Current Medical Research and Opinion Vol. 10, No. 4,1986

Effects of long-term ergoloid mesylates (‘Hydergine’) administration in healthy pensioners: 5-year results

F. Huber, M.D., S. Kbberle,’M.D., H. Prestele,’ Ph.D., and R. Spiegel,* Ph.D.

First Geriatric Clinic, Felix Platter Hospital, Basle, and *Clinical Research, Sandoz Ltd., Basle, Switzerland

Curr. Med. Res. Opin.. (1986), 10,256. Received: 1st July 1986

Summary Five-year results are reported of a controlled long-term comparative study to assess the effects of ergoloid mesylates (1.5 mg 3-times daily) and placebo on medical, psychological and electrophysiological variables. Initially, I48 healthy elderly volunteers of both sexes were included. Eighty-nine subjects (48 on ergoloid mesylates and 41 on placebo) are still in the double-blind study; 39 subjects have left the trial for various reasons (6 deaths, 25 drop-outs due to disease, and 8 withdrawals) and 20 subjects are partickating under ‘open’ condi- tions. Formal statistical comparison of the two groups in terms of I0 medical and psychometric outcome variables did not produce significant differences. How- ever, a number of relevant findings and trends with regard to the effects of ergoloid mesylates were established: (i) the drug was well tolerated objectively and subjectively; (ii) subjective complaints such as frequent dizziness, cardiac symptoms and leg cramps were improved; (iii) there was less increase than on placebo in the number of subjects with pathological ECG findings; (iv) there was less increase than on placebo in the number of subjects taking digitalis; (v) fewer subjects than in the placebo group had an increase in the number of major diagnoses; (vi) the decrease in some lipid fractions was more pronounced than on placebo; and (vii) performance in some psychometric tests (WAIS Vocabulary, WAIS Performance) was better in the ergoloid mesylates group. None of these

findings, by itself, would be evidence of a dramatic effect of ergoloid mesylates on the participants in the double-blind trial. Taken together, however, they fall into a pattern, suggesting that ergoloid mesylates was partly effective in maintain- ing physical and mental health in these healthy elderly individuals, The finding of more disease-related and symptom-related drop-outs in the placebo group (25 vs. 20 in the ergoloid mesylates group) supports this assumption. Furthermore, the fact that a number oj’subjects who had left the double-blind trial for medical reasons improved on subsequent ergoloid mesylates administration may be seen as a further argument in favour o f a prophvlactic effect of ergoloid mesylates on pathological concomitants o f ageing.

Key words: Dihydroergotoxine - ageing - psychometrics - health status

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F. Huber, S. Koberle, H. Prestele and R. Spiegel

Introduction We have previously reported on the 3-year results of a long-term study in healthy elderly subjects that had been initiated in order to study the effect of ergoloid mesylates (‘Hydergine’t, co-dergocrine mesylate, dihydroergotoxine) on medical, psychological and electrophysiological parameters of normal ageing.6 Since a comprehensive description of our intentions and methods and of the 3-year results has recently been published? only a summary of the procedures is given here.

Subjects and methods The study, which is on-going, is a double-blind comparison between ergoloid mesylates and placebo in two parallel groups of male and female elderly volunteers. Great care was taken to match the groups with regard to age, sex, intelligence as estimated by the Progressive Coloured Matrices? medical status and risk factors. These data were collected in a 3-month placebo baseline period.

The subjects (84 men, 64 women: initial average age 63 years) were retired employees of Sandoz Ltd. and their spouses who lived in the area of Basle, Switzerland. They had been approached by letter or at regular social gatherings. It had been emphasized from the beginning that participation in the study was completely voluntary and withdrawal possible at any time. Conditions for inclusion were that the subjects should not be suffering from any severe physical or mental disorders and that they should be capable of understanding the tests and details of the investigation. A first group of 113 subjects was included in 1976/77 and a second group of 35 subjects in 1978, making a total of 148 subjects.

At the beginning of the trial, the ergoloid mesylates group was composed of 75 subjects, 33 women and 42 men, and the placebo group of 73 subjects, 31 women and 42 men. The mean age of both groups was 63 years (range: 52 to 72 years in the ergoloid mesylates group; 56 to 71 years in the placebo group). They had similar distributions for both marital and educational status.

From the time of entry, after the 3-month placebo baseline period, subjects have been treated with 1.5 mg ergoloid mesylates 3-times daily or the corresponding number of placebo tablets. Variables investigated Once yearly, patient history was taken and a detailed assessment of clinical status was made, including laboratory tests, an electrocardiogram, and a clinical electro- encephalogram.

The psychometric tests comprised: (i) a short form of the Hamburg-Wechsler Intelligence Test for Adults (HAWIE, a German version of the Wechsler Adult Intelligence Scale, WAIS7); (i i) the Coloured Progressive Matrices?’ and (iii) the Maudsley Personality Inventory (MPI), from which ratings of extroversion and neuroticism were derived. With the exception of the Coloured Matrices, which were performed every third month, all psychological tests were repeated once a year.

An EEG was recorded at 3-month intervals, the bipolar derivation CZ-02 being

ttrade mark, Sandoz

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Effects of long-term ergoloid mesylates (‘Hydergine’) administration in healthy pensioners: >year results

registered for 5 minutes on tape and analyzed by computer to produce power spectra.

Statistical analysis In order to assess the possible benefit of ergoloid mesylates treatment in the sense of confirmatory statistical analysis, main emphasis was given to the following variables: (i) systolic blood pressure, sitting; (ii) diastolic blood pressure, sitting; (iii) heart rate, recumbent; (iv) WAIS vocabulary; (v) WAIS block design; (vi) Coloured Progressive Matrices; (vii) ECG assessment (normal vs. pathological); (viii) number of relevant medical diagnoses; (ix) subjective complaints (a score sum calculated from 5 items); and (x) number of drugs used other than ergoloid mesylates.

For (i) to (vi), mean changes from baseline over the 5 years investigated were calculated for each subject. Between-group comparisons of mean changes were then made by means of the Wilcoxon-Mann-Whitney U-test. For (vii) to (x), the analysis was made by allocating each case to one of three categories: (a) deterior- ation, e.g. an increase in the number of drugs used from baseline to the last investigation; (b) no change, or mixed increases and decreases after the baseline investigation; and (c) improvement, e.g. a reduction in the subjective complaint score. Since the data level for (vii) to (x) is ordinal, the U-test could also be used for the comparison between treatment groups.

Further data were analyzed descriptively, i.e. by giving summary statistics and frequencies. In addition, the time course of each subject was graphically plotted for the most important laboratory variables, blood pressure values, and heart frequency in order to study variability and possible tendencies during the investigational period.

Results Changes in samples In the initial placebo phase, a number of subjects reported side-effects. Some of these subjects subsequently declined to continue the study, while in others these side-effects passed off spontaneously. It may be seen from Table I that the drop-out rate was relatively high in the first year of the study and then flattened out. This applied equally to the 113 subjects originally recruited for the study and to those 35 subjects included 2 years later. The number of subjects remaining in the trial after 5 years was 109,89 of whom were being treated under double-blind conditions.

Four subjects in each group declined to participate further in the trial either because it was taking up too much of their time (n=6) or because they moved away from Bade (n=2). Three subjects in each group died. Eleven subjects in the ergoloid mesylates group and 14 in the placebo group discontinued treatment because of serious diseases. If symptoms such as dizziness, tinnitus or signs of impaired cerebral function (‘ergoloid mesylates-sensitive’ symptoms) developed in a subject, he or she was taken out of the double-blind study and treated according to the recommendations of his or her family doctor. This was necessary

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F. Huber, S. Koberle, H. Prestele and R. Spiegel

Table 1. subjects

Changes from baseline in the sample population over the 5-year period: number of

Subjects ~~ ~

With- Deaths Serious Total No. No. draw a Is diseases no. studied studied

drop- double- open outs blind

Baseline Ergoloid mesylates Placebo

75 73

1 year Ergoloid mesylates 2 5 7 65 3 Placebo 3 2 8 13 55 5

Zyears

Placebo 3 3 9 15 50 8 Ergoloid mesylates 4 1 7 12 58 5

Syears Ergoloid mesylates 4 1 8 13 55 7 Placebo 3 3 11 17 46 10

Byears Ergoloid mesylates 4 1 10 15 52 8 Placebo 4 3 12 19 43 11

Syears

Placebo 4 3 14 21 41 11

*Includes 1 subject who has not yet reached the full 5-year period

Ergoloid mesylates 4 3 11 18 48. 9

for 9 subjects receiving ergoloid mesylates and 11 subjects receiving placebo. Also included in this group are 4 subjects (1 on ergoloid mesylates, 3 on placebo) in whom diseases developed during the course of the study and whose code was broken on the request of the treating physician. One subject (receiving ergoloid mesylates) joined the study later than all others and has not yet reached the 5-year mark.

The 5-year results presented below apply to those subjects who have undergone the full 5th-year examination and are still under double-blind conditions. They comprise 47 subjects (29 men and 18 women) in the ergoloid mesylates group and 41 subjects (22 men and 19 women) in the placebo group (Table 11). Further- more, a description will be given of subjects who were withdrawn from the double- blind trial and who are still being followed up.

Medical history Alcohol consumption and smoking habits. These did not change to a remarkable extent over 5 years. There had been more smokers in the ergoloid mesylates group at the outset, and after 5 years the percentages of smokers were 26% in the ergoloid mesylates and 15% in the placebo group.

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Effects of long-term ergoloid mesylates (‘Hydergine’) administration in healthy pensioners: 5-year results

Table 11. subjects or mean values

Details of subjects still taking part in double-blind study after 5 years: number of

Subjects Ergoloid mesylates

Placebo

No. studied Sex: Male

Female Age (years): Mean

Range Previous maximum body weight (kg) reported: Mean

Range Present weight (kg): Mean

Range Body-mass index: Mean

Range Body build Light Mediuim Heavy

47 29 18 63 52 to 72

79 55 to 124 74 52 to 111 26.8 20.1 to41.7

11 28 8

41 22 19 64 56 to 71

76 54 to 100 71 53 to 98 26.0 20.5 to 35.2

11 27 3

Marital status Single Married Separated/divorced Widow/widower Education Primary Secondary Apprenticeship University graduate

5 40

2

47 12 29 4

6 34

1

41 5

30 2

Diet. The number of subjects on a low fat diet increased in both groups (from 2 to 10 in the ergoloid mesylates, from 4 to 8 in the placebo group); this was a consequence of our recommendations to subjects who had abnormally high lipid levels at baseline.

Visits to physicians. The number of visits to physicians, general practitioners or specialists, increased in both groups so that 4 out of 5 subjects had seen a general practitioner in the year previous to the 5th-year check-up (compared with 3 out of 5 subjects initially). Slightly more than 50% of all subjects had consulted a specialist in the year previous to the 5th-year check-up, compared with less than 30% at baseline. The percentage of subjects who were sick at least once during the year preceding the check-up also increased in both groups and, similarly, there was a slight increase in the percentage of subjects who had been hospitalized for at least 1 day in the previous year. We assume that these increases are due partly to the increasing age of the subjects and partly to the greater awareness of health problems raised by their participating in the study.

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F. Huber, S. Koberle, H. Prestele and R. Spiegel

Drug consumption. The frequency of consumption of drugs other than ergoloid mesylates and placebo was considered under several aspects. Table I11 gives the numbers of subjects taking different types of medication; the frequency of consumption is not taken into account in this Table.

Table 111. subjects

Details of different types of medication being taken by subjects: number of

Medication Ergoloid mesylates (n=47) Placebo (n=41)

Baseline At 5 years Baseline At 5 years

Specific antihypertensives 4 6 7 9 Diuretics. 4 (1) 4 (2) Beta-blockers* 1 2 (2) 2 1 Digitalis 1 2 5 9 Coronary vasodilators Anti-arrhythmic agents Anticoagulants Oral antidiabetic agents Antirheumatic agents Analgesics Psychotropic drugs (including hypnotics) Laxatives Other drugs

3 1 1 1 3 6

10

4 17

3 1 3 1 5 4

10

1 22

4 1

2 1 1 3 2 4 9 5 5 7

6 16 17

~~ ~~

*Figures in parentheses indicate the number used as antihypertensives

An interesting feature is the uneven distribution of digitalis consumption in the two groups: at the beginning of the study, 1 ergoloid mesylates and 5 placebo subjects were receiving digitalis, and the difference became even more marked after 5 years, when 2 ergoloid mesylates and 9 placebo subjects were taking digitalis. It should be mentioned that all prescriptions were made by the subjects’ private physicians without any interference from our side. The consumption of coronary vasodilators did not change in the ergoloid mesylates group but increased from 0 to 4 in the placebo group. The number of subjects taking psychotropic drugs was higher in the ergoloid mesylates group initially (10 vs. 5 ) and did not change over 5 years; there was, however, an increase from 5 to 7 in the placebo group.

The percentage of subjects taking 0, 1,2,3, and 4 or more drugs simultaneously is shown in Figure 1.

The percentage of subjects taking no drugs was higher initially and decreased from 34% to 23% in the ergoloid mesylates group, but increased from 24% to 29% in the placebo group after 5 years. On the other hand, the percentage of subjects taking 2 or more drugs concomitantly increased from 31% to 36% in the ergoloid mesylates group, but increased somewhat more in the placebo group (from 36% to 49%). Overall, there were no statistically significant changes in the number of drugs taken.

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Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: 5-year results

Figure 1. Percentages of subjects taking drug medication

Base- Syears Base- Syears

100-

S 50-

line line

0 N o drugs

2 drugs 3 drugs

1 1 drug

3 4 drugs

" Ergoloid Placebo mesylates (n=41) (n=47)

Subjective neurological andpsychological symptoms. The frequency of subjective neurological and psychological symptoms (Table IV) did not change in a uniform way: while reports on headaches, tiredness, dizziness and paraesthesias were less frequent after 5 years than initially, tinnitus and, in particular, disturbances of hearing and vision became more common with increasing age of our subjects. Altogether, there were no statistically significant differences between the two treatment groups.

Table 1V. Subjective neurological and psychological symptoms: number of subjects reporting

Symptoms Ergoloid mesylates (n=47) Placebo (n=41)

Baseline At 5 years Baseline At 5 years

Headache: Occasional

Pareses Tiredness Dizziness: Occasional

Frequent Tinnitus: Occasional

Continuous Hearing disturbances Vision disturbances Paraesthesias

Frequent 12 4 2 7

14 4 2 1

10 2

11

5 1 2 5 9 1 4 2

14 5 6

15 4 2

13 11 3 5 2 8 1

12

4 2 1 7 5 3 5 4

11 3 6

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F. Huber, S. Koberle, H. Prestele and R. Spiegel

A total score of 'subjective neurological symptoms', based on the symptoms headache, tiredness, dizziness, tinnitus and paraesthesias, was then calculated, since some of the subjects had reported more than one of these symptoms simultaneously and different frequencies of occurrence had been recorded for these symptoms. Individual symptom frequency varied within the following ranges: headaches - 0 to 2 (not present, occasional, frequent); tiredness - 0 to 1 (not present, present); dizziness - 0 to 2 (not present, occasional, frequent); tinnitus - 0 to 2 (not present, occasional, permanent); and paraesthesia - 0 to 1 (not present, present).

The total score for subjective neurological symptoms varied between 0 and 8 points, and Figure 2 shows the percentages of subjects with different scores at the outset and after 5 years.

Figure 2. Percentages of subjects with subjective neurological symptoms

Base- 5 years Base- .5 years

100

* SC

a

!ine line

Ergoloid mesylates (n=47)

Placebo (n=41)

0 icore sum Dl 0 2 a3

2 4

Some improvement in subjective neurological symptoms was noted in both groups. However, while the percentage of subjects with no or only 1 symptom increased from 60% to 81% in the ergoloid mesylates group, there was less improvement (from 54% to 64%) in the placebo group.

Subjective somatic symptoms (Table V). Cardiac symptoms, particularly dyspnoea of effort or palpitations, were reported more frequently in the ergoloid mesylates than in the placebo group at the start of the study. The number of subjects with these symptoms did not change in the ergoloid mesylates group, but it increased in the placebo group over the 5 years. The frequency of leg pains, mostly cramps,

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Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: .$-year results

decreased somewhat in the ergoloid mesylates and increased slightly in the placebo group during the study. Respiratory symptoms, mainly coughing and/or expector- ation, were reported more frequently in the ergoloid mesylates than in the placebo group at the beginning of the study. The frequency of these symptoms declined in both groups, more markedly in the ergoloid mesylates group. Gastro-intestinal symptoms, mostly constipation or meteorism, decreased markedly in both groups over the 5-year period. Table V.

Symptoms Ergoloid mesylates (n=47) Placebo (n=41)

Subjective somatic symptoms: number of subjects reporting

Baseline At 5 years Baseline At 5 years

Cardiac 19 18 12 17 Veins 23 24 24 23 Arteries 3 3 2 2 Other leg pains e.g. cramps 7 2 5 7 Respiratory 16 9 8 6 Gastro-in testinal 23 13 24 11 Urogenital 12 11 14 16 Post-menopausal 1 3 Locomotor 34 36 34 33

The mean body weight (data not shown; see Spiegel et al.6) was initially somewhat higher in the ergoloid mesylates than in the placebo group, but did not change appreciably over the 5-year period. The same holds true for the body-mass index (body weight in kg divided by the square of the height in m), which showed little change over 5 years in both groups.

Clinical status Mental changes. Owing to the selection criteria applied and to selective drop-out in the course of the study (see below), the number of subjects with psychiatric disorders is small. At the start of the study, there were more subjects in the placebo group with an abnormal mental condition (6 in the placebo, 2 in the ergoloid mesylates group). The most frequent disorder observed was symptoms of depression. The number of subjects with depression declined from 5 to 1 in the placebo and from 1 to 0 in the ergoloid mesylates group over the 5-year period. Incipient dementia was diagnosed in 1 subject in each group; this figure did not change over 5 years.

Bloodpressure. This was measured in the recumbent position by the physician and in the sitting position by the nurses. In our previous report, only the physician's values were included in the evaluation. It will be noticed (Figure 3) that blood pressure values determined by the physician and by the nurses were similar initially, while the physician's values after 1 year and subsequently were somewhat higher. There had been changes of physicians after the initial and after the 1st-year examination that may be responsible for this difference. Blood pressure values measured by nurses did not change throughout the 5 years: similarly, after

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F. Huber, S. Koberle. H. Prestele and R. Spiegel

Figure 3. values

Blood pressure measurements made by nurses and by the physician: mean ( 3 . D . )

N u rses Ph vsician

E l

0 1 2 3 4 5 Time (years)

M Ergoloid mesylates o---o Placebo

0 1 2 3 4 5 Time (years)

the 1st-year examination the physician’s values did not change any more. It has been described that blood pressure values obtained by physicians tend

to be higher than nurses’ why this effect did not occur in our initial measurements remains unexplained. Statistical analysis of the diastolic and systolic blood pressure values over 5 years did not reveal significant differences between the two treatment groups.

Subjects who, after 5 years, had a diagnosis of hypertension (16 in each group) were considered separately. Table VI gives details of the nurses’ measurement of blood pressure in this sub-group. Table V1. measurements

Blood pressure in patients with hypertension: mean (2S.D.) values of nurses’

Measurement Ergoloid mesylates (n= 16) Placebo (n = 16) (mmHg) Baseline At 5 years Baseline At 5 years

Systolic Diastolic

141216 136*21 76*13 7329

135*15 139214 76*12 78*14

~~

It will be seen that the mean systolic and diastolic blood pressure values decreased slightly in hypertensive subjects on ergoloid mesylates, while hyper- tensive subjects on placebo showed a marginal increase. Differences between these sub-groups were not tested for statistical significance.

Electrocardiogram findings. Mean pulse rate and mean heart rate (as determined from the ECG) showed a decrease by about 6 beats per minute from baseline values in both treatment groups. This reduction was present after 1 year of study (see Spiegel et af. ,6 Figure 2) and there was no further change in pulse and heart rates as the study went on. Differences between the two treatment groups were not significant. Subjects with low pulse rates at the start of the study (<60 beats per minute; 5 subjects in the ergoloid mesylates and 2 in the placebo group) did

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Effects of long-term ergoloid mesylates (‘Hydergine’) administration in healthy pensioners: 5year results

not show a further decrease, but rather a slight increase over 5 years (data not shown).

The results of the visual ECG evaluation and some quantifiable parameters are shown in detail in Table VII. Table VII. abnormalities

Abnormality Ergoloid mesylates (n =47) Placebo (n=41)

Electrocardiogram findings, visual evaluation: number of subjects with

Baseline At 5 years Baseline At 5 years

Arrhythmias Heart block Pduration20.11” P height22.5 mm in D, and/or>l.O mm in V, Necrosis J-depression ST-depression ST-segment slope Isolated T wave change

2 6 8 11

12 19

1 2

4 7

1

1 1 5

10 9

22

2 6 6 7

12

The frequency of cardiac arrhythmias (particularly extrasystoles), heart block (particularly atrioventricular conduction disorders), lengthening of the P wave, and abnormalities of the ST segment and T wave increased in both groups over the 5-year period. All these unfavourable changes were more frequent in the placebo than in the ergoloid mesylates group. In addition to the detailed evaluation of the electrocardiograms, an overall assessment was made on a 5-point scale (1 =normal, 2 = evident coronary disease, necrosis, 3 =possible coronary disease, 4=other abnormalities, and 5 =not evaluable). As shown in Table VIII, there was an increase in the number of patients with cardiovascular abnormalities other than coronary disease in both groups, particularly in the placebo group. Table VIII. Electrocardiogram findings, overall assessment: number of subjects with abnormalities

Overall Ergoloid mesylates (n =47) Placebo (n=41) assessment 1smrt=\ Baseline At 5 years Baseline At 5 years

Normal (1) 31 20 Evident coronary disease (2) Possible coronary disease (3) Other abnormalities (4) 16 27 Not evaluable (5)

28 12 1 2 1 2

11 25

figure 4 compares the percentages of subjects who showed improvement, deterioration, or no change in the overall assessment of their ECGs after 5 years.

There were a few improvements in ECG findings in the ergoloid mesylates group only, and the percentage of ECGs unchanged after 5 years was somewhat higher in the ergoloid mesylates than in the placebo group. Deteriorations after 5 years were more frequent in the placebo group, but the difference between groups was not statistically significant.

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F. Huber, S. Koberle, H. Prestele and R. Spiegel

Figure 4. Changes in ECG assessments: percentages of subjects

Ergoloid Placebo mesylates (n=41) (n=47)

Laboratory tests Only abnormal or otherwise conspicuous values are discussed in this section.

There was a marked increase in the number of subjects with an elevated 1-hour erythrocyte sedimentation rate in the ergoloid mesylates group over 5 years. Median initial values for 2-hour erythrocyte sedimentation rate were raised in both groups and increased slightly in both groups over the 5 years (Table 1x1. Individual values were analyzed in detail and showed that there were only few subjects with very high values. These individuals were suffering from intercurrent infectious diseases or chronic inflammations.

A possibly relevant increase in the number of subjects with low serum potassium levels was noted after 5 years in both groups, particularly in the ergoloid mesylates group. These subjects with low potassium levels were taking either laxatives or diuretics without substitution of potassium. Since baseline values were available from a few subjects only, the significance of the changes observed is doubtful.

The number of subjects with elevated plasma levels of inorganic phosphorus increased over the 5-year period, mainly in the ergoloid mesylates group. Detailed graphic analysis of individual values over 5 years showed great variation and no systematic trend which might be related to treatment.

A significant decrease in serum creatinine levels was apparent in both groups after 5 years. Moreover, the number of subjects with increased creatinine values had reduced in both groups. This decrease may be attributed to the fact that subjects with elevated creatinine values had been recommended to increase their fluid intake.

Median uric acid levels increased in both groups, with more pronounced increases after 5 years in the ergoloid mesylates group. The number of subjects

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Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: %year results

with elevated values increased in both groups after 5 years, more markedly so in the ergoloid mesylates group. However, the median values observed during the 5-year period are within the normal range in both groups. Individual values showed considerable variation and the apparent increase in the number of subjects with high values after 5 years is due to the fact that measurements of uric acid in the plasma were not carried out at the beginning of the study in 1976.

The median serum cholesterol values decreased slightly in both groups. The number of subjects with raised initial levels decreased markedly in the ergoloid mesylates group and increased somewhat in the placebo group. There was a slight decrease in median triglyceride levels in both groups, the decrease being greater in the placebo group. Median serum beta-lipoprotein concentrations and the number of subjects with raised levels decreased to a relevant extent in the ergoloid mesylates group over 5 years. In the placebo group, the median value after 5 years was almost the same as at the beginning, and the number of subjects with raised levels increased slightly. Median serum phospholipid levels did not change in the ergoloid mesylates but increased in the placebo group. The number of subjects with raised levels increased mainly in the placebo group. Detailed analysis revealed that a few individuals had excessively high lipid levels; these subjects were alcoholics.

Overall, median serum lipid levels and the number of subjects with raised serum lipid values declined in both treatment groups, since subjects with pathologically raised lipid levels were recommended to follow a low-fat diet. Nevertheless, the decrease for several of the lipid fractions was somewhat greater in the ergoloid mesylates group. Table IX. Serum levels of haematological and biochemical variables investigated: median values and number of subjects with values outside the normal range

Measurement Baseline At 5 years

Median No. above No. below Median No. above No. below norm norm norm norm

Enthrocvte sedimentation rate (mm/hr) 1st hour: 0 to 10 Ergoloid mesylates 7 11 a 17 Placebo 7 14 7 12 2nd hour: 0 10 20 Ergoloid mesylates 24 25 27 31 '

Placebo 25 26 26 30 Haemoglobin (g/dll: males - 13.Sto 18.0:,females - 11.Sto 16.0

Placebo 14.7 1 14.3 4 LeucocJjtes f X 109/1): 3.0 to 9.0

Placebo 5.3 6.1 2 1

Blood glucose. postprandial fmmol/l): 3.89 to 8.88

Placebo 5.5 2 4.9 1 4 Sodium fmrnol/l): 1.73 to 14.5

Placebo 142 141 1 268 fcont.)

Ergoloid mesylates 15.0 1 14.5 3

Ergoloid mesylates 6.4 2 5.9 4 2

Ergoloid mesylates 5.3 1 4.8 2 3

Ergoloid mesylates 142 1 141 3 2

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Table IX Icont.). median values and number of subjects with values outside the normal range

Serum levels of haematological and biochemical variables investigated:

Measurement Baseline At 5 years

Median No. above No. below Median No. above No. below norm norm norm norm

Potassium Immol/l): 3.5 to 5. I

Placebo 4.1 4.0 4 Calcium ImrnoUl): 2.2.5 to 2.7.5

Placebo 2.3 2 2.3 5 Inorganic phosphorus Immol/l): 0.81 to 1.29 Ergoloid mesylates 0.9 2 0.9 1 17 Placebo 0.9 2 0.9 4 7 Urea ImmoUl): 3.3 to 6.7

Placebo 6.5 18 1 6.0 18 Creatinine (pmoUI): 5.7 to 124

Placebo 112 12 88 2 1 Uric acid (pmoUI): males - 226 to 434:,females - 17Y to 34.5

Placebo 226 I 29 1 3 5

Cholesterol (mmol/l): 3.9 to 7.8

Placebo 6.49 5 6.18 6 Triglvcerides Immol/l): 0.60 to 2. 90

Placebo 1.37 2 1.17 1 1 Beta-lipoproteins (X I000 0. D.): 400 to 900

Placebo 60 1 1 2 599 3 4 Phospholipids Immol/l): 2.S to 3.8

Placebo 2.8 1 3.1 8 3 Total bilitubin Iprnol/l): 0 to 1.5.4 Ergoloid mesylates 9.5 9.0 2 Placebo 7.0 1 8.0 3 SGOTIU/I):6to2.? Ergoloid mesylates 11 12 1 1 Placebo 14 12 1 1 SGPT IU/l): 5 to 27 Ergoloid mesylates 14 2 12 2 3 Placebo 13 2 11 1 5 Gamma-GT (U/l): 0 to 60 Ergoloid mesylates 18 1 13 4 Placebo 28 1 1s 3 Alkaline phosphatase (U/l): 38 to I20 Ergoloid mesylates 33 1 29 61 3 3 Placebo 30 29 60 4 Acidphosphataseprostate (U/l): 0.1 to 1.0 Ergoloid mesylates 0.4 1 0.1 14 Placebo 0.2 0.2 3 4

Ergoloid mesylates 4.1 1 3.8 8

Ergoloid mesylates 2.4 2.4 5

Ergoloid mesylates 6.7 22 1 6.6 20

Ergoloid mesylates 113 16 96 4

Ergoloid mesylates 229 1 316 8

Ergoloid mesylates 6.41 11 6.27 2 I

Ergoloid mesylates 1.47 1 1 1.41 4 1

Ergoloid mesylates 665 8 1 578 2 5

Ergoloid mesylates 3.3 1 3.2 1 3

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Serum alkaline phosphatase values increased in both treatment groups over 5 years, the median values in both groups remaining within the normal range. Two individuals in the ergoloid mesylates group had very high levels; one was suffering from a carcinoma with bone metastases and the other from Paget’s disease of the bone. The apparent increase in the number of subjects with low serum levels of acid phosphatase (prostate) over 5 years is due to the fact that this variable was measured in all subjects only after 2 years of study.

Major diagnoses Details of the major diagnoses in subjects on entry and after 5 years are given in Table X.

Table X. Major diagnoses: number of subjects

Diagnosis Ergoloid mesylates (n =47)

Baseline At 5 years Baseline At 5 years

Placebo (n=41)

Hypertension 15 16 Diabetes mellitus 2 4 Hyperlipidaemia 6 15

Vascular disease 2 6 Cerebral vascular disease Neoplasms 4 6

Coronary artery disease 3 3

12 16 1 5 3 15 2 5 1 3 1 1 3 5

The diagnosis of hypertension, which was given at the outset of the study in about 30% of both ergoloid mesylates and placebo subjects, was mainly based on medical history; in a few cases, the diagnosis was based on results of the baseline medical examinations. After 5 years, the number of hypertensive subjects had increased by 1 in the ergoloid mesylates and by 4 in the placebo group. Consump- tion of antihypertensive drugs increased in both groups to about the same extent (Table 111).

The number of subjects with diabetes mellitus increased slightly in both groups over 5 years. None of these subjects needed treatment with insulin; 1 of the ergoloid mesylates and 3 of the placebo subjects were treated with oral antidiabetic agents.

The apparent increase in the number of subjects with hyperlipidaemia in both groups after 5 years is partly due to the fact that lipid status results collected under fasting conditions were not available from all subjects initially and thus a diagnosis could not always be made with certainty at the beginning of the study.

The number of subjects with coronary artery disease did not change in the ergoloid mesylates group over the 5-year period, but increased from 2 to 5 in the placebo group (see previous paragraph).

The diagnosis ‘vascular disease’ comprises clinically relevant diseases of the peripheral arteries (Stage I, Widmer and Waibe18) and vascular diseases of the eye. The number of subjects with vascular diseases increased from 2 to 6 in the ergoloid mesylates and from 1 to 3 in the placebo group over 5 years. Two of the ergoloid mesylates subjects with newly diagnosed vascular disease were suffering 270

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from occlusion of a branch of the central retinal vein, and 2 subjects in both groups showed occlusions of a branch of the central retinal artery. These disturb- ances are common in advanced age and were probably unrelated to treatment.

The number of subjects with cerebral vascular disease did not change over 5 years. It should be mentioned, however, that subjects who had developed cerebral vascular disease or symptoms of impaired cerebral function discontinued the study or were followed up under open conditions (see below).

The incidence of neoplasms increased somewhat in both groups. Since many subjects had more than one major diagnosis, it is of interest to

consider the changes in percentages of subjects having 0, 1, 2 or more of the diagnoses set out in Table X. This is shown in Figure 5, suggesting somewhat different changes in the two groups: the percentage of subjects without any major diagnosis, which had been higher initially in the placebo group, showed a marked decrease in this group but little change in the ergoloid mesylates group. Conversely, the percentage of subjects with 2 and more major diagnoses increased from 32% to 44% in the ergoloid mesylates but from 14% to 39% in the placebo group.

Figure 5. Percentages of subjects with major diagnoses

Base- Syears Base- Syears

100-

a-" 50-

line line

" Ergo 1 o i d mesylates (n=41) (n=47)

Placebo

Major diagnoses 0 None a 1

0 2 a3

2 4

Psychometric variables Table XI gives details of the changes in the psychometric variables during the 5-year study period.

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110

Table XI. Results of psychological tests: mean (2S.D.) values

I - c c I-- - 1 - - - - - -1.. . . I Ergoloid mesylates

Test (score)

Ergoloid mesylates (n=47) Placebo (n=41)

Baseline At 5 years Baseline At 5 years

WA IS Time required (min) 38.5k7.8 28.4k5.4 40.9k9.9 27.4k6.2 Total I.Q. 11 1.329.4 110.3k8.5 107.5-Cl3.9 105.8+12.0 Verbal 108.7210.6 106.2k8.8 104.3212.8 100.0~10.1 Performance 112.5k9.7 113.5k11.0 108.6k13.8 109.9k16.2

General comprehension 13.4*3.1 13.3k2.6 1 1.723.6 1 1.93.1 Vocabulary 54.0k11.9 49.9k10.2 51.9213.3 46.2211.6 Block design 27.0k7.1 24.8k6.6 24.4k7.7 23.6k8.2 Object assembly 18.8k1.9 19.9k2.9 18.2k3.3 18.9k4.2

Coloured Progressive 29.5k3.6 31.3f4.0 28.8k3.5 30.0k4.4 Matrices

Maudsley Personality Inventory N score 17.0k10.5 14.1k10.1 17.0k8.8 15.7k9.5 E score 24.4k7.7 25.4k8.2 22.6k8.1 21.9k9.5

W A I S ( Wechsler Adult Intelligence Scale). The time required to complete the WAIS decreased markedly in the first 3 years of study; this was highly significant for both groupss and indicates that subjects learned to carry out the WAIS more quickly. This learning effect plateaued after 3 years, and there was no difference at that stage (data not shown) or after 5 years between the two treatment groups with regard to test time. Total WAIS score (IQ) showed some transient increase during the period considered; after 5 years this variable, however, was slightly lower than at the outset of the study (Figure 6). Score (IQ) in the ergoloid mesylates group was higher throughout, but after-minus-before differences had not been found to be significant after 3 years. N o statistical test was made with the 5-year data.

90’ 1 1 I I I 1 0 1 2 3 4 5

Time (years)

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WAIS Verbal performance showed a pattern very similar to that of Total Score i.e. a transient increase and after 5 years a slight decrease below initial levels. Here, too, ergoloid mesylates subjects had shown better performance at the out- set, and this difference from the placebo group increased somewhat towards the 5-year point. The WAIS Performance also indicated some transient improvements in both groups and a persistent superiority of the ergoloid mesylates subjects. N o tests of significance were applied to these data.

Two WAIS sub-tests, one from the Verbal (Vocabulary) and one from the Performance (Block Design), were subjected to significance testing. The after- minus-before differences in the Vocabulary test were not significant between treatment groups (Figure 7). In the Block Design Test, performance had been significantly better in the ergoloid mesylates group at the beginning of the study; after-minus-before differences did not distinguish the two treatment groups (Figure 8).

Figure ! 7. Changes in WAIS ‘Vocabulary’ sub-test over 5 years: mean T T

I 1S.D.) number of points Changes in WAIS ‘Vocabulary’ sub-test over 5 years: mean 1S.D. ) number of points T -

- - -

Ergoloid rnesylates v)

S Placebo 0 a

40-

J-LJ I---T =‘T

Ergoloid rnesylates

Placebo

0 1 2 3 4 5 Time (years)

30

Figure 8. points

Changes in the WAIS ‘Block Design’ sub-test over 5 years: mean (*S.D.) number of

v) - .c 2 0 a

Ergoloid rnesylates Placebo

101 , I I I I 1 0 1 2 3 4 5

Time (years)

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.g - in 30- 35- P,

25-

Coloured Progressive Matrices test (CPM). This test revealed a very clear learning effect, particularly for the first 3 years of study. The difference between the two treatment groups was not statistically significant. Descriptively, it may be seen that the slight difference in favour of the ergoloid mesylates subjects at the beginning of the trial became larger as the study went on (Figure 9). Separate analysis of subjects with baseline values above or below the median showed that subjects with poorer initial performance in the CPM had an increase of about 9% on ergoloid mesylates compared with 5% on placebo.

GCLLI-I - I - - -1 - --r - - -r - - 1 Placebo Ergoloid mesylates

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Table XII.

Subject Sex Age at Months Cause of death No. death (years) in study

Details of patients who died during the study

Ergoloid mesylates 72 Male 64 23 55 Male 71 54

133 Female 65 62

Myocardial infarction Chronic obstructive lung disease Acute attack of bronchial asthma

Placebo 124 Male 61 9 129 Male 62 13 93 Male 66 30

Neoplasm of the brain Neoplasm of the liver Myocardial infarction

Drop-outs due to serious disease. Twenty-five subjects, 11 in the ergoloid mesylates and 14 in the placebo group, discontinued the trial because of serious diseases. Their mean age at the beginning of the study was not different from that of the whole sample, and the proportion of females to males was similar to that in the total sample (Table XIII). Reasons for drop-out were not different for subjects on ergoloid mesylates and on placebo; it is, however, of interest that the median duration in the trial before dropping out had been about 50% longer for subjects on ergoloid mesylates than for those on placebo.

Table XIII. Dropouts due to serious disease: number of subjects

Subjects Ergoloid mesylates

Placebo

No. drop-outs 11 Sex: Male 7

Female 4 Mean (S .D . ) initial age (years) Months in trial (median) 18

6526

14 9 5

65k4 12

Main diseases Neoplasms Central nervous system Cardiovascular system Respiratory tract Gastro-intestinal tract Urinary tract Locomotor system Alcoholism Mental changes

1 3

1 1 3

Subjects followed up under open conditions. Subjects who developed ‘ergoloid mesylates-sensitive symptoms’ (see Table IV) were taken out of the double-blind study and continued the trial under open conditions. This was necessary for 6 subjects in the ergoloid mesylates and 8 subjects in the placebo group. Five

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of 6 subjects formerly on ergoloid mesylates continued this treatment under open conditions. The 8 subjects formerly on placebo were switched to ergoloid mesylates medication and continued under open conditions (Table XIV). Of the 5 ergoloid mesylates subjects who remained on this treatment, 4 improved sub- sequently with regard to the symptoms for which they had been taken out of the double-blind study (1 with memory problems, 3 with cervical syndrome). One (with stroke) did not change. Of the 8 subjects switched from placebo to ergoloid mesylates, 5 showed subsequent improvement (2 with stroke, 2 with cervical syndrome, 1 with peripheral vascular disease) and 3 did not change (2 with memory problems, 1 with tinnitus).

Table XIV.

Subjects Ergoloid Placebo

Follow-up of subjects under open conditions and changes in treatment

mesylates

No. subjects 9 Sex: Male 4

Female 5 Mean ( 3 . D . ) initial age (years) 65*6 Months in trial before change (median) 24

1 1 7 4

66k4 24

Reason for change Treatment Change Change to Change to open study unchanged to no ergoloid to no

treatment mesylates treatment

Stroke 1 Memory problems 1 Tinnitus Cervical syndrome 3 Vascular disease Cardiovascular disease Other 2

2 1

At the request of the treating physician, 3 more individuals in the ergoloid mesylates group and 3 more of the placebo group who suffered from cardio- vascular and other diseases were taken out of the double-blind trial. They were treated according to the recommendations of their doctor, i.e. 2 remained on ergoloid mesylates, 1 was switched from placebo to ergoloid mesylates, and 3 continued without any medication. Their follow-up is not considered here.

Discussion The present study differs from previously reported therapeutic trials with ergoloid mesylates in that it involves the prophylactic administration of this drug to a group of healthy, non-institutionalized elderly individuals. Our subjects constitute a positive selection from the elderly population as regards health, physical and mental activity, social stability and motivation to participate in a long-term study. Accordingly, the drop-out rate within the 5-year period was low, in spite of the considerable amount of time demanded of the subjects taking part.

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A first and interesting finding is that, irrespective of which treatment (ergoloid mesylates or placebo) they were receiving, many of the subjects who remained in the double-blind trial feel better at the end of the 5 years than they did at the beginning. This improvement is manifest as follows: (i) subjective ‘neurological’ symptoms such as headaches, tiredness, dizziness and paraesthesias were less frequently reported; (ii) the frequency of subjective somatic symptoms, mainly respiratory and gastro-intestinal complaints, decreased; (iii) the number of depres- sive subjects declined - the Neuroticism Score of the MPI showed a decline rather than the increase described for this age range;4 (iv) consumption of analgesics and laxatives was somewhat reduced, and the proportion of smokers decreased; (v) serum creatinine and serum lipid levels and the number of subjects with abnormally high levels decreased (clearly as a result of advice on fluid intake and nutrition); and (vi) time needed to perform the Wechsler Intelligence test (WAIS) declined, total performance in this test showed little decrement and performance in the CPM intelligence test improved.

Evidently, some aspects of this positive development can be explained by selective drop-out of less healthy and poorly motivated subjects, by attitudinal changes independent of the trial, by learning effects, etc. The fact remains, however, that participation in this longitudinal study has paid off medically and emotionally for a high proportion of our subjects: their physical and mental health status was continually supervised, they received medical and social attention and - if required - advice and help in difficult situations. If diseases occurred or abnormal findings were detected, they consulted their doctors more frequently than they used to, and probably also more frequently than the elderly population in general.

On the other hand, even regular and careful supervision did not prevent a number of age-related changes from occurring: (i) the frequency of disease and hospitalization increased clearly, and the number of subjects having medically relevant diagnoses increased; (ii) consumption of medication increased slightly; (iii) the proportion of pathological ECGs increased; (iv) pulse frequency de- creased; (v) blood pressure, as measured by the physician, showed an average increase of 10 mmHg systolic and 8 mmHg diastolic pressure, although blood pressure values measured by the nurses did not show an increase over 5 years: and (vi) although total performance in the WAIS did not show a decline from baseline values, the Vocabulary test (probably tapping long-term memory) showed a steady decline over 5 years.

Thus, a number of age-related - presumably physiological and pathological - changes were taking place, including death and disease. Six subjects died from various causes: they were equally distributed between the ergoloid mesylates and the placebo group (3 in each). Twenty-five subjects dropped out from the study due to serious medical problems of different kinds. Eleven of them had been on ergoloid mesylates and 14 on placebo. Twenty subjects were taken out of the double-blind trial because they had developed one or more so-called ‘ergoloid mesylates-sensitive’ symptoms. Again, there were somewhat more placebo (n = 11) than ergoloid mesylates subjects (n =9) who had to leave the double-blind trial.

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In view of some of these factors (positive selection of study sample; selective drop-out of subjects showing deterioration, particularly in the placebo group), no dramatic effect was to be expected from the 5-year treatment with ergoloid mesylates. In fact, none of the 10 formal statistical comparisons between the two groups of subjects remaining in the double-blind trial revealed significant differences. Nevertheless, some of the findings are noteworthy:

(i) Ergoloid mesylates was well tolerated on controlled long-term administration. N o side-effects or drug-related changes in laboratory values were recorded after regular administration of this drug over 5 years. Some changes in median values or in the number of subjects with values outside the normal range were explained by laboratory variation and concomitant diseases or medication; none of them was considered related to ergoloid mesylates.

(ii) Observations on subjective symptoms (frequent dizziness, cardiac symptoms, leg cramps) suggested a positive effect of ergoloid mesylates, since the number of subjects complaining of these symptoms decreased in the ergoloid mesylates group, in contrast to the placebo group. Similarly, the Neuroticism Score of the MPI showed a greater decline in the ergoloid mesylates than in the placebo group.

(iii) The number of subjects with abnormal ECG findings increased during the study. This increase was markedly smaller in the ergoloid mesylates than in the placebo group (from 34% to 57% in the ergoloid mesylates and from 34% to 71% in the placebo group).

(iv) The number of subjects taking digitalis had been higher in the placebo group at the beginning of the study. It increased further during the course of the trial (from 5 to 9), but changed little in the ergoloid mesylates group (from 1 to 2).

(v) The reduction in mean values of some lipid fractions and in the number of subjects with elevated values was more pronounced in the ergoloid mesylates group.

(vi) The percentage of subjects who had an unchanged or even lower number of major diagnoses, in particular hypertension and coronary artery disease, was higher in the ergoloid mesylates than in the placebo group (68% vs. 56%).

(vii) Some of the psychometric variable (WAIS Vocabulary, WAIS Performance and CPM in subjects with poorer initial performance) developed more favourably in ergoloid mesylates-treated subjects.

While none of these findings, by itself, is spectacular and none of the group differences is statistically significant, they all fall into a pattern suggesting that ergoloid mesylates (‘Hydergine’) was helpful in maintaining subjective and objec- tive aspects of health and well-being in healthy elderly subjects. The occurrence of more numerous disease-related and symptom-related drop-outs in the placebo group supports this assumption, and the fact that a number of subjects who had left the double-blind trial for medical reasons subsequently showed improvement on ergoloid mesylates argues in favour of this drug. The present study thus provides evidence that long-term use of ergoloid mesylates may help to prolong the physically and mentally healthy years and to reduce the phase of physical and psychological dependence in the life of persons who have reached the age of retirement.

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References 1 . Ayman, D., and Goldshine, A. D., (1940). Blood pressure determinations by patients with essential hypertension: the difference between clinic and home readings before treatment. Am. J. Med. Sci., 200,465-474. 2. Koberle, S., and Spiegel, R., (1984). A long-term study with co-dergocrine mesylate (Hyder- gine) in healthy pensioners: results after 3 years. Gerontology, 30, Suppl. 1 , 1-52. 3. Mancia, G., Grassi, G., Pimidossi, G., Gregorini, L., Bertinieri, G., Parati, G., Ferrari, A., and Zanchetti, A., (1983). Effects of blood-pressure measurement by the doctor on patient’s blood pressure and heart rate. Lancet, 2,695-698. 4. Neugarten, B. L., (1977). Personality and aging. In: “Handbook of the Psychology of Aging“. pp. 626-649. Eds.: J. E. Birren and K. W. Schaie. Van Nostrand, New York. 5. Raven, J. C., (1965). “The Coloured Progressive Matrices. Sets A, Ab and B”. Lewis. London. 6. Spiegel, R., Huber, F., and Koberle, S., (1983). A controlled long-term study with ergoloid mesylates (Hydergine) in healthy, elderly volunteers: results after three years. J. Am. Geriatr.

7. Wechsler, D., (1964). “Messung der Intelligenz Erwachsener”. Huber, Bern. (German translation of “The Measurement of Adult Intelligence”, Williams & Wilkins. Baltimore 1944). 8. Widmer, L. K., and Waibel, P., (1972). “Arterielle Durchblutungsstorungen in der Praxis”. Huber. Bern.

SOC., 31,549-555.

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