The Journal of International Medical Research 1990; 18: 240 - 244
Indobufen in Secondary Prevention of Transient Ischaemic Attack J. Rogan and Multicentre Ischaemic Attack Study Group 'Medical Department, Farmitalia Carlo Erba ROSCA, Vienna, Austria
The secondary prevention of transient ischaemic attacks was assessed in 270 patients treated orally with 100 mg indobufen given twice daily for 12 months. After 1 month's treatment, the average number and average incidence of transient ischaemic attacks were reduced significantly (P < 0.001) and remained suppressed throughout the treatment period. Treatment was interrupted in 17 patients: in two because of side-effects (gastric disturbances); in 10 because of fatal events (six completed strokes, two myocardial infarcts and two unrelated deaths); and in five due to poor protocol compliance. Progression to reversible ischaemic neurological deficit occurred in five patients. Most sideeffects were mild and transient, mainly occurring in the first month of treatment. Overall, indobufen was judged to have good efficacy and safety by both patients and physicians. KEY WORDS: Indobufen; transient ischaemic attack; secondary prevention.
INTRODUCTION
P
atients diagnosed as having had a transient ischaemic attack (TIA) or those that have recovered almost completely from an ischaemic stroke are at risk due to the recurrence of a primary event and/or a fatal secondary vascular event. In general, the natural course of TIA and of mild stroke are similar, 1 the incidence of subsequent stroke
Received for publication 26 February 1990; accepted 2 March 1990. Address for correspondence: Dr J. Rogan, Medical Department, Farmitalia Carlo ErbaROSCA,Karlsplatz 1,1010 Vienna, Austria.
240
and of myocardial infarction being comparable.? The severe vascular events experienced by these patients are as likely to be cardiovascular as cerebrovascular, with the majority of the conditions being considered to be due to thrombotic and embolic complications of atheroma. Properly balanced inhibition of thrombosis, therefore, might prove useful for patients who have experienced TIA as well as for those with mild stroke. Several anti-platelet drugs have been studied in order to establish their efficacy in the secondary prevention of fatal cardiovascular events: for example, aspirin and dipyridamole have been used in numerous © Copyright 1990 by Cambridge Medical Publications Ltd
Indobufen in transient ischaemic attack trials either alone or in combinations. Both these drugs have proved effective in the secondary prevention of either type of vascular mortality. 3 When considering TIA, the results of relatively large randomized trials have often been contradictory;" - 8 however, overall it has been suggested that there is a need for a safe and stable long-term antiplatelet treatment. In order to design and perform a trial to assess the efficacy and safety of a relatively new anti-platelet substance, indobufen, a collaborative group was set up. The results of this open, multicentre trial are reported in this paper. PATIENTS AND METHODS
Patients A total of 323 patients (223 males, 100 females; mean age 56.7 years, range 30 74 years) were entered into the study, 270 being finally evaluated. All patients were diagnosed as having had at least one TIA,9 the last attack having been recorded within 3 months of inclusion in the study. The incidence of attacks prior to the trial varied: 128 (47.4%) patients had experienced only one attack; 83 (30.7%) two to four attacks; and the remaining 59 (21.9%) five or more attacks. The duration of the longest attacks also varied: in 84 (31.1%) patients they had lasted 1- 30 min; in 15 (5.6%) up to I h; in 70 (25.9%) up to to h; and in tol (37.4%) 10 - 24 h. In the majority of patients (60.7%), the left carotid area had been involved and in 33.6% the right had been involved; in the remaining patients (5.7%) both carotid and the vertebrobasilar areas were affected. Analysis of risk factors revealed that only 43 (16%) patients were smoking more than 20 cigarettes a day, to7 (39.6%) were non-smokers, 65 (24%) had given up smoking and 14 (5.2%) were consuming more that I dl alcohol per day. The average systolic blood pressure was 156.7 ± 1.75 mmHg and the mean diastolic pressure was 91.5 ± 0.7 mmHg; the mean ponderal index
was 40.5 ± 0.7. Scans were normal in 86.4% of the 149 patients examined by computerized tomography and findings were normal in 23.2% of the 99 patients examined using Doppler sonography; abnormalities did not consist of infarct or ischaemic changes. Treatment Patients received 100 mg indobufen orally twice daily for 12 months after a light meal. Clinical assessment LaboratorytestswereperformedusingWorld Health Organization standard references before and duringtreatment, Patients were clinically examined I month after the start of treatment and at 3-month intervals thereafter. Stroke and/or death and myocardial infarction, side-effects of treatment and compliance to treatment, assessed by the number of remaining tablets at each visit, were recorded. After 12 months' treatment both patients and physicians evaluated the efficacy and safety of the therapy. Statistical analysis Data was analysed using the x2-testand the Student's t-test. RESULTS
Of the 323 patients who entered the trial, 270 were finally evaluated. The majority of the drop-outs (35 patients) were due to inconsistent data in the case report forms. Other reasons for not being included in the evaluation were: abnormal neurological tests (two patients); concomitant disease (four patients); side-effects (four patients); and poor patient compliance (eight patients). After treatment with 100 mg indobufen twice daily for I month the average number of patients with TIA declined significantly (P < 0.001) and thereafter remained at a similar level for the remaining II months of treatment (Fig. I). A similar, significant (P < 0.(01) decline in the number of TIA per patient was recorded. Treatment, however, was not effective 241
I.Rogan, Multicentre Ischaemic Attack Study Group
100
-0- • -
Average number ofTIA Incidence of TIA per patient
•• -\ •• •
-.......... ....... .
-
OL..L-.-----L
L..-
o
4
--'-
. . . .-.
10
12
....L-
7
--'
Treatment time (months)
Fig. 1. Average number of transient ischaemic attacks (TlA) and incidence of TlA per patient following treatment with 100 mg indobufen given orally twice daily for 12 months.
in all patients; five progressed to reversible ischaemic neurological defect; six suffered completed stroke; two myocardial infarction; and two died (Table 1). In a total of 17 patients, treatment was interrupted due to side-effects (two patients) or poor protocol compliance (15 patients). The most commonly reported side-effects were gastric disturbances and some patients also experi-
enced allergic exanthema, gingival bleeding, epistaxis and dizziness (Table 2). None of the side-effects listed in Table 2 necessitated the interruption of treatment. Serum cholesterol concentrations were elevated in 75 patients prior to treatment, as were serum triglycerides in 53 patients. Blood glucose concentrations were abnormally high in 29 patients prior to treatment
Table 1 Deaths in transient ischaemic attack patients (n = 270) treated orally with 100 mg indobufen given orally twice daily for 12 months Computerized tomography Diagnosis Reversible ischaemic neurological deficit Completed stroke Myocardial infarct
Unrelated death
242
No. of patients
Infarct
5
3 5
6
2 2
Diffuse
Not done
I 1
Indobufen in transient ischaemic attack
Table 2 Incidence of side-effects in transient ischaemic attack patients (n =270) treated with 100 mg indobufen given orally twice daily for 12 months Treatment time (months) Side-effect
1
Gastric disturbances Allergic exanthema Gingival bleeding Epistaxis Dizziness
4
Total
10
7
4
12
1 1
1 1
3
5
but only 10 were registered diabetics. In 20 patients, serum cholesterol and triglyceride levels tended to normalize, as did blood glucose in 12 patients. The majority of patients and physicians rated the efficacy and safety of indobufen as being good (Table 3). DISCUSSION
It has been suggested that drugs that sup-
press platelet function can improve the prognosis in patients with diseases associated with platelet thrombi; two such disorders - cardiac and cerebrovascular diseases - are major causes of morbidity and death. Several studies of the use of platelet-
2
3
inhibiting drugs in cardiac disease have reported promising results in secondary prevention but, at the same time, have warned about the risk/benefit ratio of primary prevention, mainly due to the side-effects of the drugs.' Similar trials in TIA patients have used the incidence of fatal events to establish some beneficial, although sometimes different, effect on platelet inhibition.4 ,6,9 - 12 The present paper reports the results of evaluation of efficacy for indobufen in secondary prevention of TIA in 270 evaluable patients. Although it is appreciated that there are deficiencies in an uncontrolled trial, several facts should be
Table 3 Patients' and physicians' evaluation of efficacy and safety of 100 mg indobufen given orally twice daily for 12 months in transient ischaemic attack patients (n =270) Patients
Physicians
Grade
Efficacy
Safety
Efficacy
Safety
Good Fair Poor
91.8% 4.1% 4.1%
96.3% 2.9% 0.8%
91.4% 3.3% 5.3%
95,9% 2.9% 1.2%
243
J.Rogan, Multicentre Ischaemic Attack Study Group
stressed. First, the main goal, at the time of the initiation of the study, was to establish the efficacy and, in particular, the safety of indobufen since it was realized that in majority of TIA patients treatment might be life-long. It is considered that both of these issues were adequately examined. Explanatory analyses has proved that indobufen was efficient in reducing both the average incidence and number of recurrent TIA during the l-year treatment period. In addition, the drug was judged to be safe by both patients and physician, and compliance to treatment was high. Secondly, although a much longer follow-up and a larger number of patients would be required to calculate the impact of indobufen therapy on general cerebrovascular mortality, in the present study only 10 fatal events (six completed strokes, two myocardial infarctions and two other deaths) were recorded. As already stressed, it was far beyond the scope of the present study to claim that there is a reduction in cerebrovascular risk but instead the intention was to show that indobufen had good efficacy and was well tolerated when administered over a long term. The results of the present study may justify further large-scale studies (similar to that reported by Mazzei et al. 12) and even comparative studies while bearing in mind recent reports of the safety of other drugs. 13 ACKNOWLEDGEMENT
Indobufen was provided by Farmitalia Carlo Erba, Austria. REFERENCES 1. Wiebers D, Wishnant JR, O'Fallon WM: Reversible ischemic neurologic deficit (RIND) in a community: Rochester, Minnesota, 1955 - 1974. Neurology 1982; 32: 459 - 465. 2. Heymann A, Wilkinson EE, Hurztiz BJ: Risk of ischemic heart disease in patients with TIA. Neurology 1984; 34: 626 - 630.
244
3. Antiplatelet Trialists' Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320331. 4. Acheson J, Danta G, Hutchinson EC: Controlled trial of dipyridamole in disease. Br Med J 1%9; i: 614 - 615. 5. Candelise L, Laudi G, Perrone P, et al: A randomized trial of aspirin and sulfmpyrazone in patients with TIA. Stroke 1982; 13: 175 -179. 6. Sorensen PS, Pedersen H, Marguardsen J, et al: Acetylsalicylic acid in the prevention of stroke in patients with reversible ischemic attacks. A Danish Cooperative Study. Stroke 1987; 18: 325 334. 7. A Swedish Cooperative Study: High dose acetylsalicylic acid after cerebral infarction. Stroke 1987; 18: 325 - 334. 8. UK - TIA Study Group: United Kingdom transient ischaemic attack (UK - TIA) aspirin trial: interim results. Br Med J 1988; 296: 316 - 320. 9. Bousser MG, Eschwege C, Haguenan M, et al: "A1CLA" controlled trial of aspirin and dipyridamole in secondary prevention of athero-thrombotic cerebral ischemia. Stroke 1983; 14: 5 - 14. 10 Canadian Cooperative Study Group: A randomized trial of aspirin and sulfmpyrzaone in threatened stroke. N Engl J Med 1978; 299: 53 - 59. 11. Belcaro G, Errichi BM, Laurora G, et al: Trattamento cronico della patologia vascolare con indobufene. Minerva Cardioangiol 1989; 37: 241-250. 12. Mazzei B, Carelli A, GaudioG, et al: Prevenzione delle recidive di episodi di eschernia cerebrale. Minerva Med 1988; 79: 703 -706. 13. Paganini-Hill A, Chao A, Ros RK, et al: Aspirin use and chronic diseases: a cohort study of the elderly. Br Med J 1989; 299: 1247 - 1250. .APPENDIX The Transient Ischaemic Attack Study Group comprised the following: I. Cinca, Colantina Hospital, Bucharest, Romania; E. Fabian, Na Siupi Hospital, Prague, Czechoslovakia; D. Hadziev, Institute of Neurology, Sofia, Bulgaria; L. Orlandini, Farmitalia Carlo ErbaROSCA, Vienna, Austria; M. Panic, Hospital M. Misovic, Belgrade, Yugoslavia; P. Pemov, Neuropsychiatric Hospital, Skopje, Yugoslavia; C. Popa, G. Marinescu Hospital, Bucharest, Romania; M. Porse, Clinical Centre, Ljubljana, Yugoslavia; J. Rogan, Farmitalia Carlo Erba ROSCA, Vienna, Austria; A. Slaby, Charles University, Prague, Czechoslovakia; W. Staszkiewicz, Medical Academy, Warsaw, Poland; 1. Tichy, Charles University, Prague, Czechoslovakia; J. Tratnik, Farmitalia Carlo Erba, Zagreb, Yugoslavia.
Indobufen in Secondary Prevention of Transient Ischaemic Attack J. Rogan and Multicentre Ischaemic Attack Study Group 'Medical Department, Farmitalia Carlo Erba ROSCA, Vienna, Austria
The secondary prevention of transient ischaemic attacks was assessed in 270 patients treated orally with 100 mg indobufen given twice daily for 12 months. After 1 month's treatment, the average number and average incidence of transient ischaemic attacks were reduced significantly (P < 0.001) and remained suppressed throughout the treatment period. Treatment was interrupted in 17 patients: in two because of side-effects (gastric disturbances); in 10 because of fatal events (six completed strokes, two myocardial infarcts and two unrelated deaths); and in five due to poor protocol compliance. Progression to reversible ischaemic neurological deficit occurred in five patients. Most sideeffects were mild and transient, mainly occurring in the first month of treatment. Overall, indobufen was judged to have good efficacy and safety by both patients and physicians. KEY WORDS: Indobufen; transient ischaemic attack; secondary prevention.
INTRODUCTION
P
atients diagnosed as having had a transient ischaemic attack (TIA) or those that have recovered almost completely from an ischaemic stroke are at risk due to the recurrence of a primary event and/or a fatal secondary vascular event. In general, the natural course of TIA and of mild stroke are similar, 1 the incidence of subsequent stroke
Received for publication 26 February 1990; accepted 2 March 1990. Address for correspondence: Dr J. Rogan, Medical Department, Farmitalia Carlo ErbaROSCA,Karlsplatz 1,1010 Vienna, Austria.
240
and of myocardial infarction being comparable.? The severe vascular events experienced by these patients are as likely to be cardiovascular as cerebrovascular, with the majority of the conditions being considered to be due to thrombotic and embolic complications of atheroma. Properly balanced inhibition of thrombosis, therefore, might prove useful for patients who have experienced TIA as well as for those with mild stroke. Several anti-platelet drugs have been studied in order to establish their efficacy in the secondary prevention of fatal cardiovascular events: for example, aspirin and dipyridamole have been used in numerous © Copyright 1990 by Cambridge Medical Publications Ltd
Indobufen in transient ischaemic attack trials either alone or in combinations. Both these drugs have proved effective in the secondary prevention of either type of vascular mortality. 3 When considering TIA, the results of relatively large randomized trials have often been contradictory;" - 8 however, overall it has been suggested that there is a need for a safe and stable long-term antiplatelet treatment. In order to design and perform a trial to assess the efficacy and safety of a relatively new anti-platelet substance, indobufen, a collaborative group was set up. The results of this open, multicentre trial are reported in this paper. PATIENTS AND METHODS
Patients A total of 323 patients (223 males, 100 females; mean age 56.7 years, range 30 74 years) were entered into the study, 270 being finally evaluated. All patients were diagnosed as having had at least one TIA,9 the last attack having been recorded within 3 months of inclusion in the study. The incidence of attacks prior to the trial varied: 128 (47.4%) patients had experienced only one attack; 83 (30.7%) two to four attacks; and the remaining 59 (21.9%) five or more attacks. The duration of the longest attacks also varied: in 84 (31.1%) patients they had lasted 1- 30 min; in 15 (5.6%) up to I h; in 70 (25.9%) up to to h; and in tol (37.4%) 10 - 24 h. In the majority of patients (60.7%), the left carotid area had been involved and in 33.6% the right had been involved; in the remaining patients (5.7%) both carotid and the vertebrobasilar areas were affected. Analysis of risk factors revealed that only 43 (16%) patients were smoking more than 20 cigarettes a day, to7 (39.6%) were non-smokers, 65 (24%) had given up smoking and 14 (5.2%) were consuming more that I dl alcohol per day. The average systolic blood pressure was 156.7 ± 1.75 mmHg and the mean diastolic pressure was 91.5 ± 0.7 mmHg; the mean ponderal index
was 40.5 ± 0.7. Scans were normal in 86.4% of the 149 patients examined by computerized tomography and findings were normal in 23.2% of the 99 patients examined using Doppler sonography; abnormalities did not consist of infarct or ischaemic changes. Treatment Patients received 100 mg indobufen orally twice daily for 12 months after a light meal. Clinical assessment LaboratorytestswereperformedusingWorld Health Organization standard references before and duringtreatment, Patients were clinically examined I month after the start of treatment and at 3-month intervals thereafter. Stroke and/or death and myocardial infarction, side-effects of treatment and compliance to treatment, assessed by the number of remaining tablets at each visit, were recorded. After 12 months' treatment both patients and physicians evaluated the efficacy and safety of the therapy. Statistical analysis Data was analysed using the x2-testand the Student's t-test. RESULTS
Of the 323 patients who entered the trial, 270 were finally evaluated. The majority of the drop-outs (35 patients) were due to inconsistent data in the case report forms. Other reasons for not being included in the evaluation were: abnormal neurological tests (two patients); concomitant disease (four patients); side-effects (four patients); and poor patient compliance (eight patients). After treatment with 100 mg indobufen twice daily for I month the average number of patients with TIA declined significantly (P < 0.001) and thereafter remained at a similar level for the remaining II months of treatment (Fig. I). A similar, significant (P < 0.(01) decline in the number of TIA per patient was recorded. Treatment, however, was not effective 241
I.Rogan, Multicentre Ischaemic Attack Study Group
100
-0- • -
Average number ofTIA Incidence of TIA per patient
•• -\ •• •
-.......... ....... .
-
OL..L-.-----L
L..-
o
4
--'-
. . . .-.
10
12
....L-
7
--'
Treatment time (months)
Fig. 1. Average number of transient ischaemic attacks (TlA) and incidence of TlA per patient following treatment with 100 mg indobufen given orally twice daily for 12 months.
in all patients; five progressed to reversible ischaemic neurological defect; six suffered completed stroke; two myocardial infarction; and two died (Table 1). In a total of 17 patients, treatment was interrupted due to side-effects (two patients) or poor protocol compliance (15 patients). The most commonly reported side-effects were gastric disturbances and some patients also experi-
enced allergic exanthema, gingival bleeding, epistaxis and dizziness (Table 2). None of the side-effects listed in Table 2 necessitated the interruption of treatment. Serum cholesterol concentrations were elevated in 75 patients prior to treatment, as were serum triglycerides in 53 patients. Blood glucose concentrations were abnormally high in 29 patients prior to treatment
Table 1 Deaths in transient ischaemic attack patients (n = 270) treated orally with 100 mg indobufen given orally twice daily for 12 months Computerized tomography Diagnosis Reversible ischaemic neurological deficit Completed stroke Myocardial infarct
Unrelated death
242
No. of patients
Infarct
5
3 5
6
2 2
Diffuse
Not done
I 1
Indobufen in transient ischaemic attack
Table 2 Incidence of side-effects in transient ischaemic attack patients (n =270) treated with 100 mg indobufen given orally twice daily for 12 months Treatment time (months) Side-effect
1
Gastric disturbances Allergic exanthema Gingival bleeding Epistaxis Dizziness
4
Total
10
7
4
12
1 1
1 1
3
5
but only 10 were registered diabetics. In 20 patients, serum cholesterol and triglyceride levels tended to normalize, as did blood glucose in 12 patients. The majority of patients and physicians rated the efficacy and safety of indobufen as being good (Table 3). DISCUSSION
It has been suggested that drugs that sup-
press platelet function can improve the prognosis in patients with diseases associated with platelet thrombi; two such disorders - cardiac and cerebrovascular diseases - are major causes of morbidity and death. Several studies of the use of platelet-
2
3
inhibiting drugs in cardiac disease have reported promising results in secondary prevention but, at the same time, have warned about the risk/benefit ratio of primary prevention, mainly due to the side-effects of the drugs.' Similar trials in TIA patients have used the incidence of fatal events to establish some beneficial, although sometimes different, effect on platelet inhibition.4 ,6,9 - 12 The present paper reports the results of evaluation of efficacy for indobufen in secondary prevention of TIA in 270 evaluable patients. Although it is appreciated that there are deficiencies in an uncontrolled trial, several facts should be
Table 3 Patients' and physicians' evaluation of efficacy and safety of 100 mg indobufen given orally twice daily for 12 months in transient ischaemic attack patients (n =270) Patients
Physicians
Grade
Efficacy
Safety
Efficacy
Safety
Good Fair Poor
91.8% 4.1% 4.1%
96.3% 2.9% 0.8%
91.4% 3.3% 5.3%
95,9% 2.9% 1.2%
243
J.Rogan, Multicentre Ischaemic Attack Study Group
stressed. First, the main goal, at the time of the initiation of the study, was to establish the efficacy and, in particular, the safety of indobufen since it was realized that in majority of TIA patients treatment might be life-long. It is considered that both of these issues were adequately examined. Explanatory analyses has proved that indobufen was efficient in reducing both the average incidence and number of recurrent TIA during the l-year treatment period. In addition, the drug was judged to be safe by both patients and physician, and compliance to treatment was high. Secondly, although a much longer follow-up and a larger number of patients would be required to calculate the impact of indobufen therapy on general cerebrovascular mortality, in the present study only 10 fatal events (six completed strokes, two myocardial infarctions and two other deaths) were recorded. As already stressed, it was far beyond the scope of the present study to claim that there is a reduction in cerebrovascular risk but instead the intention was to show that indobufen had good efficacy and was well tolerated when administered over a long term. The results of the present study may justify further large-scale studies (similar to that reported by Mazzei et al. 12) and even comparative studies while bearing in mind recent reports of the safety of other drugs. 13 ACKNOWLEDGEMENT
Indobufen was provided by Farmitalia Carlo Erba, Austria. REFERENCES 1. Wiebers D, Wishnant JR, O'Fallon WM: Reversible ischemic neurologic deficit (RIND) in a community: Rochester, Minnesota, 1955 - 1974. Neurology 1982; 32: 459 - 465. 2. Heymann A, Wilkinson EE, Hurztiz BJ: Risk of ischemic heart disease in patients with TIA. Neurology 1984; 34: 626 - 630.
244
3. Antiplatelet Trialists' Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320331. 4. Acheson J, Danta G, Hutchinson EC: Controlled trial of dipyridamole in disease. Br Med J 1%9; i: 614 - 615. 5. Candelise L, Laudi G, Perrone P, et al: A randomized trial of aspirin and sulfmpyrazone in patients with TIA. Stroke 1982; 13: 175 -179. 6. Sorensen PS, Pedersen H, Marguardsen J, et al: Acetylsalicylic acid in the prevention of stroke in patients with reversible ischemic attacks. A Danish Cooperative Study. Stroke 1987; 18: 325 334. 7. A Swedish Cooperative Study: High dose acetylsalicylic acid after cerebral infarction. Stroke 1987; 18: 325 - 334. 8. UK - TIA Study Group: United Kingdom transient ischaemic attack (UK - TIA) aspirin trial: interim results. Br Med J 1988; 296: 316 - 320. 9. Bousser MG, Eschwege C, Haguenan M, et al: "A1CLA" controlled trial of aspirin and dipyridamole in secondary prevention of athero-thrombotic cerebral ischemia. Stroke 1983; 14: 5 - 14. 10 Canadian Cooperative Study Group: A randomized trial of aspirin and sulfmpyrzaone in threatened stroke. N Engl J Med 1978; 299: 53 - 59. 11. Belcaro G, Errichi BM, Laurora G, et al: Trattamento cronico della patologia vascolare con indobufene. Minerva Cardioangiol 1989; 37: 241-250. 12. Mazzei B, Carelli A, GaudioG, et al: Prevenzione delle recidive di episodi di eschernia cerebrale. Minerva Med 1988; 79: 703 -706. 13. Paganini-Hill A, Chao A, Ros RK, et al: Aspirin use and chronic diseases: a cohort study of the elderly. Br Med J 1989; 299: 1247 - 1250. .APPENDIX The Transient Ischaemic Attack Study Group comprised the following: I. Cinca, Colantina Hospital, Bucharest, Romania; E. Fabian, Na Siupi Hospital, Prague, Czechoslovakia; D. Hadziev, Institute of Neurology, Sofia, Bulgaria; L. Orlandini, Farmitalia Carlo ErbaROSCA, Vienna, Austria; M. Panic, Hospital M. Misovic, Belgrade, Yugoslavia; P. Pemov, Neuropsychiatric Hospital, Skopje, Yugoslavia; C. Popa, G. Marinescu Hospital, Bucharest, Romania; M. Porse, Clinical Centre, Ljubljana, Yugoslavia; J. Rogan, Farmitalia Carlo Erba ROSCA, Vienna, Austria; A. Slaby, Charles University, Prague, Czechoslovakia; W. Staszkiewicz, Medical Academy, Warsaw, Poland; 1. Tichy, Charles University, Prague, Czechoslovakia; J. Tratnik, Farmitalia Carlo Erba, Zagreb, Yugoslavia.
