The effect of orally administered bencyclane on spontaneous platelet aggregation (PA) as a function of bencyclane concentration in coded samples.
Explore the source record for details and available documents.
Administration, Oral↗
SEARCH · Search PubMed
Results for “Bencyclane”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
[Oral therapy with bencyclane. Changes in blood-flow characteristics and spontaneous thrombocyte aggregation during oral therapy with bencyclane].
Explore the source record for details and available documents.
Bencyclane↗
[Inhibitory activity of bencyclan on platelet aggregation in vitro and in vivo (author's transl)].
N-[3-(Benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine (bencyclan-hydrogenfumarate, Fludilat¿) inhibits spontaneously enhanced aggregation in the tests which detect a spontaneous aggregating activity (PAT I--III) in 10(-5) molar concentration. Bencyclan also inhibits platelet adhesiveness and ADP or collagen induced platelet aggregation. 10(-5) M of bencyclan induced a slight swelling of platelets 5 times 10(-4) Mol inhibited the formation of tentacles completely and transformed the platelets into small spheres if investigated with interference-phase contrast microscopy. It is likely that the morphologic changes induced by bencyclan are responsible for the inhibitory effect on the different platelet function tests in vitro. In vivo oral application of 300-600 mg of bencyclan per day did not inhibit platelet aggregation. In patients with enhanced aggregating tendency i.v. injection of 200-400 mg bencyclan led to a short-time inhibition of platelet aggregation which usually did not last for more than 1 h. No binding of 14C-labelled bencyclan to platelets was found. In vitro and in vivo some 14C-labelled bencyclan was bound to albumins.
Adenosine Diphosphate↗
[The mechanism of action of bencyclane on smooth musculature].
Bencyclane (N-[3-(1-benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine-hydrogenfumarate, Fludilat), inhibits phosphodiesterase(PDE)-activity in vitro similarly to several other smooth muscle relaxants. Compared with papaverine this inhibitory effect of bencyclane on PDE is weak despite of its strong relaxant effect on smooth muscle, which is about equal to that of papaverine. 14C-Bencyclane is accumulated 8-fold in the smooth muscle tissue of bovine coronary arteries, indicating that relaxation is caused by 8-fold higher concentrations in the tissue than in the organ bath. A comparison of (corrected) ED50-values for relaxation with Ki-values for PDE-inhibition obtained with several PDE-inhibitors, including bencyclane, yields a significant correlation between both parameters. Since in subsequent studies in isolated tracheal muscle strips bencyclane at maximum relaxing concentrations did not increase cAMP, which was in contrast to the actions of papaverine or aminophylline, it is likely that bencyclane-induced smooth muscle relaxation is unrelated to inhibition of PDE or cAMP. In the same dose range in which bencyclane relaxes smooth muscles it exerts a non-specific antiadrenergic inhibitory effect, possibly due to its local anesthetic action at the cell membrane. It is also possible that the myocardial inhibitory effect of bencyclane is caused by a direct Ca++-antagonistic mechanism (Fleckenstein et al. 1971).
Aminophylline↗
Effects of bencyclane on normal and cevadine-modified Na channels in frog skeletal muscle.
The effect of 10(-5) mol/l bencyclane on the repetitive electrical activity of muscle membrane was studied with the conventional microelectrode technique. Electrical activity was induced by repetitive stimulation in normal Ringer solution (train) or by a single depolarizing current pulse in the presence of 10(-6) mol/l cevadine (volley). Bencyclane decreased, in a use-dependent manner, the maximum rates of depolarization and repolarization (Vmax+ and Vmax-, resp.) of the action potentials both of the train and the volley. The inhibition of Vmax+ and Vmax- was proportional; however, it was stronger for the volleys than for the trains. The cycle length (mean interspike interval) of the volley was increased by bencyclane; the prolongation was progressive during consecutive cycles. The dissociation of bencyclane from the Na channel was studied by applying trains of different durations with equal pulse numbers. Bencyclane at a higher concentration (5 x 10(-5) mol/l) caused a reversible tonic block: the overshoot potentials, Vmax+ and Vmax- were markedly reduced. The reduction of Vmax- was slightly stronger than that of Vmax+. Slow membrane potential oscillation (SMPO) was evoked by treating the muscle with 10(-4) mol/l of cevadine. The administration of 5 x 10(-6) mol/l bencyclane decreased the frequency of SMPO, while 10(-5) mol/l bencyclane terminated the slow oscillation activity without changing its baseline potential. The present results indicate that bencyclane induces use-dependent inhibition of Na channels in muscle, similarly as do class 1 antiarrhytnmic drugs. Inhibition was observed with both normal and cevadine-modified Na channels.
Action Potentials↗
[Cardiodepressive action of bencyclan (author's transl)].
In the isolated guinea pigs atria as well as in anaesthetized cats and dogs we studied the cardiovascular effects of bencyclan. The following results were found: 1.) Bencyclan causes a dose-dependent diminution of the force of contraction, the maximal rate of rise of contraction, and the frequency of the isolated atria, while the functional refractory period is prolonged. 2.) The negative inotropic effect of bencyclan can be antagonized in the isolated atria by increasing Ca+++ -concentrations. 3.) In the isolated left atria the effect of orciprenaline is unchanged while the effect of serotonin is diminished by bencyclan. 4.) In the anaesthetized cat 5 mg/kg of bencyclan cause a significant decrease of blood-pressure and contractility. While the fall of blood-pressure is reversed within a few minutes, the contractility is diminished for a longer time. 5.) 2 of 10 cats and 2 of 3 dogs died within a few minutes when 5 mg/kg bencyclan and 1 mg/kg propranolol were injected within an interval of 15 minutes. 6.) Pretreatment with 20 mg/kg propranolol i.m. does not increase the acute toxicity of bencyclan in mice significantly.
Animals↗
Use-dependent blockade of sodium channels induced by bencyclane in frog skeletal muscle and canine cardiac Purkinje fiber.
Applying conventional microelectrode technique, the effect of bencyclane was studied on the maximal rate of rise (Vmax) of the transmembrane action potential in frog skeletal muscle and canine cardiac Purkinje fiber. Bencyclane (10 microM) decreased the Vmax from 333.7 +/- 6.9 V/sec to 302.7 +/- 10.2 V/sec (n = 6, p less than 0.05) in skeletal muscle without changing the resting membrane potential. If repetitive stimulation with different constant cycle lengths was applied, a further, frequency-dependent decrease of Vmax developed in both tissues with similar frequency-dependence. In skeletal muscle bencyclane increased the time of 50% repolarization by 33.3 +/- 2.5% (n = 7, p less than 0.01) and decreased the overshoot potential by 11.3 +/- 0.72 mV (n = 7, p less than 0.01) measured at 250 msec cycle length. In cardiac Purkinje fiber bencyclane shortened the action potential duration (APD90) from 258.3 +/- 15.4 msec to 241.7 +/- 12.1 msec (n = 6, p less than 0.05) without changing the resting membrane potential and action potential amplitude measured at 500 msec cycle length. The comparable size of the Vmax-block at the same cycle lengths observed in skeletal muscle (short APD) and Purkinje fiber (long APD) suggests that the inhibition may by mainly attributed to the open sodium channel population. It was concluded that the antiarrhythmic action of bencyclane, based on the use-dependent blockade of sodium channels, might be an important component of the therapeutic effect of bencyclane.
Action Potentials↗
[In vitro incubation of lenses. Model for testing substrate utilization of substances of the energy metabolism, demonstrated with bencyclane-hydrogen-fumarate (author's transl)].
When bovine lens homogenate was treated with bencyclane-hydrogen-fumarate, the carbohydrate metabolism was activated. This may chiefly be due to the fumarate part of the substance. A 24 H In vitro incubation of whole bovine lenses in TC-199 with and without bencyclane-hydrogen-fumarate did not show the above effect. On the model of former investigations by J.E. Harris et al. we modified the test procedure by selecting the medium and the time of incubation so that the endogenous carbohydrates of the lens were consumed, thus creating new metabolic balances. This metabolic condition allows investigations intended to activate metabolic processes and to restore the steady state of metabolic parameters. We investigated the effect of bencyclane-hydrogen-fumarate using the same method and found that given certain conditions the lens recovers when incubated for 2 h in TC-199 (containing 1 g glucose/1) with addition of a 10(-4) M solution of bencyclane-hydrogen-fumarate. The ATP-content of these lenses in particular gives proof of this result. As already observed in former investigations on homogenates, this effect is probably due to metabolization of the fumarate part of the bencyclane-hydrogen-fumarate by the citric acid cycle. The method used explains the differences observed when using lens homogenates or whole lenses under the same experimental conditions.
Adenine Nucleotides↗
[Effect of Bencyclane on regional cerebral circulation. Quantitative local measurement of cerebral circulation in healthy persons and patients with cerebrovascular insufficiency, awake or in light general anesthesia].
The effect of intravenous continuous drip infusion of Bencyclan (8mg/min) on regional cerebral blood flow was investigated in 30 adult patients, using the intraarterial 133-Xe-clearance-method and a 10-detector-equipment. The application of Bencyclan in 5 persons with normal cerebral circulation entailed no significant change of rCBF. In 5 from 15 patients with cerebrovascular disease in the awake state continuous drip infusion of Bencyclan caused a decrease of global and regional cerebral blood flow with reduction of the regional flow values about 15.3 to 28.4 p.c. In 10 patients there was seen no statistical significant change of regional cerebral blood flow as compared with the flow values in the resting state. In 10 patients rCBF-examinations were performed prior and after intravenous injection of Bencyclan in a state of a very light nitrous-oxide-halothan analgesia. In all patients Bencyclan caused an overall decrease of cerebral blood flow about 8.8 p.c. to 24.3 p.c. which in 5 cases achieved statistical significance.
Adult↗
A contribution to the pharmacokinetics of bencyclane (Fludilat) in man.
The quantitative determination of bencyclane from the biological material was carried out with the aid of a combined microchemical method (thin-layer chromatography and measurement of fluorescence) using NBD chloride. The original method [J. Reisch, Z. Analyt. Chemie, 247 (1969) 56; J. Monforte, Clinical Chemistry 18 (1972) 1329; R.S. Fager, Anal. Biochemistry, 53 (1973) 290, etc.] was so modified as to enable attainment of optimal results in respect of sensitivity and accuracy in the determination of bencyclane. The sensitivity of this modified method is 0.1 mug/ml plasma. Volunteer subjects and patients received under standard conditions 2 coated tablets Fludilat (i.e. 200 mg bencyclane hydrogen fumarate) orally as a single dose or repeated 3 times daily over 5 days, or 4 ampoules (= 200 mg) in a single intravenous injection. After a single oral administration, maximum plasma concentrations of approximately 2 mug/ml were attained in about 2 hours. The elimination half-life was about 360-480 min. The appearance of a second peak after about 6-7 hours indicates involvement of several compartments. On intravenous administration, maximum plasma concentrations of above 2 mug/ml were attained. A second peak in the late phase of the elimination was also detected here. The repeated oral administration led to maximum plasma concentrations of above 3 mug/ml without there being any indication of accumulation. Protein binding of about 30% was determined with the aid of the equilibrium dialysis method. A parallel "in vitro" study with 14C-bencyclane (U.R. Kleeberg, 1973, unpublished) showed an approx. 40% protein binding, an approx. 30% erythrocyte binding, and an approx. 10% thrombocyte binding. About 20% bencyclane remain free.
Administration, Oral↗
The long-term tolerability of bencyclane ('Fludilat') in patients with peripheral occlusive disease: a 48-week prospective double-blind controlled study versus placebo.
In a controlled, multi-centre, double-blind trial, 75 patients with Stage II peripheral occlusive disease (Fontaine IIa) were treated with either 200 mg bencyclane twice daily or placebo over a period of 12 months. Undesired drug effects and concomitant phenomena were documented, and efficacy was evaluated. Bencyclane caused a slight, clinically negligible decrease in blood pressure. The pulse rate remained mostly unchanged, ECG and laboratory parameters showed no changes which would indicate a specific effect of the test substance. In the context of the generally low incidence of concomitant effects, patients in the bencyclane group mentioned symptoms such as insomnia, depressive mood, sweating and reduced motoricity more often than those in the placebo group. These symptoms are regarded as signs of the central nervous actions of the drug. The parameters used to assess the efficacy, i.e. the pain-free walking distance estimated by the patients and the physician's global judgment based on Ratschow's test, the palpability of the pedal pulse, the walking range and the patients' subjective statements about the incidence of chill, formication, and pain in the legs, showed a constant and statistically significant superiority of bencyclane over placebo.
Arterial Occlusive Diseases↗
Radioimmunoassay of bencyclane in human serum.
A radioimmunoassay of bencyclane in human serum was developed. Male rabbits were immunized with p-(3-carboxy-propoxy)bencyclane-bovine serum albumin conjugate, giving antisera with high titers. 125I-p-Hydroxybencyclane with a high specific activity was prepared as a labelled antigen by a chloramine-T method. In the radioimmunoassay procedure, a mixture of serum sample, diluted antiserum and 125I-antigen solution were incubated at 4 degrees C for 18 h, and bound-free separation was carried out by a dextran-coated charcoal method. The detection limit of bencyclane in human serum was 1.0 ng/ml, and the cross-reactivity of the antiserum with metabolites was found to be very low. Serum samples from healthy volunteers dosed orally with bencyclane fumarate were analyzed by both of the radioimmunoassay and gas chromatography-mass spectrometric methods. An excellent correlation was observed between the values obtained by both methods.
Animals↗
[The effect of bencyclan on shear induced platelet aggregation (author's transl)].
The platelet aggregation inhibiting effect of N-[3-(1-benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine (bencyclan, Fludilat) was studied by a new method for quantification of platelet aggregation in viscometric flow. In vitro-addition of bencyclan shows significant inhibition in a concentration of 1 mg/100 ml, total inhibition of platelet aggregation is found at a concentration of 5 mg/100 ml. Peroral application of bencyclan shows no significant effect on platelet aggregation. Intravenous application of bencyclan studied in three patients results in inhibition of platelet aggregation, however, no information about the duration of this platelet-inhibiting effect is yielded.
Adenosine Diphosphate↗
[Blood circulation, oxygen pressure and pH of the cerebral cortex under the influence of bencyclane].
The effect of N-[3-(1-benzyl-cycloheptyl-oxy)-propyl]-N,N-dimethyl-amine (bencyclan-hydrogenfumarate, Fludilat¿ on the cerebral vascular system was studied by means of the following methods: 1. In pigs regional cerebral cortical blood flow was continuously recorded with a heat conduction device, cortical pH with a glass electode in which the flat measuring surface and the reference were close together. Cortical pO2 was recorded with a multiwire platinum electrode. Systemic arterial blood pressure was monitored by means of a Statham transducer. 2. In a second series in cats the perivascular space of small pial arteries or arterioles was perfused with cerebro-spinal fluid (CSF) to which bencyclan had been added. The perfusion was performed by means of micropipettes. Local cortical blood flow increased slightly for some minutes after slow infusion of 1--3 mg/kg bencyclan. Rapid injection caused initially a significant decrease in arterial blood pressure, which was accompanied by a transient decrease in CBF and in cortical pH. After the return of the arterial blood pressure to its initial value, CBF increased. Cortical pO2 and cortical pH returned to initial values. After slow infusion of the substance the pH variation was usually very slight or it was missed completely. Perivascular microperfusion wtih CSF containing bencyclan caused dilatation of those pial sections which were in contact with the drug. High concentration of the drug caused stronger dilatations than did low concentrations. It is concluded that the substance causes dilatations of the cerebral vessels and that this dilatation occurs also during constant perivascular pH.
Animals↗
[Treatment of disorders of cerebral performance in the aged in ambulatory care using bencyclane. Results of a controlled double-blind phase III study versus placebo].
A placebo-controlled, randomized double-blind study conducted at a general practitioner's surgery was designed to investigate the efficacy of bencyclane in 120 outpatients with cerebral dysfunctions based on organic brain syndrome. The study started with a 4-week placebo washout phase and then continued with a 12-week treatment phase. 200 mg Bencyclane-hydrogenfumarate was administered b.i.d. Efficacy was assessed by a doctor's symptom rating (SCAG) and a study nurse's rating (BGP) as well as by two performance tests (CFF and ZVT-G). Data from 106 patients (52 under bencyclane and 54 under placebo) were statistically analysed. More side effects were seen under bencyclane than under placebo, in particular insomnia, headache, akathisia, nausea and vomiting. As an a priori hypothesis, it was stated that after alpha-adjustment there should be a statistically significant difference in symptomatology (SCAG, BGP) and performance (CFF, ZVT-G). With regard to performance, the zero hypothesis could be rejected on the 5% level, and on the 1% level with respect to symptomatology. The experimental error on both the performance and the symptom level was below 6%. The drug effects were significant on a confirmatory level and are considered to be also of clinical relevance.
Aged↗
Pharmacokinetics of bencyclane after single dose administration to healthy volunteers.
The pharmacokinetics of bencyclane were studied in 4 healthy volunteers. In a randomized cross-over design, 35 and 70 mg of bencyclane were infused intravenously and 71 and 143 mg were given orally as a solution in water. After intravenous application bencyclane is distributed very rapidly into tissues (t1/2 approx. 7 min). The volume of distribution is about 600 l. In almost every subject the plasma levels rose again after this distribution phase. Bencyclane is eliminated mainly by metabolism. At the most 3% of the dose is excreted as unchanged drug in the urine. Total clearance is appr. 44 l/h, the elimination half-life approx. 12 h. Oral bioavailability ranges between 18 and 84%.
Adult↗
[Demonstration of bencyclane effects in a clinico-pharmacologic vigilance model].
The effects of 8 weeks' treatment with 2x 200 mg Bencyclan daily were investigated versus placebo in 50 patients. A clinical diagnosis had revealed the onset of organic mental disorders in all patients who, after fulfilling neurophysiologically and neuropsychologically defined screening criteria, were admitted to the trial. The patients were randomly allocated to two parallel groups of 25 for this controlled, double-blind study. Patients had to show 50% subvigil phases in a 15 min resting-EEG recording. We define such behaviour as a neurophysiological disturbance of vigilance. Scores in the Benton test were to be 2 points below the expected value or the NAF-score was to be above a standard value attained in an old people's home (greater than 14). On a neurophysiological level, inference statistical tests indicated effects in line with the hypothesis: A statistically significant difference in favour of Bencyclan was apparent after 8 weeks' treatment when compared with placebo. The Vigilance Index (VI) was higher under Bencyclan than after placebo. We regard the VI as a plausible indicator of vigilance-dependent disturbances in the elderly. On a behavioral level, Bencyclan was tendentially superior with respect to age-dependent complaints and performance-related activatedness, whereby one could not exclude the possibility that there were chance findings. The clear proof of efficacy on the neurophysiological level and the unclear effectiveness on the behavioral level can be attributed to the fact that time- and placebo effects were less marked on the former level. The intensive supervision of the patients led to considerable placebo effects on the behavioral level. Two groups of 25 patients are therefore not sufficient to be able to detect drug effects within a treatment period of only 8 weeks.
Aged↗
Bencyclane as an anti-sickling agent.
A vasodilating Ca2+ channel blocker, bencyclane, was used in 18 patients with homozygous sickle cell anaemia (SCD) to test the possible anti-sickling effect. With bencyclane intervention the Na(+)-K+ ATPase activity increased from 256 +/- 29 to 331 +/- 37 nmol Pi/mg protein/h (P < 0.0001) and the Ca(2+)-Mg2+ ATPase level increased from 172 +/- 12 to 222 +/- 44 nmol Pi/mg protein/h (P < 0.0001). The intracytoplasmic Ca2+ concentration reduced from 3.5 +/- 0.6 to 2.7 +/- 0.25 mumol/l (P < 0.0001). The patient's blood contained fewer irreversibly sickled cells (ISCs) (a reduction from 21.4% to 14.4%) (P < 0.05). At the same time MCHC of the erythrocytes decreased from 34.5 to 33.0 g/dl (P < 0.05). Bencyclane appears to be a promising anti-sickling agent that can be used orally in SCD.
Adolescent↗