The effect of orally administered bencyclane on spontaneous platelet aggregation (PA) as a function of bencyclane concentration in coded samples.
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Administration, Oral↗
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[Oral therapy with bencyclane. Changes in blood-flow characteristics and spontaneous thrombocyte aggregation during oral therapy with bencyclane].
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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↗
[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↗
[Acute acoustic trauma. The therapeutic effect of bencyclan in a controlled clinical trial (author's transl)].
In a retrospective study 103 patients with acute acoustic trauma (AAT) were investigated. The control group (53 patients) was treated with Dextran 40 (10% solution), neurotrop vitamins and Betahistin. Bencyclan was administered additionally in the test group (50 patients). Statistical analysis of the audiometric data showed the following results: 1. Mean hearing levels of the test group showed better improvement of threshold shifts, if the therapy started within 2 days or after more than 10 days after the AAT. 2. Regression-and correlation coefficients, however, in a regression analysis of absolute hearing gains and hearing losses before therapy, did not indicate a substantial effect of Bencyclan. 3. Neither did statistical tests with relative hearing gains show any significant differences between test-and control groups. Consequently Bencyclan is not likely to have a positive effect in AAT, if it is administered in the above mentioned way.
Adolescent↗
[Cardiac output and central-hemodynamic parameter under bencyclan (author's transl)].
In 17 patients with peripheral arterial occlusive disease the influence of intra-veinously applicated Bencyclane (Fludilat) on cardiac output and central-hemodynamic parameter has been investigated. While 100 mg (n = 8) of Bencyclane almost do not influence cardiac output, 200 mg (n = 9) cause a significant decrease of minute-volume of the heart by-17.22% and of heartfrequency by-8.85%. With either dose there is also a significant increase of aortic pressure, pulmonary arterial pressure and pulmonary vessel resistance to be seen. These results correlate with the animal-experimental proof of a negative inotropy under Bencyclane, and they have to be considered in therapeutical use.
Arterial Occlusive Diseases↗
Action of bencyclane-hydrogen-fumarate on the carbohydrate metabolism of bovine lens homogenates.
1-Benzyl-1-(3-dimethylaminopropoxy)cycloheptane (bencyclane-hydrogen-fumarate; Fludilat) in a concentration of 10-2 M effects an increase in the O2 consumption and the formation of CO2 in a 10% bovine lens homogenate. This effect is even increased if the glucose-substrate supply is raised from 25 mM to 37 mM. Investigations on the concentrations at ATP, ADP and AMP show that bencyclane is able to stabilize the physiologic distribution pattern of the three free adenine nucleotides. Further, the observed changes in the distribution pattern indicated that the fumaric acid rest of bencyclane may serve as a substrate for this reaction in the same way as fumarate.
Adenosine Diphosphate↗
[Bencyclan (Fludilat) in the treatment of patients with ischaemic cerebral infarction (author's transl)].
In 50 patients suffering from local cerebral circulation disturbances the effects of bencyclan--administered intravenously in a dosis of 500 mg per day--were evaluated under double-blind conditions. At the same time all patients received digitalis and physiotherapy. Besides a detailed recording of the neurological and psychopathological status a number of psychological tests were applied in order to get objective data about psychomotor function, cerebro-organic capacity and mood. The control recordings after a three weeks' treatment demonstrated an improvement of the clinical as well as the psychological parameters in either group. There were no marked, statistically significant differences in the extent of improvement between the bencyclan and the placebo group; that means bencyclan has no effect on the signs of ischaemic cerebrovascular disease, which exceeds the effects of digitalis and physiotherapy.
Adult↗
[Cardiac side-effects of bencyclan].
Bencyclan (Fludilat), used therapeutically as a vasodilator drug, exerts a distinct negative inotropic and chronotropic action on myocardium, in contrast to papaverine. It prolongs the functional refractory period in the isolated heart preparation. In isolated myocardial mitochondria it decreases the velocity of oxidative phosphorylation and the rate of calcium uptake. These results indicate that heart function should be checked if bencyclan is applied at high dosage, especially if other cardio-depressive substances such as narcotics, antidepressive and antiarrhythmic agents as well as beta-adrenergic blockers are used at the same time. On the other hand, the results suggest that bencyclan should be tested for possible use in the treatment of ischaemic heart disease as well as ventricular and supraventricular tachycardia.
Adrenergic beta-Antagonists↗