation. The stimuiation was composed of a series of 50 slides extracted from pornographic magazines; both series were standardized and the stimulation was equilibrated between periods. During phase 3, subjects were again left quiet. At the end of each phase, subjects were asked to give their impression (ranging zero-5) assessing penile tumescence and rigidity. Concerning penile stiffness, “2” was considered stiff enough to allow penetration with the help of a hand, and “3” without help. Subjects were asked not to touch their penis to check the stiffness, and they could not see it neither, as their pelvic area was covered with a sheet in order to allow observation of subjects through a TV camera. Statistical Analysis The area under curve was analyzed by a three-way ANOVA (subject, period, treatment) with time as a repetition factor (three levels). The overall effect of apomorphine was deducted from the treatment effect and the repetition by treatment interaction, Orthogonal decomposition of the interaction term was calculated in order to check the time-course of the effect. Between-treatment comparisons were done using t-tests for each phase when an overall effect existed. The individual vectors were averaged and plotted but not analyzed (see Figure 3). Correlations between
Erectogenic Drugs and Plethysmography
VOLTS (x10-2) 30-
5min
262624 222018 16 14 12 10 (I(I42-
phase
1
2
3
FIGURE 3. Mean erectile response following placebo (P) and apo~~hine (A). Erotic stimulation (ERS) was administered during the second of the ZO-min lasting phases.
objective (AUC) and subjective (their impression) were examined through Spearman rank correlation. RESULTS Apomorphine induced an erection in phase 1 (no stimulation) in all subjects (lo/ IO), starting as a mean at the end of the fourth minute. Plethysmographic AUC was significantly, increased in phase 1 (p = 0.~8) and in phase 2 (p = 0.0012) (Figure 4). Under both treatments, the AUC was greatly increased by the visual stimulation. The time by treatment interaction was of the first order (p = 0.0196), confirming the observation that the effect was maximum during phase 1. Self-assessed penile stiffness was increased during phase 1 (placebo: 0 Z!Z0, apomorphine: 2.44 + 0.603, p = 0.0041, phase 2 (placebo: 1.30 + 0.448, apomorphine: 3.700 rt 0.395,~ = 0.0008), and during phase 3 (placebo: 0.3 + 0.152, apomorphine: 1.5 z!z 0.477, p = 0.035). Seif-assessed penile tumescence followed the same changes and was increased during phase I (placebo: 0.2 rf: 0.113, apomorphine: 2.778 +- 0.618, p = 0.003) and
65
66
P. Danjou et al.
AUC (volt 8. seconds) xl00 300
*
T * p(O-01
250
200
* * 150
100
i
50
-
0
phase
1
FIGURE 4. Area under curve of plethysmographic subjects SEM, during the three phases.
2
3 data, expressed in mean and between-
phase 2 (placebo: 2.6 + 0.452, apomorphine: 3.80 2 0.388, p = 0.059) but was not modified during phase 3 (placebo: 1.1 2 0.314, apomorphine: 1.9 s 0.504, p = 0.198). During phase 1, when the greatest changes were observed, self-assessed tumescence and self-assessed stiffness were highly correlated (r = 0.948, p = 0.004; see Figure 5). Both penile tumescence and penile stiffness showed a trend to be correlated to the AUC (respectively, r = 0.59, p = 0.073, and r = 0.62, p = 0.064) but failed to reach the 5*X, significance threshold.
--
.
-.
_
TUMESCENCE
. . -. ... -
- -
r
C
/-
l-
--
- - --
A.U.C.
8
68
P. Danjou et al.
DISCUSSION The results demonstrate that numeric plethysmography allows one to quantify precisely data for which analogic paper recorders would have either required a manual planimetric integration or an electronic capacitor integrating device. The major problem using a size-adapted strain gauge was the variability intergauge that was statistically included in the subject effect, as the same gauge was used during the two periods of each subjects. In case of parallel groups, an individual calibration session would be recommended in order to express results as a function of the maximal vacuum (Nadig et al., 1986) or vibrator-induced erection (Riley et al., 1982). The estimation of an erection level by the volume changes of the penis is possible as long as the erection is submaximal. At high levels of erection, volume changes would be negligible and only rigidity would progress. In the case of our data, it was obvious that without mechanical maneuvers the subjects could not distinguish stiffness from tumescence as both parameters were intercorrelated. Subjects seem unaware of their penile stiffness level at low or medium level of sexual arousal, and a rigidimeter could be helpful to study that parameter. The major obstacle using a rigidimeter (Bradley et al., 1985) is not only the high cost of this device, but also the fact that a mechanical stimulation might interfere with the observed data. The results obtained are consistent with those of Lal et al. (1984) and confirm the erectogenic activity of apomorphine in humans. COMPONENTS
LIST
Resistors (t/4 w):
Rl : 2.2 K fz R4: 1 fz R7: 10 K Q
R2: 1OOKfZ R5: 2.2 K Sz R8: 10 K fz
RZ%:-IKft R6: I KfZ
Capacitors Wv) Cl:
500 *F
C2: 50 *F
Integrated Circuits lC1 = tC2 = 114 (LM 358)
fC3: 7812 ~regulator~
REFERENCES Bradley WE, Timm CW, Gallagher J/vi, Johnson BK (1985) New method for continuous measurement of nocturnal penile tumescence. Urology XXXVL:4-9. Ferrari F, Biaggio C, Mangiafico V (1985) The dopamine autoreceptor agonist B-HT 928 mark~ly stimulated sexuai behavior in male rats. Experientia 41: 636-533.
Foreman MM, Hall IL (1987) Effects of D2 dopaminergic receptor stimulation on male rat sexual behavior. 1 Neural Transm 68:153-170. Lal 5, Ackman D, Thavundayil IX, Kiely ME, Etienne P (1984) Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects, Frog Ne~#~s~c~o~~arrnacol Bio! Psychiatry 11:235-242.
Erectogenic Drugs and Plethysmography Lal S, Larya E, Thavundayil JX, Vasavan Nair NP, Negrete J, Ackman D, Blundell P, Gardiner RJ (1987) Apomorphine-induced penile tumescence in impotent patients-preliminary finding. Prog Neoropsychopharmacol Biol Psychiatry 11:235242. Nadig PW, Ware JC, Blumoff R (1986) Non-invasive
device to produce and maintain an erection-like state. Urology XXVII :126-131. Riley Al, Riley EJ, Davies HJ (1982) A method for monitoring drug effect on male sexual response: The effect of a single dose of labetalol. Br] C/in Pharmacol14:695-700.
69