Objective evaluation of cyclandelate in treatment of intermittent claudication associated with arteriosclerosis obliterans.
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Bakker GA, Rekker RF: Determination of the isomer ratio in cyclandelate by NMR spectroscopy.
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Humans↗
Oral vasoactive medication in intermittent claudication: utile or futile?
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.
Administration, Oral↗
In vivo pharmacokinetics of aldose reductase inhibitors: 3-fluoro-3-deoxy-D-glucose NMR studies in rat brains.
Direct quantification of the inhibitory effects of orally administered drugs (sorbinil, cyclandelate and sulindac) on aldose reductase activities in rat brains was performed non-invasively using the 3-fluoro-3-deoxy-D-glucose (3-FDG) 19F NMR spectroscopic technique. Quantitative data obtained directly from the target organ (brain) allowed for unprecedentedly accurate analysis of drug effects in the brain in vivo. Sorbinil, a potent aldose reductase inhibitor, exhibited a classic monophasic organ response, whereas cyclandelate and sulindac showed biphasic suppression patterns. The latter indicate that there are metabolites of these drugs which possess aldose reductase inhibitory activities. The estimated potency of aldose reductase inhibition for each of the three drugs in this study was significantly discrepant from the in vitro studies indicating the complicated nature of the bioavailability of a pharmaceutical agent in vivo, especially where pharmacologically active metabolites of a given drug are involved. Our method allows for a direct quantitative assay and hence the most reliable technique for evaluating aldose reductase inhibitory activities in the target organ.
Aldehyde Reductase↗
Evidence for neuronal dysfunction in migraine: concurrence between specific qEEG findings and clinical drug response--a retrospective analysis-.
OBJECTIVE: The aim of this analysis was to verify objective correlates of the clinical improvement of migraine in patients by means of quantitative topographical EEG (qEEG). METHODS: Overall 40 migraine-outpatients participated in this retrospective analysis of prophylactic migraine treatment over 3-8 months with 1600 to 2000 mg cyclandelate daily. In all patients qEEG was recorded and analysed using the Fast Fourier Transformation and the determination of the Abberation Index (AI = the statistical probability of belonging to a qEEG reference group of healthy people, n = 500). RESULTS: A clinical response (> 50% reduction of migraine attack frequency and duration) was observed in 77.5% (n = 31). The number and duration of migraine attacks per month (median values) were reduced in a highly significant manner. In this observation 75% of all patients investigated showed a pathological positive Aberration Index at a single electrode or a cluster of neighbouring brain sites. This consisted in a power increase in theta, alpha and/or beta1 activity, and 73.3% of them had also a corresponding negative AI-focus (power decrease). In 15 patients EEG aberrations (positive AI clusters) within one frequency band were found, whereas 15 patients showed aberrations in more than one frequency. Positive AI s were mainly found in fronto-temporal and occipital brain areas with one single topographical difference between the patients with and without aura. CONCLUSIONS: Positive AI values were the main electrophysiological findings in these migraine patients. This was supported by the highly significant decrease of the median amount of the positive AI after clinically successful treatment with cyclandelate. Twenty four out of thirty patients with positive AI foci showed concurrence between qEEG-changes and clinical response. Patients with positive AI foci involving the lower or middle frequencies (theta and/or alpha 1) seemed to show a better clinical response (84.6%) than those with AI foci with participation of only faster frequencies (alpha 2 and/or beta 1; 54.5%). A controlled study is needed to confirm these observations.
Adolescent↗
Quinine blindness.
A young women was treated with intravenous quinine and chloramphenicol for suspected severe malaria and/or typhoid fever. On the second day of quinine therapy (after 2.25 g of quinine) she suddenly developed total bilateral loss of vision. Both drugs were stopped and cyclandelate therapy was started. She showed slight improvement in vision but on referral her visual acuity was limited to seeing waving hand movement only; visual fields were constricted and colour vision was absent. Both pupils were fixed and dilated. The fundi showed macular oedema and attenuated retinal arteries. She was treated with dexamethasone, cyclandelate, vitamin B complex and vitamin C. Colour vision was completely recovered after 5 days of treatment. Full recovery of the direct light reflex occurred after 10 days. Visual acuity improved slowly over a period of one month to 6/15 vision in both eyes. At this time macular oedema and retinal arteriolar attenuation were still present but less severe. In the context of this case report the condition of quinine blindness is briefly reviewed and the management discussed.
Adult↗
Inhibition of purified pig and human liver retinyl ester hydrolase by pharmacologic agents.
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 from <2.6 up to >540 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.
Animals↗
Effect of cyclospasmol on early diabetic retinopathy.
A randomized, double-blind, placebo controlled study to investigate the long-term effect of Cyclospasmol (cyclandelate) on the abnormal permeability of the blood-retinal barrier was performed in 26 patients with insulin-dependent diabetes mellitus for at least 1 year and minimal retinopathy. Cyclospasmol 400 mg or placebo capsules were taken 4 times daily for 12 months by equal numbers in both groups. Each patient underwent a routine ophthalmoscopic examination, retinal fluorescein angiography and quantitative vitreous fluorophotometry to assess the permeability of the blood-retinal barrier just before the trial and following 6 and 12 months of therapy. Laboratory tests for determining blood and urine glucose levels and blood HbA1-levels were also carried out at these assessments. Statistically significant changes in diabetic control, in HbA1-levels or in the frequency of retinal microaneurysms could not be shown in either treatment group during the trial, nor were there any significant differences in these parameters between the two groups. Analysis of fluorophotometric data on fluorescein penetration into the left posterior vitreous demonstrated significant reductions in this parameter during the trial compared to the pretreatment level in Cyclospasmol treated diabetics. These changes in the pretreatment level after 6 and 12 months also differed significantly between the two groups. However, this statistically significant beneficial reduction in fluorescein penetration into the left posterior vitreous did not occur in the right eye in the Cyclospasmol group. In placebo treated patients a consistently deleterious trend for this parameter was observed for both eyes during the one year study.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Treatment of sudden deafness: carbon dioxide and oxygen inhalation and steroids.
The results of treating 86 patients with sudden deafness are reviewed in this paper. They were treated with intravenous ATP-2Na, Vitamin B1, B6, B12 and C, stellate ganglion block, peroral steroids, cyclandelate and Kallidinogenase. Fifty-one of 86 patients were additionally treated with carbon dioxide and oxygen inhalation. The first 35 patients (no gas inhalation group) and the latter 51 patients (gas inhalation group) were compared with each other concerning hearing improvement, and recovery rate associated with age of the patients, untreated period and effect of steroids. There was no statistical difference between the two groups with regard to these parameters.
Adenosine Triphosphate↗
Vasodilator drugs in peripheral vascular disease.
The use of vasodilator drugs in peripheral vascular disease is reviewed. Discussed are actions and efficacy of direct-acting drugs such as isoxsuprine, papaverinek niacin and cyclandelate; the beta-receptor stimulating drug, nylidrin; and drugs which affect the sympathetic nervous system, such as tolazoline, reserpine, guanethidine, methyldopa, ergot alkaloids and alcohol. Both animal and clinical studies reveal little evidence of the effectiveness of vasodilator drugs in the treatment of obstructive arterial disease. In some patients with vasospastic diseases, vasodilators which act upon the sympathetic nervous system (reserpine and guanethidine) may have an ameliorating effect by increasing cutaneous capillary blood flow.
Arterial Occlusive Diseases↗
Chemotherapy of cognitive disorders in geriatric subjects.
Many of the neurochemical changes associated with aging brain, particularly lower choline acetyltransferase and higher monoamine oxidase, occur with greater severity in senile dementia, Alzheimer's type (SDAT). These alterations correlate with neuropathologic indices, e.g., the number of senile plaques and tangles. Although many different treatment techniques have been used, most have been unsuccessful. No strong data have supported the use of stimulants, Gerovital H3, or hyperbaric oxygen. Among the vasodilators, cyclandelate and hydergine may be of value in some but not most patients. Much recent work has focused on techniques to increase acetylcholine brain concentrations. To date, precursors, such as choline, seem to have very limited value. Postsynaptic treatments, e.g., physostigmine, hold more hope for future benefit, if longer acting oral preparations are developed. Other compounds, such as ACTH, vasopressin, and piracetam, may have some value but need better definition and treatment indications. Recent discoveries on the influences of lecithin on membrane fluidity and receptor binding, may affect the focus of future pharmacologic investigation.
Adrenocorticotropic Hormone↗
[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-trimethylcylcohexanol 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.
Animals↗
Heterogeneity of biochemical actions among vasodilators.
Thirty-four vasodilators were screened in several in vitro biochemical assays related to smooth muscle excitation-contraction coupling, binding to beta 1-,beta 2-, and alpha-adrenergic receptors, inhibition of phosphodiesterase activity, and antagonism of calcium accumulation. Isoproterenol and perhexiline only exhibited binding to beta-adrenergic sites. Ergocryptine, tolazoline, and amotriphene only bound to alpha-adrenergic receptors. Leniquinsin, papaverine, proquazone, dioxyline, hoquizil, quazodine, and theophylline were active only as phosphodiesterase inhibitors. Isoxsuprine, nylidrin, and bencyclane bound to alpha- and beta-receptors. Pentoxifylline bound to beta 1-sites and inhibited phosphodiesterase. Cyclandelate bound to beta 2-sites and blocked calcium accumulation. Cinnarizine and flunarizine antagonized calcium accumulation and bound to alpha-sites. Prazosin bound to alpha-sites and inhibited phosphodiesterase. Ethaverine and dipyridamole were inhibitors of phosphodiesterase and calcium accumulation. Nafronyl bound to beta 2- and alpha-sites and antagonized calcium accumulation. Mebeverine bound to beta 2- and alpha-receptors and inhibited phosphodiesterase activity and calcium accumulation. Verapamil bound to alpha-sites, and blocked phosphodiesterase and calcium accumulation. Quinazosin bound to beta 2- and alpha-receptors and antagonized both phosphodiesterase activity and calcium accumulation. Vasodilators that were inactive in all assays included niacin, nicotinyl alcohol, inositol nicotinate, amyl nitrite, sodium nitroprusside, diazoxide, hydralazine, and protoveratrine. Vasodilators should not be considered as a single drug class since they act on various mechanisms related to coupling of neuronal excitation to muscular contractility.
3',5'-Cyclic-AMP Phosphodiesterases↗
Antimigraine drugs.
Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, phonophobia, and malaise. This review summarizes new treatment options for therapy of the acute attack. Mild or moderate migraine attacks are treated with antiemetics followed by analgesics such as aspirin, paracetamol, nonsteroidal anti-inflammatory drugs, or antiemetics combined with ergotamine or dihydroergotamine. Sumatriptan, a specific serotonin (5-HT)1B/D agonist is used when attacks do not respond to ergotamine, or when intolerable side effects occur. The new migraine drugs zolmitriptan, naratriptan, rizatriptan, and eletriptan differ slightly in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence, and side effects. New drugs in migraine prophylaxis include cyclandelate, valproic acid and magnesium.
Analgesics↗
Separation and estimation of seven vasodilators using packed column supercritical fluid chromatography.
This paper reports a method for an isocratic separation and simultaneous estimation of seven vasodilators: isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), cyclandelate, nimodipine, amlodipine, pentifylline and pentoxifylline using packed column supercritical fluid chromatography (SFC). An arbitrary choice of vasodilatory compounds with respect to their chemical structures was made to examine the viability of this technique for analysis of drugs and pharmaceuticals. Elution was performed on a RP-C18 column. SFC offers several degrees of freedom: temperature, pressure and modifier concentration to attain optimum resolution and sensitivity. The effects of these parameters on retention time have been studied using methanol modified carbon dioxide. The analytes were identified and measured by UV-detection. The chromatographic points of merit have been listed. Detection limits appear to be similar to those found in liquid chromatography. Modifier concentration does generally make major changes in retention and selectivity. A full scale validation for the seven vasodilators has been attempted and the statistical quality evaluated.
Atmospheric Pressure↗
The effects of 3,5,5-trimethylcyclohexanol on hepatic cholesterol synthesis, bile flow and biliary lipid secretion in the rat.
The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significantly inhibited hepatic S-3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1 h. TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.
Animals↗
Affinity of various compounds for benzodiazepine binding sites in rat brain, heart and kidneys in vitro.
Binding of several psychoactive, antiinflammatory, antihypertensive, and antiarrhythmic drugs to central and peripheral benzodiazepine (BZ) binding sites was studied in the brain, heart and kidneys of rats. Diazepam exhibited the highest affinity for all binding sites (Ki values at 0.01 microM level); another 1,4-BZ, oxazepam, had markedly lower affinity for peripheral binding sites (Ki 21-37 microM). Non-BZ compounds had low affinity for central BZ receptors; proquazone was the most potent (Ki 9.5 microM). The affinities of non-BZ compounds were higher for peripheral BZ binding sites. The Ki value for proquazone was approximately 0.1 microM; and many other antiinflammatory agents, and the vasodilators cyclandelate and nifedipine, produced Ki values in the micromolar level. beta-Blocking drugs, and several other antihypertensive and antiarrhythmic agents lacked affinity for both central and peripheral BZ binding sites. According to the results, the affinity for peripheral binding sites is independent of an affinity for central BZ receptors. Non-BZ compounds that bound to brain BZ receptors bound with equal affinity to both BZ1 and BZ2 subgroups of receptors. The compounds with affinity for peripheral BZ binding sites did not select between heart and kidneys, which suggests that these organs have similar binding sites. The role of the peripheral BZ binding sites has not yet been established. The findings of this study allow the selection of a more varied group of ligands to be used when investigating the physiological significance of these binding sites.
Animals↗