A D 0 N I S 030652519100013L
Br. J. clin. Pharmac. (1991), 31, 93-97
Effects of granisetron and lorazepam, alone and in combination, on the EEG of human volunteers CHRISTOPHER G. G. LINK, TERRY J. LEIGH & GRAEME L. FELL Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Coldharbour Road, Harlow, Essex CM19 5AD
1 The EEG effects of granisetron,
a potent and selective 5-HT3 receptor antagonist (160 ,ug kg-'), and lorazepam (2.5 mg) were examined in 12 healthy male volunteers. 2 The results indicated that lorazepam had a marked effect on the CNS, significantly increasing power in the slow (1-7 Hz) and fast (13-20 Hz; 21-30 Hz) wavebands whilst reducing power in the mid range (8-12 Hz). 3 In contrast there was no demonstrable effect of granisetron on the EEG at the dose tested, and no evidence of a pharmacodynamic interaction between the two compounds.
Keywords granisetron pharmaco EEG lorazepam Introduction A number of compounds are used alone and in combination to treat emesis associated with cytostatic therapy. Metoclopramide is currently widely in use as an antiemetic. Evidence has accumulated suggesting that the action of high dose metoclopramide is related to antagonism of 5-HT3 receptors at peripheral and possibly central sites (Miner & Sanger, 1986). The recent discovery of 5-HT3 receptor antagonists has led to the demonstration, in animal models, of the importance of 5-HT3 receptor antagonism in cisplatin induced emesis (Miner & Sanger, 1986). Granisetron (BRL 43694) is a novel compound intended for the prevention of nausea and vomiting induced by cytostatic therapy. Structurally, granisetron is one of a series of azabicyclic compounds. It is a potent and selective 5-HT3 receptor antagonist which lacks dopamine receptor antagonist activity and is therefore expected to be better tolerated than metoclopramide (Fake et al., 1987). Often anti-emetics need to be prescribed concomitantly with psychotropic medications (most likely a benzodiazepine or neuroleptic). The commonest reasons for this concomitant treatment include psychological distress, sleep disorders and adjuvant therapy for refractory nausea and vomiting. It is therefore possible that clinicians may wish to prescribe granisetron concomitantly with e.g. lorazepam. The impact of these compounds, alone and in combination, on the CNS needs to be investigated. Quantitative EEG methods are commonly used to identify the effects of drugs on the CNS (Irwin, 1982). The quantitative EEG may provide information about the magnitude and
nature of any drug effect, its time course, doseresponse relationship and possibly its therapeutic action. Most commonly the EEG signal is quantified into frequency bands and drug effects are defined as those EEG changes from pre drug that differ statistically from the changes after placebo. EEG profiles have been established for several classes of drug and by comparing patterns of variables the therapeutic action of a novel chemical entity may be determined (Fink 1969, 1978). The Spectral Difference Index, SDI is a single EEG variable, useful across individuals and drug classes, which has been shown to be a sensitive variable for identifying an EEG change (Irwin, 1982). It is a measure of the overall difference between two EEG Spectra and if an effect is shown, statistical analyses of other variables may be used to describe the pattern. The objectives of the present study were to assess the EEG effects of granisetron and lorazepam and to assess any interaction between the two compounds.
Methods
This was a randomised, single blind, crossover, placebo controlled study in 12 male volunteers (mean age ± s.d., 32.0 ± 9.7 years, range 19-46 years) who had passed a comprehensive medical examination, including medical history, clinical examination, electrocardiography, haematology, clinical chemistry and urinalysis. Volunteers gave informed consent and the study was approved by the Beecham Ethics Committee. With the exception of one volunteer, who
Correspondence: Dr C. G. G. Link, Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Coldharbour Road, Harlow, Essex CM19 5AD
93
94
C. G. G. Link, T. J. Leigh & G. L. Fell
received 2g paracetamol on one study day, volunteers abstained from medications for 2 weeks before the start of the study until its completion. In addition, subjects were required to abstain from alcohol for 24 h before dosing until 24 h after dosing on each study day. Each volunteer attended the unit at 08.30 h on four separate occasions, a minimum of 1 week apart, and received an oral capsule followed 30 min later by an intravenous infusion over 3 min. The four study sessions were as follows:
Capsule Placebo Placebo Lorazepam (2.5 mg) Lorazepam (2.5 mg)
Infusion Placebo Granisetron (160 ,ug kg-') Placebo Granisetron (160 pg kg-')
The pharmaco-EEG was measured at -1 h (pre-dose), +1 h, +3 h, +4 h, +6 h and at +24 h (times relative to start of infusion) with the volunteers lying semi-supine with eyes closed. Forty 10 s recordings of EEG activity were recorded from electrode placements FP1-FP2 and 02-A2 of the International 10-20 system. The FP1-FP2 recording was used to identify non-cerebral activity (artefact) for exclusion from the analysis. These EEG channels were selected for analysis as they are the standards classically used in EEG research of this type. The 02-A2 signal was amplified using an HDX-82 Oxford preamplifier to provide a gain of 60 dB and further amplified with a Fylde FE-265-1A variable gain amplifier to produce a total gain of 94 dB. The signal was then filtered using a Kemo VBF-17B variable filter set to give a bandpass of 1-40 Hz. Following amplification and filtering, the signal was digitized using a CED 1401 signal processor and stored with the FP1-FP2 signal on an IBM XT personal computer. The recordings were later replayed sequentially and the first 30 artefact-free samples selected by an experienced EEG technician. Each sample was subjected to a Fast Fourier Transform using the CED 1401 signal processor which produced a power spectrum. The power spectra obtained from the 30 samples were then averaged to give an average power spectrum in 1 Hz bands up to 30 Hz. An analysis of the EEG data was performed by calculating a summary measure of EEG change, the spectral difference index (SDI), as described by Irwin (1982). This is a single EEG measure used to determine whether or not a significant change in EEG has occurred post-dose. The SDI was calculated for each post-treatment power spectrum relative to the pre-dose spectrum in the same session and then subjected to statistical analysis. If the SDI was statistically significant then similar analyses of changes in percentage power within each of the frequency bands 1 Hz to 7 Hz, 8 Hz to 12 Hz, 13 Hz to 20 Hz and 21 Hz to 30 Hz were carried out in order to examine the magnitudes and directions of any significant differences indicated by the SDI analysis.
Statistical analysis The data were subjected to a repeated-measures analysis of variance which enabled evaluation of six
planned significance tests. The first test compared granisetron with placebo, the second lorazepam with placebo and the third evaluated whether there was a significant interaction effect between granisetron and lorazepam. Tests 4 and 5 evaluated whether the time profiles of granisetron and lorazepam were significantly different from placebo. Test 6 examined whether there was a drug interaction effect which varied over time. Where appropriate, degrees of freedom for F tests were adjusted using the Greenhouse-Geisser correction (Greenhouse & Geisser, 1959). Hypothesis testing was performed at the 5% significance level in accordance with usual practice. Analyses were carried out using the procedure GLM of the SAS statistical package, version 5.16, on a DEC VAX 8550 computer. Results
Twelve male subjects (mean age ± s.d. 32.0 ± 9.7 years) completed the study. Granisetron 160 jxg kg-1 was well tolerated, whilst lorazepam 2.5 mg produced the expected profile of side effects. The adverse events seen during the study are detailed in Table 1. Table 2 shows the mean SDI values by treatment and time. The figures represent the magnitude of the spectral difference detected when compared with the predose value. The reduced numbers for analysis were due to technical problems. Lorazepam had significantly higher SDI values than placebo (main effect, P < 0.001; placebo-lorazepam time profile difference, P = 0.003). There were no statistically significant granisetron or treatment interaction effects. Since a statistically significant effect was shown with lorazepam using the SDI, it was appropriate to carry out further statistical analyses of changes in percentage power within discrete frequency bands to determine where the overall changes had occurred. Lorazepam produced a statistically significant increase in percentage power in the 1 Hz to 7 Hz band (main effect, P = 0.003; placebo-lorazepam time profile difference, P = 0.022, Table 3), the 13 Hz to 20 Hz band (main effect, P = 0.002, Table 4) and the 21 Hz to 30 Hz band (placebo-lorazepam time profile differences P = 0.013, Table 5). It showed a statistically significant decrease in percentage power in the 8 Hz to 12 Hz band (main effect, P < 0.001; placebo-lorazepam time profile difference, P = 0.005, Table 6). Discussion It has recently been established that 5-HT3 receptors are present in limbic and cortical areas of the brain (Barnes et al., 1988). These areas are thought to be involved in the control of mood, emotion, memory and reward and there is experimental evidence that in animal models of anxiety, 5-HT3 receptor antagonists like granisetron are anxiolytic (Costall et al., 1988). However in this study the data did not show an effect of granisetron on the pharmaco-EEG at a dose of 160 p,g kg-'. This may be because of the dose used, and requires further study of the dose-response relationship.
Effect of granisetron and lorazepam on EEG
95
Table 1 Treatment emergent symptoms by body system
Body system
Event
Placebo (n = 12) mild mod sev
Body as a whole
Special
mild
o
o
0
0
0
1(8)
o
2
0 0
1(9) 0
0
Chills and fever
1(8) 0
0
1
1
0
5
0
0
0
0
0
0
0
0
0
0
0
Constipation Rectal bleeding
0 0
0 0
0
2(2,8) 0
Nausea
0
Flatulence
0
0 0
0 0
Diarrhoea
0 0
0 0
Blurred vision
0
Vision disorders
Hiccup
0
mod
4(3,8,9,10) 2(4,7) 0 1(7) 0 0
sev
0
0
mild
mod
4(8,9,10,12) 1(7) 0 1(3)
sev
0 0
0
0
0
0
2
0
4
2
0
0
1(2)
0
0
0
1(10)
0
0
1
0
0
0
1
1(6) 1(11) 0
0
0
0
2(6,8)
0
0
0
0
0
0
0
0
0
0 0
0
0
0
0
0
0
0 0
0
0
1(6) 0 1(8) 0 4
0
0
0 0 0 0
0
0
0
0
0
0
2(9,10)
0
0 0
1(1) 1(8) 0
0
4
2
0
0
1(6) 1
0
0
1(8)
0
0
1(7)
0
0
3(8,9,11)
0
0
0
0
0
0
0
0
1
0
0
1(9) 1
0
0
1(6) 2
0
2(9,11) 5
Incoordination
0
0
0
0
0
0
1(5)
0
0
1(8)
Ataxia
0
0
0
0
0
0
Totals
Nervous
sev
0 0
Totals senses
mod
0 1(9)
Totals Digestive system
mild
Asthenia Headache
Totals
Respiratory system
Treatment Number of volunteers dosed and severity Granisetron + Lorazepam + Lorazepam + placebo (n = 12) placebo (n = 12) granisetron (n = 12)
0 0
0
0
system
7(1,6,8,9, 2(5,7)
0
10,11,12)
Totals
7(3,4,6,7,8, 2(1,9)
0
10,11)
Amnesia
0
0
0
0
0
0
0
0
0
1(7)
0
0
Confusion
0
0
0
0
0
0
2(6,7)
1(1)
0
4(1,6,7,9)
0
0
Dizziness
0
0
0
0
0
0
Somnolence
0
0
0
2(6,8)
0
0
Emotional lability 0
0
0
0
0
0
1(6)
0
0
0
0
0
Paresthesia
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
0
1(6) 20
12
1
22
12
0
5(5,6,8,9, 2(1,7) 12)
0
5(2,6,8,10, 3(1,7,9) 11)
3(8,9,10) 7(1,2, 4,5,6, 7,11)
1(3)
4(6,8,10, 5(1,3,5, 11) 7,9)
0
0
Note: The figures in each column indicate the total number of volunteers experiencing that event. The specific volunteers are detailed in brackets.
96
C. G. G. Link, T. J. Leigh & G. L. Fell
Table 2 Mean spectral difference index values by treatment and time
Granisetron
Lorazepam
Granisetron + lorazepam
13 Hz to 20 Hz (%)
Time in relation to start of infusion (h)
Treatment
Placebo
Table 4 EEG: Group mean values for change in percentage power relative to pretreatment EEG
4
24
6
1
3
Mean s.d. n
0.77 0.55 11
1.19 0.77 11
0.99 0.58 10
1.12 0.91 10
0.89 0.38 10
Mean s.d. n
0.73 0.41 11
0.65 0.23 10
1.07 0.50 10
0.88 0.45 10
Mean s.d. n
2.49 1.32 10
2.90 0.88 8
2.93 0.70 7
Mean s.d. n
2.20 1.13 10
2.21 1.22 9
2.15 1.11 9
Time in relation to start of infusion (h) 24 4 6 3 1
Treatment
0.83 0.65 9
Mean s.d. n
0.00 0.02 11
0.01 -0.01 0.02 0.02 10 11
0.00 0.02 10
Granisetron
2.53 0.98 8
1.39 1.11 8
Mean s.d. n
0.00 0.02 11
0.00 -0.01 0.02 0.02 10 10
0.00 -0.01 0.03 0.01 9 10
Lorazepam
2.01 0.72 9
0.85 0.36 9
Mean s.d. n
0.07 0.05 10
0.06 0.06 8
0.05 0.08 7
0.08 0.05 8
0.04 0.04 8
Granisetron + lorazepam
Mean s.d. n
0.04 0.07 10
0.04 0.04 9
0.02 0.03 9
0.04 0.03 9
0.00 0.02 9
Statistical significance: Effect of granisetron Effect oflorazepam Interaction between granisetron and lorazepam Significant treatment time profile differences: Lorazepam vs placebo
n_
A
An
Br. J. clin. Pharmac. (1991), 31, 93-97
Effects of granisetron and lorazepam, alone and in combination, on the EEG of human volunteers CHRISTOPHER G. G. LINK, TERRY J. LEIGH & GRAEME L. FELL Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Coldharbour Road, Harlow, Essex CM19 5AD
1 The EEG effects of granisetron,
a potent and selective 5-HT3 receptor antagonist (160 ,ug kg-'), and lorazepam (2.5 mg) were examined in 12 healthy male volunteers. 2 The results indicated that lorazepam had a marked effect on the CNS, significantly increasing power in the slow (1-7 Hz) and fast (13-20 Hz; 21-30 Hz) wavebands whilst reducing power in the mid range (8-12 Hz). 3 In contrast there was no demonstrable effect of granisetron on the EEG at the dose tested, and no evidence of a pharmacodynamic interaction between the two compounds.
Keywords granisetron pharmaco EEG lorazepam Introduction A number of compounds are used alone and in combination to treat emesis associated with cytostatic therapy. Metoclopramide is currently widely in use as an antiemetic. Evidence has accumulated suggesting that the action of high dose metoclopramide is related to antagonism of 5-HT3 receptors at peripheral and possibly central sites (Miner & Sanger, 1986). The recent discovery of 5-HT3 receptor antagonists has led to the demonstration, in animal models, of the importance of 5-HT3 receptor antagonism in cisplatin induced emesis (Miner & Sanger, 1986). Granisetron (BRL 43694) is a novel compound intended for the prevention of nausea and vomiting induced by cytostatic therapy. Structurally, granisetron is one of a series of azabicyclic compounds. It is a potent and selective 5-HT3 receptor antagonist which lacks dopamine receptor antagonist activity and is therefore expected to be better tolerated than metoclopramide (Fake et al., 1987). Often anti-emetics need to be prescribed concomitantly with psychotropic medications (most likely a benzodiazepine or neuroleptic). The commonest reasons for this concomitant treatment include psychological distress, sleep disorders and adjuvant therapy for refractory nausea and vomiting. It is therefore possible that clinicians may wish to prescribe granisetron concomitantly with e.g. lorazepam. The impact of these compounds, alone and in combination, on the CNS needs to be investigated. Quantitative EEG methods are commonly used to identify the effects of drugs on the CNS (Irwin, 1982). The quantitative EEG may provide information about the magnitude and
nature of any drug effect, its time course, doseresponse relationship and possibly its therapeutic action. Most commonly the EEG signal is quantified into frequency bands and drug effects are defined as those EEG changes from pre drug that differ statistically from the changes after placebo. EEG profiles have been established for several classes of drug and by comparing patterns of variables the therapeutic action of a novel chemical entity may be determined (Fink 1969, 1978). The Spectral Difference Index, SDI is a single EEG variable, useful across individuals and drug classes, which has been shown to be a sensitive variable for identifying an EEG change (Irwin, 1982). It is a measure of the overall difference between two EEG Spectra and if an effect is shown, statistical analyses of other variables may be used to describe the pattern. The objectives of the present study were to assess the EEG effects of granisetron and lorazepam and to assess any interaction between the two compounds.
Methods
This was a randomised, single blind, crossover, placebo controlled study in 12 male volunteers (mean age ± s.d., 32.0 ± 9.7 years, range 19-46 years) who had passed a comprehensive medical examination, including medical history, clinical examination, electrocardiography, haematology, clinical chemistry and urinalysis. Volunteers gave informed consent and the study was approved by the Beecham Ethics Committee. With the exception of one volunteer, who
Correspondence: Dr C. G. G. Link, Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Medicinal Research Centre, Coldharbour Road, Harlow, Essex CM19 5AD
93
94
C. G. G. Link, T. J. Leigh & G. L. Fell
received 2g paracetamol on one study day, volunteers abstained from medications for 2 weeks before the start of the study until its completion. In addition, subjects were required to abstain from alcohol for 24 h before dosing until 24 h after dosing on each study day. Each volunteer attended the unit at 08.30 h on four separate occasions, a minimum of 1 week apart, and received an oral capsule followed 30 min later by an intravenous infusion over 3 min. The four study sessions were as follows:
Capsule Placebo Placebo Lorazepam (2.5 mg) Lorazepam (2.5 mg)
Infusion Placebo Granisetron (160 ,ug kg-') Placebo Granisetron (160 pg kg-')
The pharmaco-EEG was measured at -1 h (pre-dose), +1 h, +3 h, +4 h, +6 h and at +24 h (times relative to start of infusion) with the volunteers lying semi-supine with eyes closed. Forty 10 s recordings of EEG activity were recorded from electrode placements FP1-FP2 and 02-A2 of the International 10-20 system. The FP1-FP2 recording was used to identify non-cerebral activity (artefact) for exclusion from the analysis. These EEG channels were selected for analysis as they are the standards classically used in EEG research of this type. The 02-A2 signal was amplified using an HDX-82 Oxford preamplifier to provide a gain of 60 dB and further amplified with a Fylde FE-265-1A variable gain amplifier to produce a total gain of 94 dB. The signal was then filtered using a Kemo VBF-17B variable filter set to give a bandpass of 1-40 Hz. Following amplification and filtering, the signal was digitized using a CED 1401 signal processor and stored with the FP1-FP2 signal on an IBM XT personal computer. The recordings were later replayed sequentially and the first 30 artefact-free samples selected by an experienced EEG technician. Each sample was subjected to a Fast Fourier Transform using the CED 1401 signal processor which produced a power spectrum. The power spectra obtained from the 30 samples were then averaged to give an average power spectrum in 1 Hz bands up to 30 Hz. An analysis of the EEG data was performed by calculating a summary measure of EEG change, the spectral difference index (SDI), as described by Irwin (1982). This is a single EEG measure used to determine whether or not a significant change in EEG has occurred post-dose. The SDI was calculated for each post-treatment power spectrum relative to the pre-dose spectrum in the same session and then subjected to statistical analysis. If the SDI was statistically significant then similar analyses of changes in percentage power within each of the frequency bands 1 Hz to 7 Hz, 8 Hz to 12 Hz, 13 Hz to 20 Hz and 21 Hz to 30 Hz were carried out in order to examine the magnitudes and directions of any significant differences indicated by the SDI analysis.
Statistical analysis The data were subjected to a repeated-measures analysis of variance which enabled evaluation of six
planned significance tests. The first test compared granisetron with placebo, the second lorazepam with placebo and the third evaluated whether there was a significant interaction effect between granisetron and lorazepam. Tests 4 and 5 evaluated whether the time profiles of granisetron and lorazepam were significantly different from placebo. Test 6 examined whether there was a drug interaction effect which varied over time. Where appropriate, degrees of freedom for F tests were adjusted using the Greenhouse-Geisser correction (Greenhouse & Geisser, 1959). Hypothesis testing was performed at the 5% significance level in accordance with usual practice. Analyses were carried out using the procedure GLM of the SAS statistical package, version 5.16, on a DEC VAX 8550 computer. Results
Twelve male subjects (mean age ± s.d. 32.0 ± 9.7 years) completed the study. Granisetron 160 jxg kg-1 was well tolerated, whilst lorazepam 2.5 mg produced the expected profile of side effects. The adverse events seen during the study are detailed in Table 1. Table 2 shows the mean SDI values by treatment and time. The figures represent the magnitude of the spectral difference detected when compared with the predose value. The reduced numbers for analysis were due to technical problems. Lorazepam had significantly higher SDI values than placebo (main effect, P < 0.001; placebo-lorazepam time profile difference, P = 0.003). There were no statistically significant granisetron or treatment interaction effects. Since a statistically significant effect was shown with lorazepam using the SDI, it was appropriate to carry out further statistical analyses of changes in percentage power within discrete frequency bands to determine where the overall changes had occurred. Lorazepam produced a statistically significant increase in percentage power in the 1 Hz to 7 Hz band (main effect, P = 0.003; placebo-lorazepam time profile difference, P = 0.022, Table 3), the 13 Hz to 20 Hz band (main effect, P = 0.002, Table 4) and the 21 Hz to 30 Hz band (placebo-lorazepam time profile differences P = 0.013, Table 5). It showed a statistically significant decrease in percentage power in the 8 Hz to 12 Hz band (main effect, P < 0.001; placebo-lorazepam time profile difference, P = 0.005, Table 6). Discussion It has recently been established that 5-HT3 receptors are present in limbic and cortical areas of the brain (Barnes et al., 1988). These areas are thought to be involved in the control of mood, emotion, memory and reward and there is experimental evidence that in animal models of anxiety, 5-HT3 receptor antagonists like granisetron are anxiolytic (Costall et al., 1988). However in this study the data did not show an effect of granisetron on the pharmaco-EEG at a dose of 160 p,g kg-'. This may be because of the dose used, and requires further study of the dose-response relationship.
Effect of granisetron and lorazepam on EEG
95
Table 1 Treatment emergent symptoms by body system
Body system
Event
Placebo (n = 12) mild mod sev
Body as a whole
Special
mild
o
o
0
0
0
1(8)
o
2
0 0
1(9) 0
0
Chills and fever
1(8) 0
0
1
1
0
5
0
0
0
0
0
0
0
0
0
0
0
Constipation Rectal bleeding
0 0
0 0
0
2(2,8) 0
Nausea
0
Flatulence
0
0 0
0 0
Diarrhoea
0 0
0 0
Blurred vision
0
Vision disorders
Hiccup
0
mod
4(3,8,9,10) 2(4,7) 0 1(7) 0 0
sev
0
0
mild
mod
4(8,9,10,12) 1(7) 0 1(3)
sev
0 0
0
0
0
0
2
0
4
2
0
0
1(2)
0
0
0
1(10)
0
0
1
0
0
0
1
1(6) 1(11) 0
0
0
0
2(6,8)
0
0
0
0
0
0
0
0
0
0 0
0
0
0
0
0
0
0 0
0
0
1(6) 0 1(8) 0 4
0
0
0 0 0 0
0
0
0
0
0
0
2(9,10)
0
0 0
1(1) 1(8) 0
0
4
2
0
0
1(6) 1
0
0
1(8)
0
0
1(7)
0
0
3(8,9,11)
0
0
0
0
0
0
0
0
1
0
0
1(9) 1
0
0
1(6) 2
0
2(9,11) 5
Incoordination
0
0
0
0
0
0
1(5)
0
0
1(8)
Ataxia
0
0
0
0
0
0
Totals
Nervous
sev
0 0
Totals senses
mod
0 1(9)
Totals Digestive system
mild
Asthenia Headache
Totals
Respiratory system
Treatment Number of volunteers dosed and severity Granisetron + Lorazepam + Lorazepam + placebo (n = 12) placebo (n = 12) granisetron (n = 12)
0 0
0
0
system
7(1,6,8,9, 2(5,7)
0
10,11,12)
Totals
7(3,4,6,7,8, 2(1,9)
0
10,11)
Amnesia
0
0
0
0
0
0
0
0
0
1(7)
0
0
Confusion
0
0
0
0
0
0
2(6,7)
1(1)
0
4(1,6,7,9)
0
0
Dizziness
0
0
0
0
0
0
Somnolence
0
0
0
2(6,8)
0
0
Emotional lability 0
0
0
0
0
0
1(6)
0
0
0
0
0
Paresthesia
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
0
1(6) 20
12
1
22
12
0
5(5,6,8,9, 2(1,7) 12)
0
5(2,6,8,10, 3(1,7,9) 11)
3(8,9,10) 7(1,2, 4,5,6, 7,11)
1(3)
4(6,8,10, 5(1,3,5, 11) 7,9)
0
0
Note: The figures in each column indicate the total number of volunteers experiencing that event. The specific volunteers are detailed in brackets.
96
C. G. G. Link, T. J. Leigh & G. L. Fell
Table 2 Mean spectral difference index values by treatment and time
Granisetron
Lorazepam
Granisetron + lorazepam
13 Hz to 20 Hz (%)
Time in relation to start of infusion (h)
Treatment
Placebo
Table 4 EEG: Group mean values for change in percentage power relative to pretreatment EEG
4
24
6
1
3
Mean s.d. n
0.77 0.55 11
1.19 0.77 11
0.99 0.58 10
1.12 0.91 10
0.89 0.38 10
Mean s.d. n
0.73 0.41 11
0.65 0.23 10
1.07 0.50 10
0.88 0.45 10
Mean s.d. n
2.49 1.32 10
2.90 0.88 8
2.93 0.70 7
Mean s.d. n
2.20 1.13 10
2.21 1.22 9
2.15 1.11 9
Time in relation to start of infusion (h) 24 4 6 3 1
Treatment
0.83 0.65 9
Mean s.d. n
0.00 0.02 11
0.01 -0.01 0.02 0.02 10 11
0.00 0.02 10
Granisetron
2.53 0.98 8
1.39 1.11 8
Mean s.d. n
0.00 0.02 11
0.00 -0.01 0.02 0.02 10 10
0.00 -0.01 0.03 0.01 9 10
Lorazepam
2.01 0.72 9
0.85 0.36 9
Mean s.d. n
0.07 0.05 10
0.06 0.06 8
0.05 0.08 7
0.08 0.05 8
0.04 0.04 8
Granisetron + lorazepam
Mean s.d. n
0.04 0.07 10
0.04 0.04 9
0.02 0.03 9
0.04 0.03 9
0.00 0.02 9
Statistical significance: Effect of granisetron Effect oflorazepam Interaction between granisetron and lorazepam Significant treatment time profile differences: Lorazepam vs placebo
n_
A
An
