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Mandelic acids represent a key structural motif present in many drug molecules. Herein, we report the controlled meta-selective mono- and diolefination of mandelic acids by the careful design of the substrate and oxidant. Furthermore, free meta-functionalized mandelic acid was generated by selectively removing the template under mild basic conditions. The synthesis of functionalized homatropine and cyclandelate drug derivatives was demonstrated. Kinetic isotope effects revealed C-H activation as the rate-limiting step.

A highly efficient way for the direct (trans)esterification of acyl acids (esters) and alcohols in a strict 1 : 1 ratio using a zirconocene complex (1, 1 mol%), a strong Lewis acid of good water tolerance, as a catalyst under solvent-free conditions has been developed. A wide range of acid and alcohol (esters) substrates undergo (trans)esterification to produce carboxylic ester motifs in moderate to good or excellent yields with good functional tolerance, such as that towards C–Br as well as CC and CC bonds. And complex 1 can be recycled six times without showing a significant decline in catalytic efficiency. It was demonstrated that cyclandelate, which is used to treat high blood pressure as well as heart and blood-vessel diseases, can be directly synthesized on a gram scale with 81% yield (6.70 g) using complex 1.

Background: Objective of the study was to identify healthy individuals with idiopathic unilateral sudden hearing loss (USSL) and treating them under either of two different therapeutic protocols to judge the hearing recovery.Methods: Prospective crossover series study of 72 adult patients (males and females) of Indian origin was performed. Diagnosis of USSL and treating under two different protocols as; Group "A" was treated with oral combination form of Vinpocetine, Q-enzyme, Piracetam and B. Serrata over 3 months; while Group "B" was treated with Plasma expander IV Dextran, IV Dexamethasone, I/M Cyanocobalamine and Cyclandelate for 5 days followed by oral Dexametasone for 5 days Methycobalamine over 3 months. Common audiological and communicative parameters were applied in both treated groups to assess and analyse the responses incurred at the end of treatment. The graded system was applied to evaluate the SRT. Better outcomes based on the trialed drugs and their action is assessed. Results: 61 of 72 patients successfully completed the regimes. After applying Siegel's grading for judging the SRT gains; group A had 16, 10 and 5 with grade I, II, III recovery while group B had 8, 6, 16 with grades I, II, III recovery respectively. It was noticed that group A patients showed earlier recovery of higher frequencies.Conclusions: Both subject groups showed improved BC gains at end treatment. There was marked hearing recovery (Gr. I, II-Siegel's classification) in group "A" was (78%) which is significant over group "B" (50%) and above natural recovery rate.

To investigate possible differences in spasmolytic activity the four isomers of cyclandelate (the DL-mandelate of low melting 3,5,5-trimethylcyclohexanol) as well as the corresponding isomeric esters from high melting 3,5,5-trimethylcyclohexanol were prepared.

The fractional removal rate of intravenously injected fat emulsions prepared with various emulsifiers, was studied in rabbits. The emulsions were made with soya bean oil and addition of egg yolk phosphatides, acetylated monoglycerides or polyoxypropylene-polyoxyethylene condensates (Pluronic). In some studies lipid soluble drugs were also added to the emulsions. The fractional removal rates of the emulsions from the blood stream were determined by means of an intravenous fat tolerance test. Addition of phosphatides slightly promoted the elimination of the fat emulsions, whereas the surface active agent Pluronic F 108 considerably impaired the fractional removal rate. Addition of cyclandelate or nitroglycerin increased the fractional elimination rate, whereas diazepam and chlorprozamine had the opposite effect. The half-life of secobarbital in plasma was unaffected whether administered as emulsion or water solution, but the half-life of thiopental was slightly longer when given as an emulsion. The pharmacological effect of barbiturates measured as duration of sleep in mice was not affected whether these agents were dissolved in slowly or rapidly eliminated emulsions. The results support the concept that the emulsifying agent is of major importance for the fractional removal rate of the emulsion from the blood stream, and further that the pharmacological effect of barbiturates dissolved in emulsions of different types is not related to the removal rate of the emulsion particles.

The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM). We have investigated lipophilicity and airway retention of BUD, CIC/CIC-AM, fluticasone propionate (FP), and mometasone furoate (MF), and compared esterification of BUD and CIC-AM and its contribution to GC airway retention. Rat tracheas were preincubated with the esterification inhibitor cyclandelate or vehicle. A (3)H-GC ( approximately 10(-7) M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min. After incubation, one half of the trachea was used for analysis of GC uptake and the other to analyze GC release during 3 h in drug-free medium. GC species in trachea halves were analyzed by radiochromatography. At 20 min, the uptake of BUD was similar to that of CIC/CIC-AM; however, the BUD-ester pool was 9-fold greater (p < 0.01). BUD overall retention in trachea at 3 h was greater than that of other GCs (p < 0.01), and the BUD-ester pool was 3-fold greater than the CIC-AM-ester pool (p < 0.01). Cyclandelate decreased the initial BUD- and CIC-AM-ester pools (p < 0.01), and reduced the overall retention of BUD at 3 h (p < 0.01) but not of CIC-AM. Thus, BUD becomes esterified in the airways more promptly and to a greater extent than CIC-AM, and BUD esterification prolongs BUD airway retention. In contrast, airway retention of CIC-AM and CIC seems to be determined mainly by their lipophilicity, similar to FP and MF, which are not esterified.

Identification of inhibitors of retinyl ester hydrolase (REH) would help to elucidate its role in vitamin A metabolism in vivo. By using standard incubation conditions, the effects of 215 drugs as potential inhibitors of purified pig and human liver REH when acting on micellar substrate retinyl palmitate were evaluated at 16.7, 167, and 1670 microM. Out of the compounds tested, 103 were inhibitors of the pig liver enzyme. The most potent compounds, in order of decreasing activity, were chloral hydrate, lovastatin, phytomenadione, alimemazine, physostigmine, thioridazine, phenoxybenzamine, probucol, cinnarizine, cyclandelate, amiodarone, flupenthixol, and naftidrofuryl; this order is roughly similar to that of their inhibition of human liver REH. Of the 10 tricyclic ring-containing drugs tested, alimemazine was the most potent enzyme inhibitor. The concentrations necessary for 50% enzyme inhibition ranged from2.6 up to540 microM. Moreover, inhibitory kinetic studies showed that at least two pharmaceuticals, chloral hydrate and amiodarone, are potent REH inhibitors at therapeutically achievable serum concentrations. First-pass metabolites were inactive as REH inhibitors compared to that of the parent compounds, in the cases of chloral hydrate, lovastatin, and cyclandelate.

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 baseline18) 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-Cog20 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-Cog25 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.

X-ray diffraction data have been obtained for 12 vasodilators in current use by the powder diffractometer technique. They include isoxsuprine HCl, perhexiline maleate, xanthinol nicotinate, suloctidil, pentoxyfylline, prenylamine lactate, nylidrin HCl (buphenine HCl), nifedipine, nicametate citrate, hexobendine, cyclandelate, and bamethan sulfate. The results, obtained by using the McCreery and Bystrom−Asklund methods of sample loading, were averaged and tabulated in terms of the lattice spacings and the relative line intensities. The method is valuable in the identification and characterization of pharmaceutical compounds from the possible polymorphic behavior of the same drug substances.

A reproducible and fast method has been developed for the assay of cyclandelate in bulk and drug forms using packed column supercritical fluid chromatography using dicyclohexyl phthalate (DCHP) as internal standard. The drug and the internal standard were resolved by elution with supercritical fluid carbon dioxide doped with 14.29% (v/v) methanol on an RP-C18 column and detected spectrophotometrically at 228 nm. Chromatographic figures of merit using C8, C18, cyano and phenyl columns have been assessed. Parallel experiments have been performed by HPLC and the data have been compared. Supercritical fluid extraction using CO2 modified with a small amount of methanol was found to give quantitative analytical recoveries of cyclandelate from a dosage form. SFC has been shown to be a viable, faster alternative technique to HPLC generating less disposable waste.

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.

The Whelk-O 1 chiral stationary phase is generally useful for the chromatographic separation of the enantiomers of many classes of analytes including aryl propionic acid non-steroidal anti-inflammatory drugs, aryl epoxides, sulfoxides, alcohols, amides and esters. We herein report some additional recent enantioseparations obtained with this column, including a number of pharmaceuticals such as thalidomide, nicardipine, isradipine, mephenytoin, nirvanol, cyclandelate, bendroflumethiazide, bupivicaine, tolperisone, proglumide, tropicamide and indapamide. The separation of the enantiomers of a collection of additional analytes is also reported, including several compounds containing basic nitrogen, a heretofore difficult class of compounds to resolve with this column.

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-Ruger 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 Nurnberger Selbsteinschatzungs-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 (3,3,5,-trimethylcyclohexanylmandelate) caused a dose-dependent decrease in the metabolism of radioiodinated low density lipoprotein [ 125 I-LDL] by J774 mouse macrophages. This was probably an indirect effect dur to the inhibition of cholesterol esterification by the cells rather than a direct one one the interaction of LDL with its receptor, since no inhibition was seen in cells which had been cholesterol-depleted by prior incubation with lipoprotein-depleted serum for 48 hr. Cyclandelate also inhibited immediately de novo synthesis of cholesterol from [1- 14 C]acetate in J774 cells, suggesting a direct action of the drug on an enzyme of the cholesterol biosynthetic pathway. The drug was an efficient inhibitor of hamster and rat intestinal acylcoenzyme A: cholesterol acyltransferase (ACAT) activity in vitro with an ic 50 of 20 μM. Addition of cyclandelate to the diet of meal-fed rats caused a marked inhibition of the rate of appearance of dietary [4- 14 C]cholesterol in the plasma. A nonhydrolysable ether analogue of cyclandelate, benzyl3,3,5-trimethylcyclohexanol, was prepared to compare hepatic and extrahepatic actions of the two molecules. The analogue inhibited cholesterol esterification in J774 cells, transformed human macrophages U937 and human umbilical vein endothelial cells with an ic 50 of 20 μM and had effects similar to those of cyclandelate on 125 I-LDL metabolism in J774 cells. Differences between the analogue and cyclandelate were seen in hepatocytes and hepatic microsomal fractions, where preincubation with the analogue inhibited cholesterol esterification in both systems while cyclandelate had no inhibitory action in either. Consequently, preincubation of rat hepatocytes with benzyl3,3,5-trimethylcyclohexanol for 17 hr caused a marked decrease in the binding of 125 I-LDL to the cells, whereas binding to cells preincubated with cyclandelate was the same as to control cells.

Cyclandelate (trimethylcyclohexanyl mandelate) inhibited cholesterol esterification in a transformed mouse macrophage cell line (J774) with a concentration of approximately 20 μM being required for half-maximal inhibition. The intact drug was required for its inhibitory action since neither of its hydrolysis products, trimethylcyclohexanol and mandelic acid, caused any inhibition even at high concentrations. The drug entered the cells very rapidly with inhibition being apparent within the shortest time possible to measure esterification (15 min after drug addition). The rate of cholesterol esterification returned to control values when drug-inhibited cells were incubated in drug-free medium indicating a rapid loss of drug from the cells. Loading of cells with cholesterol had no effect on the inhibitory action of cyclandelate, and the inhibition of esterification of cholesterol appeared to be specific, since the syntheses of phospholipid and triacylglycerol (which also involve the action of acyltransferases) were not affected by the drug. Similar inhibitions of cholesterol esterification were seen in four other cell lines, a human osteosarcoma, Chinese hamster ovary cells, a human transformed macrophage cell line (U937) and human umbilical cord vein endothelial cells, as well as in slices of pig aorta, indicating a general action in extra-hepatic tissues where the drug is not hydrolysed.

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.

The effect of cyclandelate (Natil®) on the CNS was tested in a double-blind, placebocontrolled 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 arithmetics. Under resting conditions the power in the alpha2 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 arithmetics no drug related effect was observed in the EEG. The cyclandelate induced increase of spectral power in the alpha2 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.

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, α2-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.

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.

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.

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).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).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.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.

Objective: To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication. Setting: We limited our study to the products on the market in Belgium: cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. Data sources: We conducted a systematic literature search involving Medline, International Pharmaceutical Abstracts, the Cochrane Library, direct contact with marketing companies and key authors, snowballing and Science Citation Index search. We looked for randomised placebo-controlled trials (RCTs) in patients with Fontaine stage II, in which pain-free and/or maximal walking distance were measured using a standardised exercise test. For isoxsuprine and xanthinol nicotinate, no trials conforming to these criteria were found. Thirty-six trials on cinnarizine, cyclandelate, buflomedil, naftidrofuryl and pentoxifylline met our inclusion criteria. Study selection: After quality assessment, 26 trials were excluded, mainly because of short trial duration (less than 12 weeks), small sample size (less than 30 patients) and/or failure to report details on variability (standard deviation or confidence limits). For cinnarizine and cyclandelate, none of the three selected RCTs was included. Data extraction: For buflomedil, of six published RCTs, two were included after quality assessment, each showing a marginally positive effect of buflomedil versus placebo. For naftidrofuryl, nine RCTs were selected; six were included of which five showed a significant positive result. The likelihood of publication bias and the heterogeneity of the results within and between trials precluded a meta-analysis. For pentoxifylline, of the 18 selected RCTs, only two could be included, both with inconclusive results. Conclusion: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication rather than to reimbursement of these products with doubtful efficacy.

Cyclandelat (1), der cis-3,3,5-Trimethylcyclohexylester der Mandelsaure, findet zur Behandlung zerebraler Stoffwechsel- und Durchblutungsstorungen Verwendung. Es wird die Synthese der heteroanalogen Verbindungen 2–4 beschrieben. Cylandelate and Analogous Compounds Cerebral disorders of metabolism and blood circulation are treated by cyclandelate (1), cis-3,3,5-trimethylcyclohexyl mandelate. The syntheses of the hetero analogous compounds 2–4 are described.

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.

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.

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 inhibits calcium-induced contraction of vascular smooth muscle cells, platelet aggregation induced by thrombin, platelet-activating-factor and adenosine, and also suppresses a provoked 5HT release from platelets. This pharmacological profile suggests that cyclandelate may have a potential prophylactic effect in migraine. To test this hypothesis, a double-blind multicentre study was performed in 214 patients to investigate the efficacy and tolerability of cyclandelate compared to placebo and propranolol. After a 4-week baseline period, eligible patients (randomization 3:2:3) were treated for 12 weeks with daily doses of 1.200 mg cyclandelate (n = 81), placebo (n = 55) or 120 mg propranolol (n = 78). The number of migraine attacks (or = 50% responders) and the migraine duration/month were compared based on the difference between baseline and the last 4 weeks of prophylactic treatment. The percentage of patients with a reduction in migraine attacks ofor = 50% treated with cyclandelate (37.0%) or propranolol (42.3%) was not significantly superior to placebo (30.9%; p0.025). The mean duration of migraine in hours (h) per month decreased in both active treatment groups (cyclandelate: 36.8 h, p = 0.046; propranolol: 34.4 h, p = 0.039) compared to placebo (13.7 h) without reaching statistical significance (alpha/2 = 0.025). The clinical efficacy of cyclandelate and propranolol was comparable. Adverse experiences were reported by 13 patients (16.0%) treated with cyclandelate, by 5 patients (9.1%) treated with placebo and by 19 patients (24.4%) treated with propranolol. These were drug-related in 7.1% (n = 6) of patients treated with cyclandelate and in 9% (n = 7) of patients treated with propranolol. In summary, cyclandelate has a comparable efficacy to that of propranolol, an established drug of first choice in the prophylaxis of migraine. Both drugs were better than placebo, but not significantly so. Both active treatments were well tolerated.

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.

In an open randomized cross-over study 800 mg cyclandelate (Natil, CAS 456-59-7) was applicated to 24 young, male volunteers. Before and during 24 h after application of a single dose a 17-channel, quantitative topographical pharmaco-EEG was recorded. A significant increase of the spectral power density was observed in the alpha 2, beta 1 and beta 2 frequency bands starting 2 h after application until 4.5 h. The increase in beta 1 and beta 2 power was observed in the parietocentral area of the cortex. The difference between the circadian development of the EEG power and the development after medication was obvious after 3 until 4.5 h. For the beta frequencies only a weak statistical confirmation could be obtained, but for the alpha 2 frequency a significant difference between the circadian and the EEG power under cyclandelate was found using the sign test. Altogether a quantitative effect on brain activity was detected after oral application of cyclandelate, reaching its maximum before the blood concentration of the metabolites cyclandic glucuronide and mandelic acid reached their peak heights.

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).

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.

Summary Cyclandelate and flunarizine, two vasoactive Ca 2+ channel or Ca 2+ 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 Ca 2+ fluxes. There is some indication that cyclandelate might also act in a similar way at the molecular level.

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.

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.

The bioavailability in beagle dogs and the dissolution rates of cyclandelate from five capsule preparations commercially available in Japan were measured. One of the capsules that showed an extremely low bioavailability in humans also showed the lowest bioavailability in beagle dogs, although the difference in bioavailability with the highest preparation was smaller than in humans. A significant correlation was obtained between the results of the studies in humans and beagles. However, the power of the test using beagles was extremely low in comparison with that in the human study. Food enhanced the bioavailability of cyclandelate from the capsules having the highest and lowest bioavailability in the fasted state in beagles as observed in the human study previously. The bioinequivalence of the cyclandelate capsules detected in the fasted state disappeared in the fed state in the beagle dog study, while the bioinequivalence still remained in the non-fasted state in human subjects. Thus bioequivalence testing in the fed state led to different results in both species. The most poorly bioavailable capsule in both species in the fasted state showed a slow dissolution rate by several dissolution methods with moderate stirring. In order to obtain a good correlation with in vivo bioavailability, a large volume of test solution and addition of Tween 80 were required. Extensive growth of whiskers (needle-like crystals) was observed in the entire capsule mass having the lowest bioavailability.

The raw material of cyclandelate was examined for preparation of the "Cyclandelate Reference Standard". Analytical data obtained were as follows: melting point, 60 degrees C; ultraviolet spectrum, lambda max = 252, 258 and 264 nm E1%1cm = 6.1 (252 nm), 7.5 (258 nm), 5.9 (264 nm); infrared spectrum, 3454, 2948, 1730, 1453, 1202, 737, 695 cm-1; thin-layer chromatography, no impurities were detected until 1000 micrograms; high-performance liquid chromatography (HPLC), one impurity was detected, loss on drying, 0.00%. Based on the above results, this raw material was authorized to be the Reference Standard of the National Institute of Hygienic Sciences.

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.

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.

A 54 year old man was admitted because of repeating (10–12/day) visual disturbances in the left eye. He reported shrinkage of the visual fields and a shadow-like visual impairment progressing to complete darkness within about 3 min and lasting about 10 min, followed by complete recovery. There was no personal history of hypertension, diabetes, and smoking. General …

In fibroblasts deprived of exogenous cholesterol to induce low density lipoprotein receptors there is a continuing flux of cholesterol esterification. The structurally unrelated inhibitors of acyl-CoA: cholesterol acyl-transferase, progesterone, trimethylcyclohexanyl mandelate and 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl] propanamide, (58035), could all inhibit this basal rate of esterification within 1h of addition. Exposure of cholesterol-deprived fibroblasts for 17h to progesterone or trimethylcyclohexanyl mandelate caused decreased specific binding and metabolism of low density lipoprotein. The effect was not a direct inhibition of lipoprotein binding; it was time dependent and followed from the reversible inhibition of cholesterol esterification by these two compounds. The irreversible inhibition of esterification by 58035 left the receptor number unaffected. The results indicate that down regulation of low density lipoprotein receptors is initiated by accumulation of cholesterol in a specific intracellular pool. Inhibition of cholesterol esterification by progesterone and trimethylcyclohexanyl mandelate causes accumulation of cholesterol in this pool but 58035 does not.

Determination of free and conjugated cis-3,3,5-trimethylcyclohexanol in plasma and urine A gas chromatographic procedure was developed to determine free and conjugated cis-3,3,5-trimethylcyclohexanol in plasma and urine. The sample is extracted with dichloromethane when free cis-3,3,5-trimethylcyclohexanol is determined, or with hexane after enzymatic hydrolysis, when conjugated cis-3,3,5-trimethylcyclohexanol is determined. An aliquot of the organic extract is injected into a stainless-steel column (packed with Carbowax 20M, 15% on Chromosorb W AW 100–120 mesh) and detected with a flame ionization detector. Extraction recovery from plasma and urine was almost 100% and the limit of quantification was fixed at 100 ng/ml plasma or urine. The procedure was evaluated in a pharmacokinetic study of cyclandelate and its metabolite cis-3,3,5-trimethylcyclohexanol.

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.

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).