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PubMed1988

Fendiline and calmidazolium enhance the release of endothelium-derived relaxant factor and of prostacyclin from cultured endothelial cells.

We investigated the effects of fendiline, calmidazolium and trifluoperazine, compounds described as calmodulin antagonists, on the release of the endothelial autacoids prostacyclin (PGI2) and endothelium-derived relaxant factor (EDRF). Cultured bovine aortic endothelial cells were grown on microcarrier beads and continuously superfused with Tyrode's solution. Samples collected from the superfusate were assayed for PGI2 concentration (6-keto PGF1 alpha radioimmunoassay) and for EDRF activity (stimulation of soluble guanylate cyclase in vitro). Stimulation of endothelial cells by ATP (3 microM) resulted in a 6.9 +/- 1.4-fold increase of PGI2 concentration in the superfusate (p less than 0.01) and an 8.6 +/- 3.4-fold enhanced guanylate cyclase activity (p less than 0.01). In the presence of calmidazolium (10 microM), the basal values of PGI2 concentration increased 28-fold (p less than 0.01) and the guanylate cyclase activity 10-fold (p less than 0.01). Further enhancement of both was observed after additional administration of ATP. Fendiline (30 microM) did not affect autacoid release by non-stimulated cells. However, the ATP-induced release of PGI2 and EDRF was more than doubled (p less than 0.01) in the presence of this drug compared to ATP-stimulation alone. Trifluoperazine (10 microM) had no enhancing effect on EDRF release, and the ATP-induced release of PGI2 was even significantly attenuated by 84 +/- 12% (p less than 0.01). Calmidazolium and fendiline were also applied to endothelial cells loaded with the fluorescent indicator of free calcium concentration (Ca2i+), indo-1. However, effects of calmidazolium on Ca2i+ could not be quantified since calmidazolium caused some leakage of indo-1 out of the cells. A smaller leakage was observed during the combined application of fendiline and ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1982

Single dose pharmacokinetics of fendiline in humans.

Fendiline was administered intravenously (3 mg) and orally (50 mg and 75 mg) in a cross-over study to six healthy volunteers. The plasma levels of unchanged fendiline and of total radioactivity were measured. Fendiline was absorbed well and its concentration declined biexponentially with mean terminal half-lives of 20-35 h. Since the drug is extensively metabolized, only 12% of total radioactivity in plasma corresponded to fendiline in the case of intravenous administration as compared to less than 2% after oral administration. 56-65% of the administered dose are excreted via the urine and 18-25% with the feces within five days.

Adult↗
PubMed1991

Double-blind, randomized study of the anti-anginal and anti-ischaemic efficacy of fendiline and diltiazem in patients with coronary heart disease.

In a 6-week, randomized, double-blind trial, the drug effects of the calcium antagonists, fendiline (75 mg twice daily) and diltiazem (90 mg twice daily), as measured by subjective and objective parameters of coronary heart disease, were studied in 79 patients with stable angina pectoris. The statistical analysis included the data of 71 patients. The results of exercise-ECG tests showed that both medications were effective anti-ischaemic agents. Fendiline was found to be effective in reducing ST-segment depression at maximum comparable load (71 watts) as well as at the time of reaching the individual maximum tolerated load (discontinuation of exertion). Diltiazem, on the other hand, proved effective only at maximum comparable load (72 watts). There was no significant difference between the groups with regard to the reduction after 6 weeks. As regards work tolerance, the duration of exercise and time until appearance of a ST-segment depression of 0.1 mV, before and after treatment comparisons revealed significant changes only in the group receiving diltiazem and the differences between fendiline and diltiazem were statistically significant with regard to these three parameters. Reduction in the frequency of anginal attacks and the diminution of nitroglycerin consumption were comparable in both medication groups, and the changes from baseline were statistically significant. Assessment of the efficacy and tolerability of the medications by patients as well as by investigators revealed no statistically significant differences between the two groups. Blood pressure and heart rate were clearly lowered by diltiazem, whereas fendiline induced only a slight decrease in blood pressure. The results indicate that both medications are equally suited for the treatment of stable angina pectoris.

Aged↗
PubMed1991

Enhancement of the mutagenicity of anticancer drugs by the calcium antagonists verapamil and fendiline.

The enhancement of the mutagenicity of anticancer drugs by the calcium antagonists verapamil (CAS 52-53-9) and fendiline (CAS 13042-18-7) is reviewed. Both calcium antagonists enhance synergistically the induction of chromosome aberrations (dicentric and ring chromosomes) in cultured human lymphocytes by the antitumor agent bleomycin. Since two other calcium antagonists, nifedipine and diltiazem, when tested with the same system, did not show this effect, the comutagenicity of verapamil and fendiline does not seem to be related with calcium antagonism per se. Verapamil furthermore potentiates the induction of various chromosome and chromatid aberrations in Chinese hamster ovary (CHO) cells in vitro by the antitumor agent mitomycin C. In bacteria (Salmonella typhimurium) verapamil enhances synergistically the induction of gene mutations (frameshifts) by several anticancer drugs, including various anilinoacridine derivatives. When applied alone, neither verapamil which was tested in each of the three studies (human lymphocytes, CHO-cells, and bacteria) nor fendiline, which was tested only in human lymphocytes, proved to be mutagenic. To explain the comutagenicity of verapamil and fendiline, it is assumed that they prevent the mutagen (e.g., bleomycin) to be extruded from the cell. Consequently, the mutagen would be accumulated intracellularly and this would enhance its efficiency.

Animals↗
PubMed1987

Fendiline: a review of its basic pharmacological and clinical properties.

Fendiline is an anti-anginal agent for the treatment of coronary heart disease. Together with other diphenylalkylamines it is sub-classified in the group of lipophilic calcium antagonists. It binds to the calcium channel and to calmodulin with rather similar affinities. Pharmaco-dynamically, it exerts the typical calcium as well as calmodulin antagonistic actions: inhibition of the transmembrane calcium current, smooth muscle relaxation, negative inotropism, cardioprotection, inhibition of calmodulin-activated myosin light-chain kinase and phosphodiesterase. Pharmacokinetics reveal slow onset of action and a long half-life. The anti-anginal and anti-ischaemic efficacy of fendiline has been proven in several placebo-controlled, double-blind trials. It does not interfere with digoxin therapy. Direct comparison with other calcium antagonists by means of controlled studies revealed that its potency is at least equal to that of nifedipine but, in contrast to nifedipine, verapamil, and diltiazem, its anti-anginal action increases during chronic therapy, reaching a steady state of action after 2 to 3 weeks. In addition, the anti-ischaemic and anti-anginal potency is about equal to that of isosorbide dinitrate but fendiline has the advantage of lacking tolerance development. Nevertheless, the data presented indicate that a combination of fendiline with low doses of ISDN may be beneficial. Adverse cardiac and haemodynamic actions, such as increase or decrease in heart rate, disturbance of AV nodal conduction, impairment of cardiac contractile performance or considerable decrease in arterial pressure in hypotensives and normotensives, are lacking.

Fendiline↗
PubMed1980

[Fendiline and isosorbide dinitrate in coronary heart disease (author's transl)].

In a randomized cross-over double-blind study of 30 out-patients with true angina the efficacy of fendiline and isosorbide dinitrate (ISDN) was compared. In randomized order the patients daily took either 3 X 50 mg fendiline or 2 X 20 mg ISDN (plus 1 placebo tablet). Each treatment period lasted for six weeks. Ergometric tests were performed at the onset of the study and at intervals of three weeks. The main criterion for the efficacy of the treatment was a change in S-T segment (at 0.06 s after the QRS). With either drug there occurred a statistically significant reduction in S-T depression and in the frequency of anginal attacks during the first treatment period. But there was a difference between the two drugs: Whereas with ISDN a marked reduction in S-T segment depression was observed after three weeks, this effect slightly receded in the second part of the treatment period, while with fendiline the reduction in S-T depression continued over the entire treatment period. There was no significant difference between the two drugs as to side-effects or tolerance.

Adult↗
PubMed1989

Intracellular localization of the calcium- and calmodulin antagonist fendiline.

Microautoradiograpic studies of mouse heart sections were performed to evaluate intracellular localization of the antianginal drug fendiline (Sensit). 15 microCi 3H-fendiline/g b. w. (0.5 mg/kg b.w.) were injected intravenously. 10 min p.a. the heart was removed and either frozen in acetone/dry ice or, after perfusion in situ with dextran 40 and formaldehyde, fixed in formaldehyde. Frozen, paraffin-embedded, and semithin epoxy resin sections were prepared and coated with Ilford K2 emulsion. After 7 to 30 days exposure and development in amidol silver grains were counted above cells, nuclei and extracellular space. The results show that fendiline is able to enter myocardial cells.

Animals↗
PubMed1976

[Cardioprotection by oral application of the calcium antagonist fendiline. Prevention of isoproterenol-induced myocardial necroses in rats (author's transl)].

1. N-(2-Benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride (fendiline, Sensit) -- in accordance with its characteristics as a Ca++-antagonist -- shows a strong cardioprotective effect in rats against isoproterenol-induced myocardial necroses. 2. Fendiline is effective via oral administration. 3. The protective effect of fendiline on the myocardium is demonstrated by means of histopathological and histoenzymatic techniques. 4. A particularly reliable method of quantifying the cardio-protective effect of a drug has proven to be the measurement of mitochondrial enzyme activity (cytochrome oxidase, succinate dehydrogenase) using histoenzymatic microphotometry.

Animals↗
PubMed1983

Identification of fendiline metabolites in human urine.

After oral application of 14C labelled fendiline, 13 metabolites of this drug could be identified in human urine. Only traces of parent fendiline were excreted in the urine. The main pathway of metabolism is hydroxylation of phenyl groups with subsequent glucuronidation and sulphation. On the other hand, oxidative dealkylation occurs with the amino group remaining at the 3,3-diphenylpropyl moiety and p-hydroxyacetophenone being formed almost entirely from the 1-phenylethyl group.

Adult↗
PubMed1991

Determination of fendiline in human plasma by means of capillary gas chromatography and nitrogen-phosphorus selective detection.

A sensitive and specific method for the determination of fendiline in human plasma is presented. Fendiline was extracted from human plasma after the addition of phosphate buffer two times with 4 ml of n-hexane. The organic phase was separated and evaporated to dryness at 40 degrees C under a stream of nitrogen. The residue was dissolved and an aliquot was injected into the gas chromatograph. Chromatographic separation was performed with a DB-1 column with helium as carrier gas. Nitrogen-selective detection was performed. Quantification was performed with the signal output. The limit of detection was 1 ng/ml of plasma.

Chromatography, Gas↗
PubMed1983

Comparison of two calcium antagonists, verapamil and fendiline, in an experimental model of myocardial ischaemia mimicking classical angina on effort.

1 The effects of verapamil (0.15/kg) and fendiline (3 mg/kg) were studied in anaesthetized, thoracotomised dogs with a critical constriction of the left anterior descending coronary artery, paced in excess of the initial rate by 60-70 beats/min. Epicardial ST-segment elevation and changes in lactate uptake were used to assess the severity of myocardial ischaemia. 2 Both drugs prevented the ST-segment elevation and the reduced lactate uptake that resulted from atrial pacing. 3 The anti-ischaemic effect of fendiline is mainly due to its negative chronotropic action, whereas that of verapamil is due in part to bradycardia and in part to the reduced preload and afterload. In addition, both agents increase coronary flow to the ischaemic area and thus improve the myocardial oxygen supply/oxygen requirement ratio.

Angina Pectoris↗
PubMed2005

Spectrofluorimetric determination of fendiline in tablets.

A simple, sensitive and accurate spectrofluorimetric method was developed for the assay of fendiline in tablets. Validation of the method provided good results concerning linearity, precision and accuracy. The linearity range was found to be 0.1-0.8 mg/l. The fluorescence intensity was measured at 288 nm for fendiline tablet solutions. It was also found that the excipients in the commercial tablets did not interfere with the method.

Calcium Channel Blockers↗
PubMed1987

Tolerance and pharmacokinetics of oral fendiline.

Two studies with healthy volunteers were carried out to correlate safety with pharmacokinetics of the calcium antagonistic drug N-(3,3-diphenylpropyl)-(1-phenylethyl)-amine (fendiline, Sensit) after single and multiple oral doses. In the first study single doses of 200, 400, 600, 800, 1000, and 1200 mg of fendiline hydrochloride were administered to 6 subjects per dose level. 3 additional subjects per dose level received placebo. No significant objective or subjective effects were noted in the dose range studied. The pharmacokinetic analysis revealed that doses higher than 800 mg were absorbed incompletely. In the second study initially 400 mg twice daily was given to 9 subjects. 3 additional subjects received placebo. Due to subjective intolerability (trembling, dizziness) after 5 days, the dose was reduced stepwise to 2 X 200 mg and was then continued for another 19 days. The pharmacokinetic evaluation revealed manifold interindividual differences in plasma levels for maximal concentrations (9-170 ng/ml) as well as for minimal concentrations (4-96 ng/ml). The absorption profile in both studies has linear and nonlinear components. Maximal plasma levels were reached after about 4 h. Terminal elimination half-lives were about 20 h.

Adolescent↗
PubMed2001

Determination of fendiline and gallopamil by capillary isotachophoresis.

Capillary isotachophoresis was applied for the determination of fendiline and gallopamil--calcium antagonists--in serum. The cationic electrolyte system containing Na+ with acetic acid as a counter constituent was used as a leading electrolyte with the pH 4.7 and the terminating electrolyte was beta-alanine. Most of the proteins were precipitated with methanol, ethanol and dimethylketone. The lowest limits of quantitation were obtained for the pretreatment of serum with methanol. The recoveries of both compounds varied from 91.3 to 97.5%. The relative standard deviations varied from 0.6 to 7.7%.

Calcium Channel Blockers↗
PubMed1980

[Effects of nitroglycerin on exercise hemodynamics in patients with coronary heart disease under treatment with beta-blockers (mepindolol, oxprenolol) and a calcium-antagonist (fendiline) (author's transl)].

Nitroglycerin (0.8 mg p. o.) improves exercise hemodynamics in patients with coronary heart disease by normalizing left ventricular filling pressure and elevating volume output. Exercise heart rate and mean arterial blood pressure remain unchanged. Pretreatment with a beta-receptor-blocker (Mepindolol) and the combination of beta-receptor-blocker (Oxprenolol) with a calcium-antagonist (Fendiline) reduces the efficacy of nitroglycerin. The effects of the underlying treatment on the ventricular function curve shifting rightwards are not antagonized by nitroglycerin.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Effects of fendilin hydrochloride (sensit) on systemic and coronary hemodynamics and on retrograde coronary blood flow in dogs.

Fendilin hydrochloride was tested in 9 normal anesthetized dogs and in 7 anesthetized dogs with acute coronary artery occlusion. The compound (1 mg/kg i.v.) caused a slight short lasting increase in coronary blood flow together with an increase in cardiac metabolic rate for oxygen of similar magnitude. There was no measurable effect on collateral conductance. No noteworthy effects on systemic hemodynamics were observed.

Animals↗
PubMed1975

[Coronary collateral vessels after long-term treatment with fendiline hydrochloride in a double-blind study (author's transl)].

After long-therapy with 5 mg/kg body-weight of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)amine hydrochloride (fendiline hydrochloride, Sensit) in dogs the development of functioning coronary collateral vessels can be proven by filling the vessel system with synthetic resin. From earlier studies, it is known that coronary collateral vessels can protect the heart from the consequences of stenoses and tissue damage due to hypoxia.

Animals↗