Effect of Cyclcmdelate on Dementia
BY GILBERT WESTREICH, M.D., MILTON ALTER, M.D., PH.D.,
AND SANDRA LUNDGREN, PH.D.
Abstract:
Effect
of
Cyclandelate on
Dementia
• Cyclandelate, a vasodilator, was administered to 24 patients with dementia. The dementia in
these patients was presumed to be due to cerebral ischemia caused by atherosclerosis in cerebral
vessels after other possible causes were ruled out. In a double-blind, cross-over study, patients
received 200 mg of cyclandelate four times daily for six weeks and a placebo for six weeks. Six
psychological tests, which reflect various aspects of higher cortical ability, were used to evaluate
the effect of cyclandelate on the dementia. Cyclandelate was found to be no more effective than
placebo in improving higher cortical function in these demented patients.
Additional Key Words
vasodilator
cerebral arteriosclerosis
mental function
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• Physiological research has shown cyclandelate to
be effective in causing vasodilation of the arteries of
the skull and brain in geriatric patients1 and to increase cerebral cortical perfusion in patients with
cerebrovascular disease.2 Cyclandelate has been
shown to raise the volume of blood circulated and
reduce circulation time in patients with cerebrovascular insufficiency.3 It also has been reported that
cyclandelate decreases the number of recurrences of
transient cerebral vascular attacks.4
This effect on cerebral circulation has raised the
possibility that cyclandelate also may be effective in
treating some types of dementia. The dementias have
a heterogenous etiology but a proportion are believed
to be due to cerebral ischemia caused by atherosclerosis in cerebral vessels. A vasodilator, such as cyclandelate, could conceivably improve cerebrovascular perfusion by affecting vessels which are not, as
yet, too sclerotic to dilate.
Recent behavioral studies, however, have not
been consistent in demonstrating a beneficial effect of
cyclandelate on higher cortical brain function. In one
study,6 elderly patients on cyclandelate showed significant improvement in mental functioning, but there
was no significant correlation between the changes in a
patient's score on the mental function tests and
changes in mean circulation. In addition, the psychological test measurements employed in that study
have been criticized as being too imprecise.6 In
another study,6 patients with moderate atherosclerosis
showed significant improvement on four of nine
measures (three subtests of the Wechsler Intelligence
Scales and the Raven Coloured Progressive Matrices)
considered to be sensitive to change in cortical brain
function. In a more rigorous study with a doubleDepartment of Neurology, Veterans Administration Hospital, 54th
Street and 48th Avenue South, Minneapolis, Minnesota 55417.
This study was supported by Ives Laboratories, New York,
New York.
Strode, Vol. 6, Sepfemtxr-Ocfober 197}
blind, cross-over design,7 the results were equivocal
and it was concluded that further experimental
verification was required.
The present study of cyclandelate* was also of the
double-blind, cross-over type. This design, in which
each patient serves as his own control, has the advantage of minimizing the effect of individual differences
on the assessment of benefit. If cyclandelate were
effective, dementia after six weeks on the drug should
be significantly less than during the pretrial period and
after six weeks on placebo.
Methods
SUBJECTS
The patients were all male veteran inpatients on the
Neurology Service of the Minneapolis Veterans Administration Hospital. Thirty-one patients were admitted to the
study. Of these, two patients were eliminated because of
questionable histories of chronic alcoholism, two patients
refused to complete the study, two died before the completion of the study, and one was terminated after a rash
developed.! Thus, 24 patients contributed analyzable data.
These patients ranged in age from 51 to 82 years (mean 70.8
years).
PROCEDURE
All patients admitted to the Neurology Service with a
diagnosis compatible with dementia were first screened
medically. Baseline medical status for a variety of categories
was established using the battery shown in table 1. Patients
with various illnesses likely to preclude completion of the
study, such as carcinoma, severe lung disease or severe cardiac insufficiency, were identified in the medical screening
and excluded. Patients with medical complications of
chronic alcoholism or dementia so far advanced as to
preclude participation also were eliminated. Thus, patients
included in the study were essentially normal on all the tests
*Cyclandelate was supplied as Cyclospasmol® by Ives Laboratories,
New York, New York.
t When the code for this patient was broken, he was found to be
receiving placebo.
535
WISTIIICH, ALTM, LUNDORIN
TAtUI
Medical Screening Battery
•••dfU a i m r n
Cat •aery
A.
B.
General physical condition
and pertinent medical
history
Cardiovascular status
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
1.
2.
Height
Weight
Previous serious illnesses
Previous operations
Previous long-term medications
Smoking history (average number of cigarettes/day;
pack years)
Alcoholic beverage history (average cc/week)
Visual acuity
Auditory acuity
Serology for syphilis
EKG — on day of admission, pulse
Blood pressure t.i.d. x 3 days
Average
Range
Systolic
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C.
Pulmonary status
1.
2.
D.
Neurological status
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
E.
Metabolic status
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
High systolic — low systolic
Diastolic
High diastolic — low diastolic
Chest x-ray
Tidal volume
Clinical
Cranial nerves
Motor system
Reflexes
Sensation
Coordination
Laboratory
Electroencephalogram
Echoencephalogram
Brain scan
Skull x-ray
Pneumoencephalogram*
Scintimyelography*
SMA - 12 screen
Cholesterol
Calcium
Phosphorus
Bilirubin total
Albumin
Total protein
Uric acid
Urea nitrogen
Glucose
LDH
Alkaline phosphatase
SGOT
Electrolytes - N a , K, C O . , Cl
Two-hour postprandial blood sugar
•Procedure done for some patients only.
of the medical screening battery. Patients who received
medication other than cyclandelate, such as vitamins and
tranquilizers, continued to receive these drugs at constant
dosages during both the placebo and cyclandelate phases of
the study. Patients received no other vasodilating drugs.
Informed consent of the patient or, more often, a
responsible relative was obtained. Patients were randomly
allocated to one of two groups. Group 1 received
536
cyclandelate first for six weeks, followed by placebo for
another six weeks. Group 2 received placebo first, then
cyclandelate. The code was maintained by the hospital pharmacist and was unknown to either the clinicians or the
patients. Cyclandelate was given in an oral capsule of 200
mg four times daily. Daily records of capsule administration
were maintained by the nursing staff to assure that the
patients received the full dose. The patients remained in the
Slrok; Vol. 6, Stpttmbtr-Ocfobtr 1975
EFFECT OF CYCLANDELATE O N DEMENTIA
TABLE 1
Psychometric Tests
Paramstar of mentation
A.
Visual spatial
perception
B.
Memory
C.
Intelligence
D.
Logical thinking
T«it»
Bender Visual Motor Gestalt
Test
Graham-Kendall Memory-ForDesigns Test
Wechsler Memory Scale
Benton Visual Retention Test
Wechsler Adult Intelligence
Scale
Raven Coloured Progressive
Matrices
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hospital throughout the study except for an occasional
weekend pass, during which capsules were administered by a
responsible family member.
All patients were given identical programs in occupational, recreational and physical therapy. The clinical
condition of each patient was rated biweekly by a nurse and
a physician. Various aspects of higher cortical function were
evaluated using the battery of tests shown in table 2. These
tests were given on admission to the study, repeated after six
weeks, and again at 12 weeks.
Results
Table 3 shows the average pretrial scores for both
groups on each of the psychological tests and the
average scores after six weeks and after 12 weeks.
Comparisons of baseline performance revealed no
significant difference between Group 1 and Group 2 on
any of the tests, indicating that the two groups were
comparable in higher cortical functions. Moreover,
the test scores provide objective confirmation of the
clinical diagnosis of moderate dementia in these
patients. For example, patients made about 20 errors
on the Graham-Kendall Memory-for-Designs Test. A
score of 12 or more errors on this test is accepted as an
indication of impaired cerebral function.8 In addition,
the patients in the present study fell into the "dull normal" category for verbal IQ and into the "borderline"
category for performance IQ on the Wechsler Adult
Intelligence Scale (WAIS).9 On the Raven Coloured
Progressive Matrices,10 these patients also performed
at a "definitely below average" intellectual capacity.
Although significantly impaired on these tests, the
patients were not so severely demented that they fell
into the lowest category as mentally or intellectually
defective. As indicated by the Wechsler Memory
Scale,11 however, memory function was quite severely
impaired in these patients. The poor performance and
memory disability also were apparent on the Bender
Visual Motor Gestalt Test12 and the Benton Visual
Retention Test.13 Patients were able to reproduce only
about one of the eight and ten drawings, respectively,
in these tests.
The changes in performance at six weeks and 12
weeks included not only the anticipated effect of treatment but also a possible general beneficial effect of the
hospital environment and the occupational and
physical therapy programs. Statistical analyses, using
standard t tests, were carried out to evaluate the
significance of these effects, as well as the drug effect,
on each of the psychological tests. One analysis
(Bender-Gestalt, number recalled) revealed significant
(P < 0.05) improvement over time for both the
cyclandelate and the placebo phases, i.e., both groups
were able to recall more at 12 weeks than initially or
at six weeks (table 3). Only scores on the Wechsler
Memory Scale (MQ) and the WAIS full scale IQ
changed significantly (P < 0.05) during the study as a
TABLE 3
Mean Raw Scores of Pretrial, Six-Week and 12-Week Periods
Group 1
(Drug—placebo)
6-week
Pretrial1
12-week
Bender-Gestalt
Number correct
Number recalled*
Graham-Kendall
Number errors
Wechsler Memory Scale
MQ
Wechsler Adult Intelligence Scale (WAIS)
Verbal IQ
Performance IQ
Full scale I Q *
Benton
Number correct
Number errors
Raven Coloured Progressive Matrices
Number correct
Group 2
(P lacebo—drug)
Pretrial
6-week
12-week
0.8
0.2
1.2
0.3
1.7
0.7
0.4
0.4
1.0
0.3
0.8
0.9
19.8
18.4
18.3
21.4
17.0
15.8
64.6
66.5
70.1
64.6
75.4
72.8
92.0
80.3
89.0
92.0
82.4
89.6
90.6
84.6
90.7
84.4
72.5
76.7
89.6
81.7
85.4
92.6
83.4
86.8
0.9
23.0
0.7
23.7
1.5
20.9
1.2
21.7
1.6
19.6
1.8
19.4
12.2
13.7
15.2
13.4
17.1
17.6
*P < 0.05.
Stroke, Vol. 6, September-October 1975
537
WESTREICH, ALTER, LUNOGREN
result of treatment but, as shown by table 3, MQ improved more during the placebo period than during
the cyclandelate period for both groups and the
change in full scale IQ is attributable to an improvement only for Group 2 during the placebo period.
Thus, the results appear to indicate that, for the
demented patients in this study, cyclandelate was no
more effective than placebo in improving higher cortical function.
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Discussion
To our knowledge, there have been only four previous
double-blind, cross-over evaluations of cyclandelate.7- U 1 8 The results of the present study are essentially in agreement with the results of those studies.
Aderman and his associates7 studied the effects of
cyclandelate in two groups of geriatric subjects,
analogous to the groups in the present study, using six
psychological tests. Of these tests, four were identical
to or subtests of those we used. In both our study and
the Aderman et al. study, these four tests revealed that
cyclandelate had no significant beneficial effect.
Although the other two tests used by Aderman et al.
showed significant improvement, one group improved
on one test only and the other group improved on the
second test.
Judge et al.14 assessed mental function in normal
elderly male and female patients, again with a battery
of six tests. It was found that only the female patients
contributed analyzable data. For these female
patients, only two of the six measures showed significant differences in favor of cyclandelate. These two
measures were the Raven Coloured Progressive
Matrices and an abbreviated intelligence test. In the
present study and in the Aderman et al.7 study,
however, the Raven Matrices and other measures of
intelligence did not show any significant change in
favor of cyclandelate.
In the study by Young et al.,16 patients with objective signs of dementia and cerebral arteriosclerosis
were given cyclandelate and placebo. Patients did not
improve while on cyclandelate. Rather, during the
course of the study, patients declined on various
measures of neurological, behavioral and psychometric parameters. It was observed, however, that
the decline was greater during the placebo phase than
during the cyclandelate phase. No such decline during
the course of the trial was noted in the present study,
possibly because the patients in the present study
began at a lower pretrial level than in the Young et
al.15 study. Patients in that study actually began with
an "average" IQ. The results of the Young et al. study
suggest that cyclandelate may slow the progression of
dementia if administered in the very early stages of the
disease. However, in the present study of patients with
a moderate degree of dementia, cyclandelate was
found to be no more effective than placebo in improving higher cortical function. In Fine's16 study,
538
among nine measures compared, the only measure in
which sustained improvement occurred on the drug
was "orientation."
It should be realized that patients in the present
study were presumed, by a process of exclusion, to
have dementia due to cerebral arteriosclerosis, a
clinical entity which is not universally accepted.16 It is
possible that some other process (e.g., primary
neuronal degeneration) was responsible for the
dementia in these patients. If this were the case,
cyclandelate, or any other vasodilator, would not be
expected to be an effective treatment.
Acknowledgment
The authors wish to thank Ruth Loewenson, Ph.D., and Ron L.
Jacobson, Ph.D., for the statistical analyses and Deborah Graham
who assisted with testing.
References
1. Luisada AA, Jacobs R, Bruce D, et al: Action of a vasodilator
on the circulation of the skull and brain. Vase Dis 3:201-207,
1966
2. O'Brien MD, Veall N: Effect of cyclandelate on cerebral cortex perfusion rates in cerebrovascular disease. Lancet 2:729730, 1966
3. Eichhorn O: The effect of cyclandelate on cerebral circulation. A double blind trial with clinical and radiocirculographic investigations. Vase Dis 2:305-315, 1965
4. van der Drift JHA: Ischemic cerebral lesions. Angiology
12:401-418, 1961
5. Ball JAC, Taylor AR: Effect of cyclandelate on mental function and cerebral blood flow in elderly patients. Brit Med J
3:525-528, 1967
6. Smith WL, Lowrey JB, David JA: The effect of cyclandelate on
psychological test performance in patients with cerebral
vascular insufficiency. Curr Ther Res 10:613-618, 1968
7. Aderman M, Giardina WJ, Koreniowski S: Effect of
cyclandelate on perception, memory and cognition in a
group of geriatric subjects. J Amer Geriat Soc 20:268-271,
1972
8. Graham FK, Kendall BS: Memory-for-designs test: Revised
general manual. Perceptual and motor skills. Motor Skills
1 1:147-188, 1960
9. Wechsler D: Manual for the Wechsler Adult Intelligence
Scale. New York, Psychological Corporation, 1955
10. Raven JG Coloured Progressive Matrices. London, HK Lewis
& Co Ltd, 1962
11. Wechsler D, Stone CP: A standardized memory scale for
clinical use. J Psychol 19:87-95, 1945
12. Bender L: Instructions for the Use of Visual Motor Gestalt
Test. New York, Amer Orthopsychiatric Assoc Inc, 1946
13. Benton AL: The Revised Visual Retention Test. New York,
Psychological Corporation, 1963
14. Judge TG, Urquhart A, Blakemore CB: Cyclandelate and
mental functions: A double-blind, cross-over trial in normal
elderly subjects. Age and Ageing 2:121-124, 1973
15. Young J, Hall P, Blakemore C: Treatment of the cerebral
manifestations of arteriosclerosis with cyclandelate. Brit J
Psychiat 124:177-180, 1974
16. Fine EW: The use of cyclandelate in chronic brain syndrome
with arteriosclerosis. Curr Ther Res 13:568-574, 1971
Stroke, Vol. 6, September-October 1975
Effect of Cyclandelate on Dementia
GILBERT WESTREICH, MILTON ALTER and SANDRA LUNDGREN
Stroke. 1975;6:535-538
doi: 10.1161/01.STR.6.5.535
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