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PubMedDate not supplied

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.

Administration, Oral↗
PubMed1987

The influence of cyclandelate on Ca++ translocation in human platelets.

A major event in signal transduction in platelets is the mobilisation of Ca++ ions by 2 mechanisms: influx of Ca++ from the extracellular medium and release from intracellular storage sites. The calcium modulating drug cyclandelate is known to inhibit platelet aggregation induced by various agonists. Thus, by studying the effects of cyclandelate on cytosolic Ca++ concentrations in gel-filtered human platelets, an explanation was sought of the mechanism which couples receptor stimulation with the processes that execute aggregation and secretion. Cyclandelate in concentrations between 10 and 50 mumol/L induced a dose-dependent increase in the basal level of cytosolic Ca++ of unstimulated platelets. In platelets stimulated with thrombin (5 U/ml) or platelet activating factor (1 mumol/L), cyclandelate strongly inhibited the increase of cystolic Ca++ in the presence of extracellular Ca++, but in the absence of extracellular Ca++ only a weak inhibition was observed. This inhibition was dose dependent and optimal at about 50 mumol/L, the concentration at which Ca++ mobilisation was suppressed to about 10% of control values, and at which cyclandelate inhibits platelet aggregation. In contrast, the metabolites cyclandelate alcohol and cyclandelate acid were without effect at the same concentrations (50 mumol/L). Concentrations of cyclandelate greater than 50 mumol/L were found to further increase the concentration of Ca++ in the unstimulated platelet, an effect which interfered with the stimulus-induced Ca++ translocation. Thus, at concentrations which inhibit platelet aggregation, cyclandelate prevents the mobilisation of Ca++ ions induced by such agonists as thrombin and platelet activating factor. Further study is required to determine the mechanism by which cyclandelate inhibits these platelet responses.

Biological Transport↗
PubMed1987

Cyclandelate as a calcium modulating agent in rat cerebral cortex.

Cyclandelate is clinically effective in a variety of cerebrovascular indications, but its precise mode of action is unclear. Hence, this study investigated the interaction of cyclandelate, cyclandelate alcohol and cyclandelate acid with the binding sites for radioactively labelled 3H-nitrendipine, a Ca++ entry blocker of the 1,4-dihydropyridine type, on rat cerebral cortex membranes. Cyclandelate showed a dissociation constant (Kd) of 7.1 +/- 1.4 X 10(-5) mol/L (35% inhibition of 3H-nitrendipine binding at 2 X 10(-4) mol/L cyclandelate), cyclandelate alcohol had a Kd value of 1.7 +/- 0.1 X 10(-4) mol/L (maximal 70% inhibition of 3H-nitrendipine binding) whereas cyclandelate acid was inactive. For comparison, nifedipine (Kd of 2.6 +/- 0.3 X 10(-9) mol/L inhibition of 68% of 3H-nitrendipine binding), d-cis diltiazem (Kd of 1.1 +/- 0.1 X 10(-7) mol/L enhancement of 39% of 3H nitrendipine binding) and +/- -verapamil [Kd values of 1.4 +/- 0.4 X 10(-7) mol/L (38% inhibition) and 5.3 +/- 1.7 X 10(-4) mol/L (62% inhibition)] were used. Thus, cyclandelate may exert its clinical activity in cerebral ischaemia or hypoxia at least in part through a calcium modulatory effect.

Animals↗
PubMed1987

Inhibition of human platelet functions by cyclandelate.

The effects of cyclandelate and two of its metabolites, cyclandelate alcohol and acid, on several human platelet functions in vitro were investigated. Platelet aggregation was measured turbidimetrically using platelet-rich plasma. 14C-Serotonin (5-hydroxytryptamine) release from preloaded platelets, and thromboxane B2 (TxB2) formation were evaluated simultaneously with platelet aggregation. Cyclandelate and cyclandelate alcohol, but not cyclandelate acid, in a dose-dependent fashion prevented platelet aggregation and the concomitant 14C-serotonin release and TxB2 formation induced by adenosine diphosphate, platelet activating factor and collagen. In other experiments, inhibitory synergistic activities of cyclandelate and prostacyclin (PGI2) on platelet aggregation were demonstrated; cyclandelate alcohol and PGI2 showed a somewhat less pronounced synergism. The hypothesis that the calcium modulating property of cyclandelate is responsible for the inhibition of blood platelet functions is strengthened by the inability of the drug to inhibit the calcium-independent platelet aggregation induced by ristocetin.

Blood Platelets↗
PubMed1987

Influence of cyclandelate on in vitro red blood cell deformability.

Using filtration and viscosity techniques, cyclandelate, some of its metabolites and flunarizine were evaluated to determine their ability to maintain human red blood cell (RBC) deformability. In filtration studies, RBC suspensions were metabolically depleted, which decreased the capacity of the cells to pass through narrow filter pores. In viscosity measurements performed with whole blood, metabolic depletion resulted in an increase of blood viscosity values. The results of these experiments appeared to indicate that cyclandelate, cyclandelate alcohol and flunarizine were approximately equipotent in maintaining RBC filtration and blood viscosity values. Cyclandelate acid appeared to be less active in both studies. By measuring the adenosine triphosphate content of red blood cells it has been shown that this activity is not due to an action on red blood cell energy metabolism. Finally, experiments conducted with the calcium chelator EGTA showed that the activity of cyclandelate was reduced in the absence of Ca++ ions. The results strengthen the hypothesis that cyclandelate maintains red cell deformability by inhibiting calcium entry through the red cell membrane.

Adenosine Triphosphate↗
PubMed1992

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.

Adult↗
PubMed1991

[Effects of cyclandelate on the CNS--a double-blind, placebo-controlled study of healthy subjects].

The effect of cyclandelate (Natil) on the CNS was tested in a double-blind, placebo-controlled pilot study on 48 healthy males using a single oral dosage of 1200 mg. The EEG was evaluated quantitatively by spectral analysis before and one hour as well as two and a half hours after drug or placebo administration under resting conditions and while performing a test of mental arithmetic. Under resting conditions the power in the alpha 2 frequency band of the signals from the frontal and central recordings was increased in the cyclandelate group in comparison to the placebo group. This effect was still observed two and a half hours after drug intake. Under the condition of mental arithmetic no drug related effect was observed in the EEG. The cyclandelate induced increase of spectral power in the alpha 2 frequency band under resting conditions demonstrates a general effect of cyclandelate on the CNS. The results are discussed with respect to the known age related decrease of spectral power in the alpha frequency band. The established effect of cyclandelate in young healthy subjects calls for a study with chronic treatment in elderly subjects or patients with cognitive deficits.

Adult↗
PubMedDate not supplied

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.

Aged↗
PubMed1987

Cyclandelate. An inhibitor of cholesterol esterification.

In an in vitro study the action of cyclandelate on cholesterol metabolism was investigated. The addition of cyclandelate (100 mumol/L) inhibited the incorporation of acetate into sterol but not into fatty acid in human fibroblasts incubated with the drug for 3 hours. Further exposure of fibroblasts to cyclandelate for 17 hours resulted in a similar inhibition in the uptake and hydrolysis of LDL. Moreover, in the presence of cyclandelate (100 mumol/L), cholesterol esterification was inhibited by 90% in fibroblasts cultured with LDL and in human monocyte derived macrophages cultured with acetyl-LDL. It is likely that the inhibition by cyclandelate of cholesterol esterification in whole cells is due to a direct inhibition of the hepatic microsomal enzyme acyl coenzyme A: cholesterol acyl transferase (ACAT), since addition of the drug in a concentration of 100 mumol/L inhibited by 74% the activity of ACAT derived from rat liver. Furthermore, the intact drug molecule was required for maximal inhibition of microsomal ACAT.

Animals↗
PubMed1987

The effect of cyclandelate on cholesterol metabolism in patients with familial hypercholesterolaemia.

Heterozygous familial hypercholesterolaemia (HtFH) is associated with an increased risk of coronary artery disease. Prevention is possible by increasing the number of functioning receptors of low density lipoproteins (LDLs) in the liver. This is partly achieved by treatment with bile acid sequestrants, such as cholestyramine, but the effect is limited because of a concomitant increase in cholesterol synthesis. It was the purpose of this study to determine whether the increase in cholesterol synthesis could be influenced by treatment with cyclandelate, since it is known that cyclandelate inhibits cholesterol synthesis in rats. Ten patients received cyclandelate (3.2 g daily in 2 doses) or placebo in a double-blind cross-over study, with each treatment period of 3 months' duration. During these periods, treatment with cholestyramine (16 g daily) was continued. No evidence was found of inhibition of cholesterol synthesis by cyclandelate, as indicated by the serum concentration of the cholesterol precursor, lanosterol, which remained unchanged. Neither the serum concentration of LDL, nor those of high density lipoprotein (HDL) cholesterol, apolipoprotein B, A-I or A-II, were affected. Thus, it can be concluded that treatment with cyclandelate was not effective in lowering serum cholesterol concentrations in patients with familial hypercholesterolaemia who received concomitant cholestyramine therapy.

Adult↗
PubMed1990

Chemical synthesis of dual-radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells.

1. The chemical synthesis of 3,3,5-trimethyl[1-3H]cyclohexanol, 3,3,5-trimethyl[2,3-3H]cyclohexanol and 3,3,5-trimethyl[2,3-3H]cyclohexanyl[1-14C]mandelate (cyclandelate) are described. The ratio of 3H/14C radioactivity in the ester was 27:1. 2. Cultured rat hepatocytes accumulated trimethylcyclohexanol rapidly and excreted its glucuronide into the culture medium. Rat hepatocytes also accumulated cyclandelate rapidly, hydrolysing the ester and excreting trimethylcyclohexanol into the medium. This trimethylcyclohexanol then re-entered the cells and was converted to its glucuronide prior to excretion. 3. In contrast, no hydrolysis of cyclandelate was seen on incubation with J774 cells, a transformed mouse macrophage. 4. Similar differences in hydrolytic activity were seen with microsomal fractions prepared from rat liver and J774 cells. Hepatic microsomes caused a rapid hydrolysis of cyclandelate while no hydrolysis was detectable after incubations of over an hour with J774 microsomes. 5. This difference in hydrolytic activity may have important implications for the action of cyclandelate on cholesterol metabolism in extrahepatic tissues.

Animals↗
PubMed1977

The effect of cyclandelate in depressed and demented patients: a controlled study in psychogeriatric patients.

In a double-blind clinical trial the effects of the vasodilator drug cyclandelate (in a dose of 1200 mg daily) were studied in a group of patients with depressive illnesses or dementing conditions. The measures used before treatment and after six weeks' treatment were: clinical rating, psychometric tests (Paired Associate Learning Test, Digit Copying Test, Digit Substitution Test, and Serial Learning Test), cortical evoked potentials, the sedation threshold and the Gresham Questionnaire. In the depressive group there were no significant differences in the changes in scores at six weeks in three groups: those who received cyclandelate plus amitriptyline, those who received placebo plus amitriptyline, and those who received neither placebo nor cyclandelate. In the demented group there were significant changes in favour of the placebo on two measures (Digit Copying test, and one component of the auditory evoked response). The results do not support the previously reported views claiming, in a number of studies, a significant improvement in the performance of both demented and normal elderly subjects treated with cyclandelate. The significance of these findings is discussed.

Aged↗
PubMed1976

Cyclandelate in the treatment of cerebral arteriosclerosis.

Twenty-one patients with cerebral arteriosclerosis were treated for twelve months with placebo or cyclandelate (Cyclospasmol), 400 mg four times daily, in a double-blind study with medication cross-over after six months. The group included 8 men and 13 women, with a mean age of 69 years. Each patient showed at least 5 of 9 signs or symptoms adopted as "inclusion criteria" for the study. Concomitant psychotropic or other drug therapy was standardized or matched during the trial, and periodic assessments were made of the patients' behavioral, physical, neurologic and psychiatric status. No serious side effects were observed. There was no significant difference between the cyclandelate and placebo phases in measurements of physical state. Changes on the gross behavior scales were insufficient for analysis. Tests of memory, control of manual dexterity and comprehension of everyday situations showed statistically significant improvement during the cyclandelate phase. In contrast to placebo, no measurable intellectual decline occurred during cyclandelate therapy.

Aged↗
PubMed1977

Cyclandelate in the treatment of senile mental changes: a double-blind evaluation.

The treatment of cerebrovascular insufficiency and its many symptoms in the ever-increasing numbers of the aged, is of major concern to physicians engaged in such care. Despite past skepticism as to the degree of efficacy of cerebral vasodilators, there is renewed interest in this form of therapy. Our investigation was designed to assess the effectiveness of cyclandelate, under strict double-blind conditions, in 58 geriatric patients. The cyclandelate and placebo groups (32 and 26 patients respectively) received either 1,600 mg/day of cyclandelate in fractional doses, or identical-appearing placebo capsules--over a period of 12 weeks. During the initial examination and every four weeks thereafter, patients were assessed for possible changes in vital signs and for evidence of adverse reactions. In addition, the Sandoz Clinical Assessment-Geriatric (SCAG) and the Nurses Observation Scale for Inpatient Evaluation (NOSIE) were completed, with particular attention to symptom clusters. A final global assessment was made in which the physician rated patients according to their overall clinical condition. The results of our study and analysis indicate that cyclandelate is a safe and effective agent for treating certain symptoms of senility in properly selected patients, provided the therapy is carried on for at least eight weeks and, if indicated, for a longer period. Clinical evidence suggests that the prudent use of this drug may definitely delay deterioration.

Aged↗
PubMedDate not supplied

Effect of cyclandelate on dementia.

Cyclandelate, a vasodilator, was administered to 24 patients with dementia. The dementia in these patients was presumed to be due to cerebral ischemia caused by atherosclerosis in cerebral vessels after other possible causes were ruled out. In a double-blind, cross-over study, patients received 200 mg of cyclandelate four times daily for six weeks and a placebo for six weeks. Six psychological tests, which reflect various aspects of higher cortical ability, were used to evaluate the effect of cyclandelate on the dementia. Cyclandelate was found to be no more effective than placebo in improving higher cortical function in these demented patients.

Aged↗
PubMed1987

Effect of cyclandelate on prostacyclin release and cytosolic free calcium concentrations in human endothelial cells.

An increase in the concentration of cytosolic calcium plays a pivotal role in the stimulation of endothelial cells to release various mediators that are involved in vasodilatation and haemostasis. When these cells become damaged, a larger irreversible influx of calcium ions can cause 'calcium overload' and cell death. Cyclandelate may affect the influx of calcium ions in cells and act as a calcium overload blocker. Therefore, the effects of cyclandelate on prostacyclin (PGI2) release and cytosolic free calcium were investigated in cultured human endothelial cells. Cyclandelate did not inhibit the production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin. Similarly, cyclandelate (10(-6) to 10(-4) mol/L) and flunarizine (10(-6) to 10(-5) mol/L) had no effect on the increased concentrations of cytosolic free calcium in cells stimulated by bradykinin or thrombin, or on non-stimulated cells as evaluated with the calcium indicator fura-2. This was found both in serum-free conditions and in the presence of 10% human serum. It is likely that the rise in cytosolic free calcium concentration upon stimulation of cultured human endothelial cells depends on the influx of calcium ions from an intracellular storage pool.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Cyclandelate versus flunarizine. A double-blind study in a selected group of patients with dementia.

A double-blind, double-dummy clinical trial was conducted in which the efficacy of cyclandelate 1600 mg daily was compared with that of flunarizine 10mg daily in 40 patients (25 men and 15 women) with dementia of cerebrovascular origin. Parameters were assessed before treatment, and after 45 and 90 days of therapy. At 90 days, significant improvements were observed in patients given cyclandelate in measurements of P100 latency in the left eye, neurological impairment, dementia scores, ischaemia scores, Gottfries mental deterioration scale, Hamilton depression scores, short term visual memory, long term memory, Bender-Gestalt test and Koh's blocks test. In flunarizine recipients, improvements were observed in neurological impairment, ischaemia scores, Gottfries scale and Hamilton depression scores. Patients treated with cyclandelate showed significantly greater ameliorations in symptoms as assessed by the ischaemia scale, evoked visual potential, visual memory and Koh's block test compared with those given flunarizine. However, in none of the parameters was flunarizine superior to cyclandelate.

Aged↗