Acta Ncurol. Scandinav. 56, 17-28, 1977
Department of Neurology, University Hospital, Uppsala, Sweden.
A COMPARISON B E T W E E N PLACEBO, PIZOTIFEN AND
l-ISOPROPYL-3-HYDROXY-5-SEMICARBAZONO-6-OXO-2.3.5.6TETRAHYDROINDOL ( DIVASCAN @) I N MIGRAINE PROPHYLAXIS
P. 0. OSTERMAN
ABSTRACT
The effects and side-effects in migraine prophylaxis of placebo,
Divascan @ (1-isopropylnoradrcnochrome-5-monosemicarbazone) and
pizotifen were compared in a doublc-blind cross-over study. The dosage
was for Divascan 15 mg a day and for pizotifen 3 mg a day. Data from
the last 6 weeks of each test period of 8 weeks were used to assess the
effect of the treatment. Thirty patients entered the trial. Data from
28 patients treated with placebo and Divascan and 27 patients treated
with pizotifen were used for final evaluation. Pizotifen significantly
rcduced the number of migraine attacks, headache index and the consumption of crgotaminc. Divascan also secmed to have effcct. The consumption of ergotamine was reduced compared with placebo and there
was a reduction, although not significant, of headache frequency and
headache index. Pizotifen gave significantly larger reduction i n headache frequcncy and headache index than Divascan and significantly
more patients stated a preference for pizotifen compared with Divascan.
A good or very good effect was reported by 11 per cent of the patients
on placebo, 39 per cent on Divascan and 70 per cent on pizotifen.
Pizotifen had frcquent side-effects, mainly drowsiness and weight gain,
whereas Divascan in this respect did not differ from placebo. Physical
examinations and laboratory investigations did not show any significant changes, apart from weight gain.
Several different kinds of drugs, such as serotonin antagonists, gestagens, adrenergic beta-receptor blocking agents and clonidine have been
used in the prophylactic treatment of migraine. The serotonin antagonist pizotifen (Sandomigrin @) has been extensively investigated
during the last 10 years and is probably one of the most effective of the
currently used prophylactic remedies for migraine (Sicuteri et al. 1967,
Graham 1968). Its usefulness, however, is reduced by frequent sideeffects, mainly drowsiness and weight gain.
Divascan @ ( l-isopropylnoradrenochrome-5-monosemicarbazone) is
2
ACTA NEUROL. SCAND.
56, 1
a derivative of adrenochrome. It is a serotonin antagonist and also
decreases capillary permeability. Divascan has been tested as a prophylactic agent in migraine in several hundreds of patients (Folesky 1975b).
Divascan has been reported to have good effect and no serious sideeffects.
The present double-blind cross-over study was undertaken in order
to compare the effects and side-effects of placebo, Divascan and
pizotifen in migraine prophylaxis.
MATERIAL AND METHODS
Patients
All patients who attended the Department of Neurology i n Uppsala f o r migraine
from August 1975 to January 1976 were examined by the author. Those who were
healthy and fulfilled t h e criteria given below were included i n t h e study. Thc
patients were treated on a n ambulatory basis.
The material comprised 30 patients, 9 men and 21 women, aged 23-49 years
(mean 37). The mean duration of migraine was 20 ycars (range 4-34). I n 13
patients prophylactic drugs had not been tried previously. Apart from migraine
the'paticnts were healthy and none was pregnant. Five of the women had been
taking oral contraceptives for several years and this medication was not changed
during the investigation.
All the patients had a t least 2-3 migraine attacks per month. The diagnosis and
classification of migraine was based on accepted criteria (Ad hoc committee on
classification of headache 1962). Of the 30 patients 4 had classic migraine and 26
common migraine.
One man with common migraine claimed that the capsules (placebo and pizotifen)
gave abdominal discomfort and he had to be excluded. One woman with classic
migraine was excluded because of unreliable records. Because of unpleasant sideeffects one man with common migraine interrupted treatment with pizotifen. Thus,
27 patients (10 i n group I, 8 i n group 11, 9 i n group 111, see below) who were treated
with placebo, Divascan and pizotifen and one more patient (group 11) who was
treated with only placebo and Divascan remained for final evaluation.
Methods
The patients were randomly divided into three equal-sized groups. They were
givcn placcbo, Divascan and pizotifen according to t h e following alternatives :
Group I :
Group 11:
Group 111:
Divascan - placebo - pizotifen
Pizotifen - Divascan placebo
Placebo - pizotifen - Divascan
-
Each drug was given f o r 8 weeks. Accordingly, the total period of treatment
amounted to 24 weeks f o r each patient.
Divascan (l-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-2.3.5.6.-tetrahydroindol)
is a fine-cristalline powder of brick-red colour, odourless and tasteless. Like
serotonin i t is a n indol derivative. I n studies carried out on various isolated organs
19
from different animals Divascan inhibits the action of serotonin (Rietftlinp 1975).
Divascan rcduces the increase in capillary permeability caused by serotonin.
bradykinin and histamin (Reichel et al. 1975, Eerrmann h Kobulinski 1975).
Divascan is also considered to have a hemostyptic effect. This has been explained
by an increascd caplllary resistance, decmased capillary permeability and fragility
and stimulation of the viscous metamorphosis of thrombocytes with increased
liberation of platlet factors that activate coagulation and act upon the vessels
(Polesky 1975 a). Divascan seems to have a very low toxicity.
Placebo, Divascan and pirotifen were administered in capsules of identical appearance. The capsules were delivercd by LIPke OY, Finland. Each capsule contained
placebo or 2.5 mg Divascan or 0.5 mg pizotifen. A dosage schedule, which followed
the recommendations by Sandoz for pirotifen, was used for the first 11 days of each
test period. The initial dose w a s 1 capsule In the evening. The dose was increased by
1 capsule every second day so that the maintenance dose, 2 capsules 3 times daily,
was reached on day 11. Because of side-effects a11 patients could not .keep to this
dosage schedule. Two patients took &5 capsules of Divascan and 4 patients 9-5
capsules of pizotifen during the last 6 weeks of the test periods. All were allowed
to take their usual attack-aborting drugs as rcquired for attacks of headache.
Before the investigation was started the patients were informed that two different
kinds of active drugs and placebo would be tested. The patients were instructed to
keep a daily record of the occurrence of headache, the duration and severity of the
attacks, and the consumption of ergotamine and analgesics. The attacks were
graded according to intensity by the patlents themselves on an arbitrary 3-point
scale (1 = slight, 2 = moderate, 3 = severe) and were totalled for each test period
so that a “headache index” was obtained (Graham 1968).
CIinical and Laboratory Investigations
All patlents were seen at the out-patient clinic every fourth week. On each
occasion the blood pressure was recorded in the supine and erect position and the
following tests were carried out : ESR, hemoglohin, WBC, ASAT. ALAT. serum
creatinine and routine urine analyses. Before the start of the trial and after each
test period of 8 weeks a physical examination was performed and ECG and body
weight was registered. A neurological examination was made at the beginning of the
trial.
Evaluation of Data
, Only data from the last 6 weeks of each test period of 8 weeks were used for
assessing the effect of the treatment. The first 2 weeks served as a wash-out period
for the preceding drug and also made possible a slow increase of the dosage of the
drugs up to maintenance dosages.
The following criteria were used for assessing the therapeutic effect: 1. Data
registered by the patient on frequency, duration and intensity of the migraine
attacks and consumption of ergotamine. 2. the patient’s preference for medication
and 3. an overall evaluation of the treatment made by the patient in the presence
of the investigator after each test period.
Analysis of variance and the chi-square test with continuity correction was used
for the statistical calculations.
2’
RESULTS
Individual data are given in the Appendix. Mean values concerning
number of migraine attacks and headache indices are also shown in
Tables 1 and 2.
Table 1. Mean of the indiuidual mean number of attacks/week.
Number of
patients
Group I
Group I1
Group I11
10
9
9
Total mean:
___
Placebo
Divascan
Pizotifen
1.3
1.4
1.4
1.0
0.9
1.3'
0.7
1.4
1.2
0.9
1.2
1.4
~
' Only 8 patients completed the trial with pizotifcn in group 11.
Table 2. Mean of the indiuiduat mean headache indiees/week.
Number of
patients
Placebo
Divascan
Pizotifen
2.6
2.3
2.4
2.3
2.3
1.9
1.6
2.0'
1.1
2.4
2.1
1.6
~
Group I
Group I1
Group 111
10
9
9
~
Total mean :
Only 8 patients completed the trial with pizotifcn in group 11.
Number of migraine attacks: The results are given in Table 1. The
mean number of headaches per week was lower during treatment with
Divascan than with placebo but the difference was not significant.
Treatment with pizotifen gave significantly lower number of attacks
than both placebo ( P < 0.001) and Divascan ( P < 0.05).
In comparison with placebo the frequency of attacks was reduced
with 50 per cent or more in 6 patients on Divascan and in 12 patients
on pizotifen. One patient had 50 per cent fewer attacks while on
placebo compared with Divascan.
Headache index: The results are presented in Table 2. The difference
between placebo and Divascan was not significant whereas treatment
with pizotifen gave a significantly lower headache index than both
placebo ( P < 0.001) and Divascan ( P < 0.01).
Duration of attacks: The mean duration of the attacks was during
treatment with placebo f 9.1 hours, Divascan = 10.3 hours and
pizotifen = 8.4 hours. The differences were not significant.
21
Consumption of ergotamine: The mean consumption of ergotamine
in mg per 6 weeks was during treatment with placebo = 7.4, Divascan
= 6.1 and pizotifen = 5.4. According to analysis of variance the differences between placebo and Divascan ( P < 0.05) and placebo and
pizotifen ( P < 0.001) were significant whereas the difference between
Divascan and pizotifen was not. Judgments of significance, however,
are complicated by the fact that analysis of variance also shows a
strong influence on the consumption of ergotamine from the sequence
in which the drugs were tested.
Eleven patients used mere ergotarnine (difference 1 mg or more)
during treatment with placebo compared with Divascan, 3 used equal
amounts and 8 patients used more ergotamine during treatment with
Divascan. The difference was not significant.
Thirteen patients used more ergotamine during treatment with
placebo compared with pizotifen, 5 used equal amounts and 3 used
more ergotamine while on pizotifen. The difference was significant
( P < 0.025).
A comparison between Divascan and pizotifen revealed that 12
patients used more ergotamine during treatment with Divascan, 2 used
equal amounts and 7 used more ergotamine during treatment with
pizotifen. The difference was not significant.
The patients’ preference for medication: On completing ,the study
and before the code was broken the patients were asked to compare the
effect of the medication on their headaches during the three periods
of treatment. The three periods were compared two and two and the
patients were asked to state preference for one of these periods.
Comparison between placebo and Divascan showed that 7 patients
considered placebo most effective, 8 found n o difference and 13 stated
preference for Divascan. The difference was not significant.
Two patients considered placebo more effective than pizotifen, 6
found no difference and 19 preferred pizotifen. The difference was
highly significant ( P < 0.001 )
Three patients stated a preference for Divascan compared with
pizotifen, 9 found n o difference and 15 thought pizotifen superior.
Statistical analysis showed the preference for pizotifen to be significantly greater ( P < 0.01).
Overall evaluation o f treatmenf: The results are given in Table 3.
A good or very good effect of the treatment was reported by 11 per cent
of the patients on placebo, 39 per cent on Divascan and 70 per cent on
pizotifen. Divascan gave a significantly better effect than placebo
(P< 0.05) and pizotifen a significantly better effect than both placebo
(P< 0.001) and Divascan ( P < 0.05).
.
22
Table 3. Overall evaluation o f treatment (bg patient in the presence o f the
investigator after each period of treatment).
Placebo
Divascan
Pizotifen
14
7
1
~~
No effect
89 %
Slight improvement
11
Good effect
61 To
11 %
Very good effect
12
9
1
3
30 To
7
10
39 To
2
70 %
7
Side-effects: The side-effects are listed ?n Table 4. The side-effects
were frequent during treatment with pizotifen. Drowsiness and increase
in weight ( > 1.5 kg) were most common. Drowsiness often diminished
with time and the body weight tended to stabilize itself but several
patients considered the drowsiness and weight gain to be troublesome.
A s already mentioned 1 patient interrupted treatment with pizotifen
because of side-effects. Divascan, on the other hand, did not seem to
differ from placebo with regard to side-effects.
Table 4 . Side-effects.
~
_
_
_
_
_
_
~
~
Depression
Drowsiness
of which severe
Increased appetite and hunger
Weight gain more than 1.5 kg
Weight gain mnre than 4 kg
(range 4-7 Bg)
~
Placebo
Divascan
Pizotifen
1
4
1
3
2
2
B
1
2
1
3
15
9
12
21
0
0
8
The clinical and laboratory investigations did not show any significanl changes, apart from weight gain.
DISCUSSION
Pizotifen is a substance possessing a strong antagonistic action to
certain biogenic amines (for a review on the action, properties and
efficacy of pizotifen, see Speight & Avery 1972). Pizotifen has a strong
antiserotonin and antihistaminic activity and a mild anticholinergic
23
effect. The results of previous double-blind cross-over trials in general
have shown pizotifen to be significantly more effective than placebo
(Ryan 1968, Sjaastad & Stensrud 1969, Arthur & Hornabrook 1971,
Hughes & Fosfer 1971). Several other controlled and uncontrolled
investigations, often conducted on large number of patients, have also
demonstrated the usefulness of pizotifen in migraine prophylaxis
(Sicuteri et al. 1970, Lance et al. 1970, Forssman et al. 1972, DalsgaardNielsen & UZrich 1973). In some studies a beneficial effect of pizotifen
has been reported in up to 70 per cent or more of the patients but
usually the percentage is lower, approximately 40 to 60 per cent. A
50 per cent headache reduction or more has been achieved in approximately 30 to 50 per cent of the gatients.
The results concerning pizotifen in the present double-blind crossover investigation are well in accordance with those of previous studies.
Pizotifen significantly reduced the number of migraine attacks, headache index and the consumption of ergotamine. The effect was considered good or very good by 70 per cent of the patients whereas a corresponding effect was reported by only 11 per cent on placebo. In 12
out of 27 patients on pizotifen (44per cent) the number of headaches
was reduced by 50 per cent or more.
It is well established that weight gain and drowsiness are frequent
side-effects of pizotifen. According to Ekbom (1969) the increase in
weight is correlated to the maintenance dose. In the present study the
frequency of side-effects was high and several patients considered
weight gain and fatigue to be severe side-effects. Only 1 patient, however, interrupted treatment because of side-effects.
When the effects of two anti-migraine drugs are to be compared and
these drugs have different and typical side-effects which occur in a
rather high frequency, it is difficult t o give them blindly (Lundberg
1971). Divascan and pizotifen, however, both are serotonin antagonists
and they may be expected to have similar side-effects. The investigator
had no previous experience of treatment with Divascan and only little
of treatment with pizotifen. The occurrence of side-effects during the
treatment therefore did not reveal which of the two active drugs that
was tested. On the other hand, in many cases the occurrence of pronounced fatigue and weight gain showed that one of the active drugs
probably was tested and not placebo. It cannot be excluded that this
may have caused some bias. It is interesting to note, however, that
drowsiness was reported by 4 and increased appetite by 3 patients on
placebo.
Divascan has been tested in prophylactic treatment of migraine in
several hundreds of patients (Loebe 1971, Loebe et al. 1975, Beier et al.
24
1975). A positive effect has been reported in between 35 and 90 per cent
of the patients (Folesky 1975 b ) . No serious side-effects have been
reported in the dosages used (7.5 to 15 mg daily). The results of the
present study also indicate that Divascan 15 mg daily is effective in
migraine prophylaxis. The effect of Divascan was considered to be good
or very good by 39 per cent of the patients compared to only 11 per cent
on placebo, the consumption of ergotamine was reduced compared to
placebo and there was a reduction, although not significant, of headache frequency and headache index. The explanation for the effect of
Divascan in migraine prophylaxis is unknown. The effect may possibly
be explained by the antiserotonin activity (Riethling 1975) and/or the
decrease in permeability of the blood vessels caused by Divascan
(Reichel et al. 1975, Herrmann & Kobylinski 1975).
In the present study the effect of Divascan was rather weak and
pizotifen gave a significantly larger reduction in headache frequency
and headache index. Significantly more patients stated preference for
pizotifen compared with Divascan. However, pizotifen had frequent
and troublesome side-effects whereas Divascan in this respect did not
differ from placebo. The absence of severe side-effects, the limited
effect of Divascan in the used dosage and the low toxicity of Divascan
in animal studies indicate that Divascan may be tried in higher dosages
in migraine prophylaxis. Such trials are now in progress.
ACKNOWLEDGEMENTS
Placcbo, Divascan@ and pizotifen were kindly supplied by Laiike OY, Turku, Finland. The author is indebted to Gunnar Ekbohm, phil. cand., for statistical advice.
APPENDIX
(See the following two pages).
25
Individual d a t a concerning number of migraine attacks and headache indices per
6 weelis. The means and total means per 6 weeks and per week are also uiven.
Placebo
Patient
Group I
W A
BE
UE
IF
RH
MH
HL
IN
AP
GS
Age
35
34
49
46
25
41
32
41
23
36
Mean :
36
Mean per week :
Numberof
headaches
9
9
5
6
8
9
9
6
6
10
1.7
1.3
Divascan
Pizotifen
Index
Numberof
headaches
Index
Number of
headaches
Index
17
14
9
12
16
21
17
10
16
22
12
4
7
6
13
8
5
6
22
6
12
15
22
19
4
5
5
5
9
10
3
3
2
5
8
15.4
2.6
11
7
8
7
16
1.2
1.2
13.8
2.3
4
5.1
0.9
7
8
11
17
21
8
5
6
6
9.7
1.6
Group I1
U-BA
GB
ME
MF
GJ
BI.
SO
wo
BS
31
43
29
38
46
48
37
46
42
Mean :
41
Mean per week :
Group I11
DH
u
HJ
HL
GL
AS
PS
MA
MA
34
24
41
23
36
49
35
31
29
Mean :
34
Mean per week :
Total mean :
37
Total mean per week :
2
19
6
7
18
2
8
10
4
8.4
1.4
2
26
10
12
33
5
17
10
7
13.6
2.3
17
6
9
16
4
8
5
6
25
12
13
27
9
14
8
14
6
8
8.6
1.4
8.2
1.4
14.4
2.4
14.5
2.4
3
19
11
1
14
4
10
10
3
8.3
1.4
8
31
17
2
20
7
19
12
6
5
26
5
3
6
5
10
3
7.9
8
40
8
5
7
-
12
12
4
13.6
2.3
1.3
4
3
24
11
2
15
16
7
I2
9
4
7
4
3
4
4
6
5
3
3
9
9
6
6
6
6
7
7
3
6.0
1 .o
7.2
1.2
11.1
1.9
12.9
2.1
4.3
0.7
5.7
0.9
6.6
1.1
9.3
1.6
15
5
1
8
7
4
7
12.0
2.0
26
Individual data concerning mean duration of migraine attacks and consumption nf
ergotamine.
Mean duration of attacks
(hours)
Patient
Consumption of ergotamine
(mg per 6 weeks)
Placebo
Divascan
Pizotifen
Placebo
Divascan
Pizotifen
GS
6.3
10.5
3.6
12.2
7.6
11.0
19.0
17.3
7.2
8.7
3.3
28.2
4.7
21.0
7.8
21.0
20.6
20.0
6.0
7.0
7.0
11.2
4.7
16.8
5.4
6.0
16.0
19.0
9.0
3.6
15
10
7.5
4
30
15
0
7.5
8
17
15
3
6.5
1
18
Mean :
10.3
14.0
9.9
12.2
9.1
1.5
6.0
9.8
4.7
5.4
10.0
21.9
6.1
29.3
3.7
2.8
9.3
5.0
7.5
3.2
2.9
3.3
9.0
9.3
3.7
0
12.5
2
4
0
0.5
10.5
7.5
0
Group I
C-OA
BE
UE
IF
RH
MH
HL
IN
AP
30
0
4.5
10
11.5
8
0
5.5
5
11
14
6
3
1
14
~~
Group I I
U-BA
GB
ME
MF
GJ
BI.
so
wo
BS
11.0
6.6
5.0
-
22.0
6.3
17.6
0
11.5
1.5
0
6.8
0
23.5
2
1
0
1
12.5
8.5
0
0
13.5
6.5
0
~~
Mean :
10.5
6.0
9.3
4.1
3.9
5.8
5.4
6.0
10.2
3.5
9.5
4.1
7.2
9.5
1.2
5.1
18.0
12.0
3.4
30.0
4.8
5.1
15.2
2.2
6.1
21.5
3.5
1
1.3
14
2.5
3.5
0
2.5
8
0
4
12
11.5
2
2
0
2
6
0
4
4
6.3
9.1
10.6
5.9
8.4
5.2
7.4
4.9
6.1
Group I I I
DH
u
HJ
HI.
GL
AS
PS
MA
MA
Mean :
Total mean :
10.3
4.0
6.3
3.8
9.0
3.7
4.8
14.0
0
3.5
5
0
8
2
3.5
5.4
27
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Received December 28, 1976,
accepted March 15,1977.
P. 0.Osterman, M.D.
Neurologiska kliniken
Akademiska sjukhuset
Pack
S-75014 Uppsala 14
Sweden