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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.

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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↗
PubMed1987

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.

Adult↗
PubMed1981

A pilot study to evaluate the effect of acute and long-term administration of cyclandelate on the vigilance of subjects submitted to hypoxic conditions. Preliminary report.

A pilot study of a double-blind crossover design was carried out in four healthy male volunteers. 3,5,5-Trimethylcyclohexyl mandelate (cyclandelate, Cyclospasmol) 800 mg b.d. was compared with placebo using two-week treatment periods separated by a wash-out-period. Under hypoxic conditions (11.5% O2) the volunteers were asked to perform a series of tests including a computer-assisted oculodynamic test (ODT) after one dosage and after fourteen days' treatment with both cyclandelate or placebo. ODT is a very sensitive test which is independent of learning or motivation. Certain cardiovascular and respiratory parameters were simultaneously recorded during the test periods. The results showed that cyclandelate protected the volunteers against the effects of hypoxia. The results after two weeks' treatment were more definite than those after the first dose, suggesting that cyclandelate acted centrally on cerebral metabolism rather than through a direct cerebrovascular effect.

Adult↗
PubMed1994

[The Cyclandelate Reference Standard (Control 931) of the National Institute of Health Sciences].

Raw cyclandelate material was tested for preparation of the "Cyclandelate Reference Standard (Control 931)". Analytical data obtained were as follows: melting point, 57.4 degrees C; ultraviolet spectrum, lambdamax = 252.0, 258.1 and 264.1 nm and E 1cm 1% = 5.85 (252.0 nm), 6.95 (258.1 nm), 5.30 (264.1 nm), respectively; infrared spectrum, the same as that of the JP Cyclandelate Reference Standard; thin-layer chromatography, no impurities were detected up to 1000 micro g; high-performance liquid chromatography (HPLC), no impurities were detected; loss on drying, 0.03%; assay result, 101.4% by HPLC. Based on the above findings, the raw material was authorized as the JP Cyclandelate Reference Standard (Control 931).

Chemical Phenomena↗
PubMed1983

In vivo inhibition of hepatic lipogenesis in the rat by cyclandelate (3,3',5-trimethylcyclohexanylmandelate).

Rates of hepatic lipogenesis were measured in vivo in rats by incorporation into lipids of [3H] from injected [3H]H2O 17 hr after a single oral dose of cyclandelate (3,3',5-trimethylcyclohexanylmandelate, a vasoactive substance). Cyclandelate administration resulted in a significant inhibition (40-60%) of both sterol and fatty acid synthesis in the livers which was independent of the 3.2-fold diurnal variation in the rates of hepatic sterol and fatty acid synthesis. The inhibition of accumulation of newly synthesized fatty acid in intestine also reached statistical significance. The accumulation of newly synthesized sterol was significantly depressed in serum but did not result in any change in the concentration of serum total cholesterol. These results are interpreted in terms of the inhibitory effect of cyclandelate on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase previously reported by us (Biochem. Pharmac. 32, 649, 1983).

Animals↗
PubMed1990

Inhibition of acyl coenzyme A: cholesterol acyl transferase by trimethylcyclohexanylmandelate (cyclandelate).

Cyclandelate was an effective inhibitor of rat hepatic acycloenzyme A: cholesterol acyltransferase (ACAT) with a concentration of 80 microM being required for half maximal inhibition. A similar effect was seen with human and rabbit liver microsomal enzymes. The drug did not compete with oleoyl CoA or cholesterol and could be removed from enzyme preparations by washing. It was hydrolysed rapidly by rat liver microsomes to products which were non inhibitory. No hydrolysis of the drug was seen with non hepatic microsomes and the concentration of cyclandelate required to cause half maximal inhibition of ACAT in the transformed mouse macrophage J774 microsomal fraction was less than 30 microM. The possible significance of the differential actions of cyclandelate towards hepatic and extra hepatic ACAT in vivo is discussed.

Acyl Coenzyme A↗
PubMed1992

Field potential analysis in the freely moving rat during the action of cyclandelate or flunarizine.

Cyclandelate and flunarizine, two vasoactive Ca2+ channel or Ca2+ overload blockers have been compared with respect to their in vivo action on field potentials recorded from the depths of the brain in freely moving rats. Whereas cyclandelate showed a dose dependent rapid onset of action in the range of 15 to 120 mg/kg i.p., flunarizine only induced weak effects very slowly, not reaching statistical relevance before the fourth hour after the injection (0.1 to 1.6 mg/kg). Even then no clear dose dependence could be recognized for flunarizine. With respect to the frequency content of the recorded signals a rather close similarity between both drugs could be seen. Comparison of the drug effects to our reference data base of more than 80 compounds revealed a close relationship to memantine, an antiparkinson drug, suspected to act on the NMDA (N-methyl-d-aspartate) receptor-ionophor complex controlling Ca2+ fluxes. There is some indication that cyclandelate might also act in a similar way at the molecular level.

Administration, Oral↗
PubMed1991

Effect of food on the bioavailability of cyclandelate from commercial capsules.

The bioavailability of five capsules of cyclandelate that are commercially available in Japan was determined in ten healthy volunteers by measuring mandelic acid (a main metabolite of cyclandelate) excreted in the urine. Bioinequivalence among the five capsules was demonstrated. The relative cumulative excretion of mandelic acid of the most poorly bioavailable capsule was 38% of the most highly bioavailable capsule. The effect of food on the bioavailability of these two capsules was investigated by use of two different kinds of food, one containing fat and one containing high carbohydrates but very low fat. The bioavailability of the two capsules was increased when subjects consumed both types of food before drug administration, although there was a greater effect on bioavailability with food containing fat. This suggests that the absorption of cyclandelate was incomplete in fasting subjects, even from the capsule with the highest bioavailability. Bioinequivalence between the two capsules remained after postprandial drug administration.

Administration, Oral↗
PubMed1978

Cyclandelate in the treatment of senility: a controlled study.

Elderly patients often manifest a variety of symptoms (e.g., depression, memory loss, irritability, hostility), categorized as "senility" or "senile dementia," which are difficult to treat and represent a major therapeutic challenge to the geriatrician. This investigation was designed to assess, under double-blind conditions, a drug often prescribed for these symptoms--cyclandelate. In a 16-week study, 58 elderly patients were randomly assigned to two groups and received either 1600 mg of cyclandelate daily or identical-appearing placebo capsules. Initially, the every four weeks thereafter, the patients were examined for changes in vital signs and for adverse reactions, also, the Sandoz Clinical Assessment-Geriatric (SCAG) Scale and the Nurses Observation Scale Inpatient Evaluation (NOSIE) were completed. At the final evaluation, a physician's global rating was obtained. Our data suggest that cyclandelate is a safe and moderately effective treatment for certain symptoms of senescence in carefully selected patients.

Aged↗