Cyclandelate in the prophylaxis of migraine: a placebo-controlled study.

The prophylactic action of cyclandelate was investigated in a multicentre, randomized, placebo-controlled, parallel group study. A 4-week baseline period was followed by a 4-week placebo phase and a 16-week treatment period with either 1600 mg cyclandelate or placebo. Patients (n = 251) with two to six migraine attacks/month were randomized. Neither the primary study endpoint (reduction of migraine days from baseline to the last 28 days) nor most of the secondary endpoints (reduction in the number of migraine attacks, severity or duration of attacks, frequency of autonomic disturbances, medication for treatment of attacks) showed a difference between cyclandelate and placebo. Cyclandelate, however, was superior to placebo in a global impression of efficacy rated by the patients and the treating physicians. Both treatments were well tolerated. In conclusion, cyclandelate was not superior to placebo in the prophylaxis of migraine with regard to parameters usually used in migraine prophylaxis trials.

Evidence for neuronal dysfunction in migraine: concurrence between specific qEEG findings and clinical drug response--a retrospective analysis-.

OBJECTIVE: The aim of this analysis was to verify objective correlates of the clinical improvement of migraine in patients by means of quantitative topographical EEG (qEEG). METHODS: Overall 40 migraine-outpatients participated in this retrospective analysis of prophylactic migraine treatment over 3-8 months with 1600 to 2000 mg cyclandelate daily. In all patients qEEG was recorded and analysed using the Fast Fourier Transformation and the determination of the Abberation Index (AI = the statistical probability of belonging to a qEEG reference group of healthy people, n = 500). RESULTS: A clinical response (> 50% reduction of migraine attack frequency and duration) was observed in 77.5% (n = 31). The number and duration of migraine attacks per month (median values) were reduced in a highly significant manner. In this observation 75% of all patients investigated showed a pathological positive Aberration Index at a single electrode or a cluster of neighbouring brain sites. This consisted in a power increase in theta, alpha and/or beta1 activity, and 73.3% of them had also a corresponding negative AI-focus (power decrease). In 15 patients EEG aberrations (positive AI clusters) within one frequency band were found, whereas 15 patients showed aberrations in more than one frequency. Positive AI s were mainly found in fronto-temporal and occipital brain areas with one single topographical difference between the patients with and without aura. CONCLUSIONS: Positive AI values were the main electrophysiological findings in these migraine patients. This was supported by the highly significant decrease of the median amount of the positive AI after clinically successful treatment with cyclandelate. Twenty four out of thirty patients with positive AI foci showed concurrence between qEEG-changes and clinical response. Patients with positive AI foci involving the lower or middle frequencies (theta and/or alpha 1) seemed to show a better clinical response (84.6%) than those with AI foci with participation of only faster frequencies (alpha 2 and/or beta 1; 54.5%). A controlled study is needed to confirm these observations.

Cyclandelate in the treatment of patients with mild to moderate primary degenerative dementia of the Alzheimer type or vascular dementia: experience from a placebo controlled multi-center study.

A 24-week, double-blind, multi-center, randomised parallel group study compared the efficacy and safety of 800 mg bid cyclandelate with placebo in patients with mild to moderate dementia of primary degenerative or vascular origin. A total of 196 patients entered the study, 147 patients completed treatment in adherence with the protocol. Primary outcome measures were the cognitive score of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the subscale Instrumental Activities of Daily Living of the Nurses' Observation Scale for Geriatric Patients (NOSGER-IADL) and the Clinical Global Impressions of Change (CGI-C). Safety assessments included adverse events, vital signs, ECG and clinical laboratory parameters. The primary efficacy results based on a multi-level responder analysis including ADAS-Cog, NOSGER-IADL and CGI-C failed to demonstrate statistical superiority of cyclandelate in comparison to placebo. The direction of changes favored cyclandelate in each of the variables, but the differences to placebo were small and varied considerably between patients and centers. Retrospective exploratory analyses suggested that efficacy of cyclandelate might be dependent on the severity of the disease. The treatment effects in favor of cyclandelate were statistically significant in the subgroup of moderately impaired patients (MMSE at baseline <18) for ADAS-Cog (delta = -4.0 points, p = 0.015) and CGI-C (delta = -0.4 points, p = 0.043) but not for NOSGER-IADL (delta = -1.6 points, p = 0.059). When patients were stepwise selected for the severity of the disease according to ADAS-Cog at baseline (>15, >20, >25 points), statistical significance was reached for ADAS-Cog and NOSGER-IADL beginning with the step ADAS-Cog >20 points: delta ADAS-Cog = -3.9 points, p = 0.044; delta NOSGER-IADL = -1.0, p = 0.023. The treatment differences increased further with the step ADAS-Cog >25 points: delta ADAS-Cog = -7.0 points, p = 0.008; delta NOSGER-IADL = -1.7, p = 0.003. Treatment differences in CGI-C increased marginally with the stepwise selection but did not reach statistical significance. The drug was safe and well tolerated.

Clinical efficacy and central mechanisms of cyclandelate in migraine: a double-blind placebo-controlled study.

The mechanisms of action of calcium antagonists in the prophylactic treatment of migraine remain unclear. The most likely proposed mechanism seems to be via influence on the central nervous system, but the central effects of calcium entry blockers are insufficiently characterized. The aim of the present study was to investigate the central mechanisms behind the efficacy of cyclandelate in a double-blind placebo-controlled parallel-designed study using the contingent negative variation (CNV), an event-related slow potential for measuring cortical excitability and investigating preparation processes. The CNV recordings were performed in 25 females suffering from migraine without aura before treatment (baseline), after single dose administration of cyclandelate or placebo and after 8 weeks' treatment with cyclandelate (cyclandelate group, no.=15) or placebo (placebo group, no.=10). Cyclandelate reduced significantly the days with migraine and duration of migraine compared to placebo. In the cyclandelate group a significant reduction of all CNV components was observed and the changes in amplitudes compared to baseline were more pronounced after treatment. Placebo reduced the late CNV component only after single dose administration. There were no changes in the early and total CNV. Cyclandelate did not normalize the habituation of the slow negative potential. The results are discussed in terms of the influence of cyclandelate on cortical excitability and of the prevention of cortical spreading depression via antagonistic effect on calcium channels.

Cyclandelate in the management of tinnitus: a randomized, placebo-controlled study.

Cyclandelate is a vasodilating agent that, like papaverine, acts directly on the smooth muscles of blood vessels. The drug has been used primarily as an adjunctive treatment for various peripheral vascular diseases; some studies advocate its use for treating ischemic cerebrovascular disease. Early nonrandomized and uncontrolled studies suggest that cyclandelate is efficacious in treating tinnitus. Recent personal communications regarding cyclandelate's effectiveness in treating tinnitus prompted this study. Fifty-nine adult patients with constant tinnitus for more than 1 year were randomly selected for this prospective, placebo-controlled, double-blind study with a treatment period of 3 months. Audiometric testing with tinnitus pitch and loudness matching was performed before initiation of treatment and at the end of treatment, and frequent questionnaire evaluations were performed during the treatment period. Four patients in the cyclandelate group and three in the placebo group reported a subjective reduction in the loudness of their tinnitus. Audiologic testing before and after treatment showed no significant changes in tinnitus pitch or loudness. Although cyclandelate treatment was beneficial for some patients and the decrease in subjective loudness scoring was significant for the cyclandelate group, the impact of its effect did not appear to warrant its continued use by those patients. A significant percentage of patients could not tolerate the drug because of side effects.

Functional imaging of headache - first steps in an objective quantitative classification of migraine.

A highly sensitive quantitative-topographical EEG was used in order to define first steps in an objective classification of migraine. A 17-channel quantitative EEG was recorded in 30 patients suffering from migraine with or without aura during the painfree interval. These EEG s were compared to EEGs of age related healthy norm groups using a new statistical tool called the Aberration Index. A focal aberration in the area of pain was detected in 26 out of the 30 patients mostly due to an increase of alpha1 EEG power (23 patients). Alpha2 or theta power were also increased in several patients. Furthermore, a decrease in alpha power neighbouring the focus was found in 18 patients and a contralateral reduction of alpha power was seen in 16 patients. No difference was detected between migraine with aura and migraine without aura.

Pathophysiology and psychopharmacology of dementia--a new study design. 2. Cyclandelate treatment--a placebo-controlled double-blind clinical trial.

The aim of this randomized, double-blind, placebo-controlled 16-week study was to investigate the clinical efficacy of cyclandelate (Natil, 1,600 mg/day) in 139 adult outpatients with cognitive impairment (70 allocated to cyclandelate; 69 to placebo). Quantitative-topological EEG, event-related potentials (P300) and psychophysiological interview-based rating scales were used. The efficacy of cyclandelate was demonstrated in the confirmatory statistical sense using a global Hailperin-Rüger test on 10 predefined primary variables at global significance level of 0.05 relating to psychopathology, psychometry, neuropsychophysiology and behavior. At psychopathological and behavioral level the reduction of the total scores of the rating scales (Alzheimer Disease Assessment Scale, Sandoz Clinical Assessment Geriatric Scale, and Nürnberger Selbsteinschätzungs-Liste) following a 16-week therapy revealed also an individual significant cyclandelate-placebo distinction in the confirmatory statistical sense. A difference between verum and placebo was also observed by the increase of the number of correct answers during performance of the number symbol test (psychometrical level). The objective electrophysiological data (neuropsychophysiological level) support these findings. Of particular interest is that following cyclandelate treatment the absolute theta power remained almost unchanged and an increase of P300 amplitude was observed. At the same time placebo led to a distinct theta power increase and a decrease of P300 amplitude, which was interpreted as the reflection of an impairment of the initial clinical state. Summarizing, cyclandelate proved to be efficacious compared to placebo in patients with mild to moderate cognitive impairment.

Cyclandelate versus propranolol in the prophylaxis of migraine--a double-blind placebo-controlled study.

The aim of the present study was to ascertain the comparative efficacy of cyclandelate, a migraine prophylactic with calcium overload blocking properties, versus propranolol, a non-selective beta-adrenergic blocker, and placebo. Based on different statistical analysis procedures (including time series analysis) a responder and nonresponder evaluation for cyclandelate and propranolol was performed. In addition, an attempt was made to identify the dose relationship of the various drugs on headache parameters. In a double-blind placebo-controlled study 84 patients were treated in a placebo run-in phase (4 weeks). The patients were then randomized by the statistical criterion of placebo responder and nonresponder to either the cyclandelate or the propranolol group. The total treatment period included a low-dosage phase (8 weeks) and high-dosage phase (8 weeks). All patients kept a headache diary before, during and after treatment. The data were assessed by time series analysis (ARIMA), as well as by analysis of variance and nonparametric statistics. Based on ARIMA statistics, 39.3% of the patients showed a significant improvement of migraine during treatment with cyclandelate compared with 29.4% placed on propranolol. Higher doses of cyclandelate and propranolol were more effective. Using the qualitative response-criterion of a 50% reduction in migraine symptoms, cyclandelate showed a response in 67.9% and propranolol in 41.2% of all cases. It can therefore be concluded that cyclandelate as well as propranolol are two comparable substances in the prophylactic treatment of migraine, with cyclandelate showing fewer side effects.

Quinine blindness.

A young women was treated with intravenous quinine and chloramphenicol for suspected severe malaria and/or typhoid fever. On the second day of quinine therapy (after 2.25 g of quinine) she suddenly developed total bilateral loss of vision. Both drugs were stopped and cyclandelate therapy was started. She showed slight improvement in vision but on referral her visual acuity was limited to seeing waving hand movement only; visual fields were constricted and colour vision was absent. Both pupils were fixed and dilated. The fundi showed macular oedema and attenuated retinal arteries. She was treated with dexamethasone, cyclandelate, vitamin B complex and vitamin C. Colour vision was completely recovered after 5 days of treatment. Full recovery of the direct light reflex occurred after 10 days. Visual acuity improved slowly over a period of one month to 6/15 vision in both eyes. At this time macular oedema and retinal arteriolar attenuation were still present but less severe. In the context of this case report the condition of quinine blindness is briefly reviewed and the management discussed.

Efficacy and tolerance of cyclandelate versus pizotifen in the prophylaxis of migraine.

In a double-blind, parallel randomized study, the prophylactic efficacy and tolerance of cyclandelate was evaluated versus pizotifen over a period of 16 weeks in 84 patients with migraine. The trial was initiated with a single-blind four week placebo run-in phase (baseline) in order to eliminate placebo-responders and non-compliant patients (n = 23). Sixty-one patients qualified for the subsequent active treatment period of 12 weeks. Cyclandelate or pizotifen were administered at a dosage of 1600mg/day (800mg/placebo/800mg) or 0.5mg t.i.d., respectively. Cyclandelate was clinically effective in the prophylactic treatment of migraine as shown by an average reduction of greater than 60% in three migraine parameters; frequency of attacks (FA 77.6%), total pain index (TPI 64.0%) and number of awakenings with headache (AwH 72.7%). This clinical efficacy was significantly superior (p less than 0.01) to that seen with pizotifen in all migraine parameters throughout the study. An average reduction of about 50% in FA, TPI and AwH was already observed in the cyclandelate group after 4-6 weeks suggesting an early onset of action. Side-effects in the cyclandelate group were fewer and less pronounced than in the pizotifen group. All patients included in the active treatment period completed the study. Thus, we conclude that cyclandelate is an effective and well tolerated drug for the prophylactic treatment of migraine.

Cyclandelate in diabetic neuropathy. A double-blind, placebo-controlled, randomized, cross-over study.

Cyclandelate has the ability to improve the rheological properties of the blood and therefore may improve blood supply of peripheral nerves. Previous studies in diabetic neuropathy have shown beneficial effects of the drug. We performed a double-blind, placebo-controlled, cross-over study in 40 diabetic patients with cyclandelate in a dose of 1600 mg daily. Motor and sensory nerve conduction velocities, late responses, thermal discrimination thresholds, vibration perception thresholds and pain scores were studied. We were not able to show any positive effect of the drug and therefore conclude that cyclandelate is not effective in the treatment of diabetic neuropathy.

Determination of plasma concentrations of cyclandelate and mandelic acid in patients with generalized atherosclerotic vasculopathy treated with oral cyclandelate.

Cyclandelate, a vasoactive substance consisting of the mandelic acid ester of 3,3,5-trimethylcyclohexanol, was administered to 10 patients with cerebrovascular and/or peripheral vascular disease. Blood specimens were collected at 1-6 h after oral administration of 1600 mg cyclandelate, and the ester and acid were extracted from plasma in acid medium using n-hexane/isopropyl alcohol. The concentrations were determined by a high-performance liquid chromatography isocratic system. The highest plasma cyclandelate concentrations were detected at the third hour, whereas plasma mandelic acid concentrations were still increasing 6 h after administration.

The pharmacotherapy of focal cortical ischaemia in the mouse.

The measurement of cortical omega 3 (peripheral-type benzodiazepine binding) site densities provides an accurate index for the detection and quantification of ischaemic brain lesions following middle cerebral artery occlusion (MCAO) in mice. Here, we have used this marker to assess the neuroprotective activity of potential anti-ischaemic drugs belonging to several chemical classes. In untreated mice, the mean infarcted volume measured 96 h after unilateral coagulation of the middle cerebral artery was 27.9 +/- 4.3 mm3 (17.5% of the hemisphere volume) and omega 3 site densities (measured by incubation with 3H-PK 11195) were increased by 107.3 +/- 4.8% (cortical homogenates) or by 81% (coronal brain sections). The administration of the anti-ischaemic agent SL 82.0715 (10 mg/kg i.p.), 5 min, 6 h and 18 h after the occlusion and then twice daily until sacrifice evoked a decrease of similar magnitude (ca. 60-70%) in the volume of the infarction and in the proliferation of omega 3 sites. The constant tissue sparing effect of SL 82.0715 allowed the examination of the window of therapeutic opportunity. A significant diminution of cortical omega 3 sites was still noted when the first administration was delayed until 3 h post-occlusion. Moreover, the protective effect of SL 82.0715 was enhanced by repeated treatment for the first 36 h but not thereafter. Based on the histological, autoradiographic and homogenate binding results obtained with SL 82.0715, we studied the protective effects of several competitive and non-competitive NMDA receptor antagonists. When administered according to the above-described standard protocol, these drugs reduced omega 3 site levels in cortical homogenates from MCAO mice in a dose-dependent manner. The dose preventing by 50% the increase in omega 3 site levels (in mg/kg i.p.) and the maximal inhibition were respectively: MK-801 (0.2, 93%); TCP (1.6, 66%); kynurenate (260, 58%); ifenprodil (7.0, 58%); SL 82.0715 (1.1, 72%); CGS 19755 (46% at 10 mg/kg); dextromethorphan (46% at 30 mg/kg). In contrast, agents acting preferentially upon sigma (sigma) opiate receptors ((+)-3PPP, 1-10 mg/kg i.p. and haloperidol, 0.3-3 mg/kg i.p.) did not provide a significant protection. In general, calcium channel blockers (nimodipine, flunarizine, verapamil, perhexiline, diltiazem) were devoid of a clear neuroprotective potential when administered at non-toxic doses after the coagulation of the middle cerebral artery. Diltiazem (3 and 10 mg/kg i.p.) provided a significant protection when the first administration was performed 10 min prior to the occlusion. Limited protection was observed with adenosine A1 receptor agonists (N6-cyclohexyladenosine and 2-chloro-adenosine).(ABSTRACT TRUNCATED AT 400 WORDS)

Fibrinolytic activity of oral cyclandelate in patients with generalized atherosclerotic vasculopathy: a double-blind study.

In a double-blind study, a single dose of 1600 mg cyclandelate or placebo was administered to 10 patients with cerebrovascular and/or peripheral vascular disease, and fibrinolytic activity was evaluated before and 1, 2, 4 and 6 h after treatment. Cyclandelate induced a reduction in euglobulin lysis time, an increase in tissue plasminogen activator concentration and a reduction in plasminogen activator inhibitor, alpha 2-antiplasmin and immunological fibrinogen concentrations, but no changes in antithrombin III and plasminogen concentrations were observed. After placebo administration no significant changes were observed. After treating two patients with 800 mg cyclandelate twice daily for 14 days, 1600 mg cyclandelate stimulated fibrinolysis for 8 h. It is concluded that the fibrinolytic activity of cyclandelate has implications for the treatment of cardiovascular complications of atherosclerosis.

Effect of cyclospasmol on early diabetic retinopathy.

A randomized, double-blind, placebo controlled study to investigate the long-term effect of Cyclospasmol (cyclandelate) on the abnormal permeability of the blood-retinal barrier was performed in 26 patients with insulin-dependent diabetes mellitus for at least 1 year and minimal retinopathy. Cyclospasmol 400 mg or placebo capsules were taken 4 times daily for 12 months by equal numbers in both groups. Each patient underwent a routine ophthalmoscopic examination, retinal fluorescein angiography and quantitative vitreous fluorophotometry to assess the permeability of the blood-retinal barrier just before the trial and following 6 and 12 months of therapy. Laboratory tests for determining blood and urine glucose levels and blood HbA1-levels were also carried out at these assessments. Statistically significant changes in diabetic control, in HbA1-levels or in the frequency of retinal microaneurysms could not be shown in either treatment group during the trial, nor were there any significant differences in these parameters between the two groups. Analysis of fluorophotometric data on fluorescein penetration into the left posterior vitreous demonstrated significant reductions in this parameter during the trial compared to the pretreatment level in Cyclospasmol treated diabetics. These changes in the pretreatment level after 6 and 12 months also differed significantly between the two groups. However, this statistically significant beneficial reduction in fluorescein penetration into the left posterior vitreous did not occur in the right eye in the Cyclospasmol group. In placebo treated patients a consistently deleterious trend for this parameter was observed for both eyes during the one year study.(ABSTRACT TRUNCATED AT 250 WORDS)

Perceived efficacy of cyclandelate in the treatment of cochleovestibular and retinal disturbances related to cerebrovascular insufficiency. A study in general practice comprising 2772 patients.

To investigate the perceived efficacy and safety of cyclandelate when used in general practice, an open multicentre study was performed comprising 2772 patients with symptoms of vertigo, tinnitus or visual disturbances thought to result from cerebrovascular insufficiency. After 90 days' treatment with cyclandelate 1600 mg daily in 2 doses, both the severity and frequency of these symptoms declined. The general practitioners rated the overall therapeutic efficacy of cyclandelate as 'excellent' or 'good' in 81% of patients, while 77% of patients considered the efficacy of the drug to be 'excellent' or 'good'. Side effects were infrequent and of a mild nature. Thus, when used in the setting of general practice, cyclandelate seems to be a safe and apparently effective treatment for patients with symptoms of vertigo, tinnitus and visual disturbances attributable to chronic cerebrovascular insufficiency.

Calcium modulation and clinical effect. Profile of cyclandelate.

Since its original development as a vasodilator, cyclandelate has been shown to possess a pharmacological profile which reflects its primary mechanism of action-calcium modulation. Thus, the ability of the drug to improve the rheological properties of blood by maintaining red blood cell deformability and inhibiting platelet aggregation may be explained by its effects on the influx of extracellular calcium. Since elevated intracellular calcium concentrations are known to contribute to pathological changes in conditions of local cerebral ischaemia, the clinical implications for the use of cyclandelate in the treatment of such diseases are clear.

Cyclandelate in the treatment of multi-infarct dementia. Interim findings from a multicentre study in general practice.

An open, multicentre clinical trial conducted in general practice was undertaken to investigate the effects of treatment with cyclandelate 800 mg twice daily in elderly patients with multi-infarct dementia. Interim findings in 303 patients demonstrate significant improvements after 12 weeks' treatment in mean scores of cognitive functions, orientation, verbal communications, social behaviour and interest in others and in the environment as assessed by the Blessed Dementia Scale and Parkside Behavioural Scale. Although a placebo response cannot be excluded because of the uncontrolled design of the study, these findings appear to warrant further investigation in well-designed controlled clinical trials in patients with multi-infarct dementia.

Cyclandelate in the treatment of vertigo of circulatory origin. A study in general practice.

A multicentre study with 622 patients has been undertaken to evaluate the efficacy of cyclandelate 1600 mg daily in the treatment of vertigo of circulatory origin in general practice. The characteristics of the patient population were consistent with the diagnosis of vertigo of circulatory origin. Patients with some risk factors, essentially a history of thrombosis and atherosclerotic patients, had more severe symptoms at the onset of the study. During the 3-month period of treatment with cyclandelate, the average global score of vertigo (0-10) decreased from 5.57 to 2.12 and the average scores of frequency, severity and duration of vertigo (0-4) decreased from 2.53, 2.55 and 2.26 to 0.98, 0.89 and 0.84, respectively. Patients previously treated with other anti-ischaemic drugs had similar responses compared to other patients. These results indicate that cyclandelate may be useful in the management of vertigo of circulatory origin in general practice.