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PubMed1988

The effects of prenylamine on single ventricular myocytes of guinea-pig.

1. The action of prenylamine, an antianginal drug, was studied in single ventricular guinea-pig myocytes. In concentrations of 10-50 microM, prenylamine significantly (P less than 0.01) shortened action potentials, and significantly (P less than 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor-blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action. 2. Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time-dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time-independent potassium conductance. 3. It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.

Animals↗

PubMed1983

Possible female preponderance in prenylamine-induced 'torsade de pointes' tachycardia. Short communication.

Episodes of ventricular tachycardia of the 'torsade de pointes' (VTTP) types provoked by prenylamine were observed in 7 patients: 5 females and 2 males. They all received prenylamine in a dose of 120-180 mg daily for anginal pains. Syncope or syncopal equivalents occurred in all 7 patients. Q-T intervals ranged from 0.52 to 0.64 s. Review of the literature revealed 11 patients with prenylamine-induced VTTP, of whom 8 were females. The female preponderance (72.2%), hitherto not commented upon in the literature, is highlighted. Prenylamine-indiced VTTP may appear late after initiation of therapy, consequently clinical and ECG long-term follow-up is mandatory. The drug should promptly be discontinued in symptomatic patients, and particularly in females showing prolonged Q-T.

Aged↗

PubMed1985

Double-blind comparison of prenylamine and penbutolol in patients with angina pectoris.

This study was performed to re-evaluate the clinical position of prenylamine in the management of angina pectoris. After 1 week withdrawal of all anti-anginal agents, followed by another week of placebo administration, seventeen patients were allocated at random to 6 weeks treatment with either penbutolol 40 mg once a day or prenylamine 60 mg t.i.d. Clinical examination, exercise test and anginal attack rate were recorded every 2 weeks. Both drugs reduced the anginal attack rate. None of the drugs caused a significant increase in maximal workload or a significant change in ST-segment depression. Beside a substantially lower rate-pressure product at maximal comparable workload in the penbutolol group (p less than 0.001), no significant differences were observed between the two drugs. No adverse reactions were reported. From these results one can conclude that prenylamine and penbutolol do not differ in their anti-anginal effect. Therefore we are of the opinion that prenylamine has a place in the therapeutic armamentarium for the management of angina pectoris, particularly in patients where beta-blocking agents are contraindicated or in patients who have experienced side-effects of beta-blocking or calcium-entry blocking agents.

Aged↗

PubMed1976

Prenylamine inhibition of isoproterenol induced myocardial lesions. Histochemical and ultrastructural findings.

Eighty Wistar rats were divided into 4 groups. All of them received 10 mg/kg i.p. isoproterenol (ISP). The animals were sacrificed at 5 min. (groups A and B) and 24 hours (groups C and D). Groups A and C served as control of group B and D. Group B also received 9 mg/kg prenylamine (P), 30 min before ISP and group D 9 mg/kg P, 1 hour before and 1 hour after ISP. Transversal slices of each heart underwent the following procedures: hematoxilineosin, Barbeito-Lopez trichromic, "ischemia stain", acid phosphatase stain and standard electron microscopy. Group A and C showed positivity for ischemic techniques; necrotic and ischemic zones represented, in average 25.1 +/- 1.4% of the myocardial volume. Group B and D (ISP + prenylamine) showed no significant lesions. Group D (ISP + prenylamine, sacrificed at 24 hours) presented complete absence of "infarct-like" lesions in 17 out of the 20 studied animals. No evident changes in acid-phosphatase enzymes were detected. Animals treated with ISP alone presented "contraction bands" at electron microscopy as well as myofibrillar fragmentation. Those receiving also P showed only light alterations, in the electron microscopy specimens. A primary action of ISP on the calcium pump might explain the infarct-like lesions found in our study. The inhibition of these above mentioned lesions by prenylamine, a drug which acts by slowing down the ca transport, also supports this interpretation.

Animals↗

PubMed1988

Simultaneous determination of R- and S-prenylamine in plasma and urine by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of R- and S-prenylamine in human plasma and urine is described. It involves a two-step liquid-liquid extraction of prenylamine from biological material and preparation of diastereomeric urea derivatives with R-(-)-naphthylethyl isocyanate, a chiral fluorescence marker. Separation and quantitation of the diastereomeric prenylamine derivatives are carried out by a reversed-phase high-performance liquid chromatographic system with fluorimetric detection. The limit of determination is less than 2 ng of enantiomer per ml of urine and less than 1 ng of enantiomer per ml of plasma. A preliminary kinetic study on one healthy volunteer who had received a single oral dose of racemic prenylamine (100-mg film tablet) showed distinctly higher plasma and urine concentrations of the R-enantiomer.

Administration, Oral↗

PubMed1978

In vitro analysis of Ca-antagonistic effects of prenylamine as mechanisms for its cardiac actions.

Ca-antagonistic properties of prenylamine were studied using isolated guinea-pig and canine cardiac preparations. Prenylamine is a weak Ca-antagonist compared to nifedipine, verapamil and diltiazem. Lower doses of prenylamine slightly increased the tension, but higher doses decreased the tension of both the guinea-pig and canine cardiac preparations. It decreased the tension while maintaining the action potential of the normal guinea-pig atrial preparation and decreased both the tension and Ca-action potential of the depolarized guinea-pig atrial preparation. Similar to antiarrhythmic agents, prenylamine also decreased the max dV/dt of the normal guinea-pig atrial action potential.

Action Potentials↗

PubMed1990

The effect of prenylamine and organic nitrates on the bioenergetics of bovine catecholamine storage vesicles.

We have compared the cardioprotective agents prenylamine and glyceryl trinitrate (GTN) with respect to their effects on the bioenergetics of catecholamine storage vesicles. Chromaffin granule ghosts, which have a well preserved ability to actively transport and store catecholamines, were used as a model for adrenergic synaptic vesicles due to their functional similarity. Prenylamine, which partially and reversibly deplete the endogenous stores of noradrenaline in adrenergic nerves and ganglia, was found to inhibit the generation of the transmembrane proton electrochemical gradient driven by a H(+)-ATPase, mainly by acting as an uncoupler of this ATPase. The inhibition of the energy dependent dopamine uptake (and noradrenaline biosynthesis) by prenylamine could be accounted for by its effect on the bioenergetics of the storage vesicles. The organic nitrates glyceryl trinitrate and isosorbide dinitrate also partly inhibited the catecholamine uptake in parallel with their effects on the proton electrochemical gradient. It is concluded that GTN is a weak catecholamine depletor. Experiments with 3-morpholinosydnonimin-hydrochloride, a source of nitric oxide (NO), opens up the possibility that the mechanism of inhibition of the bioenergetics of chromaffin granule ghosts by GTN is mediated by NO.

Animals↗

PubMed2003

Amphetamine concentrations in human urine following single-dose administration of the calcium antagonist prenylamine-studies using fluorescence polarization immunoassay (FPIA) and GC-MS.

Prenylamine (R,S-N-(3,3-diphenylpropyl-methyl-2-phenethylamine), a World Health Organization class V calcium antagonist, is known to be metabolized to amphetamine. In this study, amphetamine concentrations after a single-dose administration of prenylamine were determined to check if they reached values that could be of analytical and/or pharmacological importance in clinical and forensic toxicology. Enantiomeric composition of amphetamine was also studied. Five volunteers received a single 120-mg oral dose of prenylamine. Urine samples were analyzed using the Abbott TDx immunoassay Amphetamine/Methamphetamine II and using our routine systematic toxicological analysis (STA) gas chromatography-mass spectrometry (GC-MS) procedure. For quantitation purposes, GC-MS was used in the selected-ion monitoring (SIM) mode (ions m/z 118, 122, 240, 244) after solid-phase extraction (Isolute Confirm HCX) and derivatization (heptafluorobutyric anhydride). Amphetamine-d5 was used as internal standard (IS). Chiral separation of the heptafluorobutyrated amphetamine enantiomers was achieved using an Astec Chiraldex G-PN column. The TDx results showed a great variability for the different volunteers. A urine sample of one volunteer showed results as high as 3200 ng/mL, whereas the urine samples of another volunteer never gave results greater than the TDx detection limit (100 ng/mL). Using the STA procedure, the presence of amphetamine could be confirmed in all urine samples with TDx results greater than the cutoff value (300 ng/mL). Using the GC-MS SIM method, amphetamine concentrations up to 1280 ng/mL were determined. Chiral analysis revealed that both enantiomers of amphetamine were present in the samples with a surplus of the S(+)-enantiomer in the early phase of excretion. Forensic implications are discussed.

Amphetamine↗

PubMed1980

Prenylamine-induced ventricular tachycardia and syncope controlled by ventricular pacing.

We describe eight patients treated for angina with prenylamine who developed life-threatening ventricular arrhythmias after QT interval prolongation. When prenylamine administration was stopped QT interval shortened to within normal values, while the ventricular arrhythmias were controlled by a temporary ventricular pacemaker and disappeared after several days. We stress the importance of surveillance of the QT interval and ventricular arrhythmias in patients receiving long-term treatment with prenylamine.

Aged↗

PubMed1980

Prenylamine-induced ventricular arrhythmias and syncopal attacks with Q-T prolongation. Report of a case and comment on therapeutic use of lignocaine.

A 70-year-old man, on prenylamine for exertional angina, complained of syncopal attacks which seemed to be caused by bursts of ventricular tachycardia associated with Q-T prolongation. These symptoms disappeared after treatment with lignocaine, and the Q-T interval gradually returned to normal when prenylamine was stopped. This communication emphasizes the possibility of the occurrence of Q-T prolongation with associated ventricular arrhythmias in patients treated with prenylamine and the usefulness of a cautious trial with lignocaine in ventricular arrhythmias linked to Q-T prolongation.

Aged↗

PubMed1977

[Influence of hexobendine, prenylamine and verapamil on the contractile response of isolated rabbit left atria and aortae to calcium (author's transl)].

In isolated rabbit left atria driven electrically at a frequency of 30/min, the contraction was abolished by increasing external K+ concentrations from 5.4 to 22mM. Addition of isoproterenol (10(-6)M) restored the atrial contraction and the magnitude of contractions increased by raising external concentrations of Ca++ to 4.4 and 6.6. mM. Hexobendine attenuated the magnitude of contractions restored by isoproterenol and excess Ca++ in a dose-dependent manner, as did prenylamine and verapamil. Hexobendine did not significantly influence the membrane depolarization induced by excess K+ and there was no evidence of a beta-adrenergic blocking action. In helical strips of rabbit aortae exposed to Ca++-free media and depolarized by excess K+, the addition of Ca++ caused a marked contraction. Hexobendine, prenylamine and verapamil caused a dose-related attenuation of the Ca++-induced contraction. Relative potencies of the inhibition by hexobendine, prenylamine and verapamil were 1:16.5:100. Inhibitory effects of these drugs were partially antagonized by excess Ca++. Greater attenuation of the contractile response to 25 mM K+ than the response to 2 X 10(-6)M noradrenaline was observed in preparations treated with hexobendine. It may be concluded that interference with the influx of Ca++ across cell membrane in atrial muscles and aortic smooth muscles participates in the inhibition of contractility by hexobendine.

Animals↗

PubMed1963

Prenylamine in angina pectoris.

The therapeutic value of prenylamine in angina pectoris was tested in two ways. Fourteen patients received 270 mg. of prenylamine per day for one month. This was preceded and followed by one month of placebo therapy. Assessment was made, first by twice-monthly treadmill exercise tests, and secondly by daily records of anginal attacks and nitroglycerin usage. The occurrence of pain and electrocardiographic changes during treadmill exercise was apparently uninfluenced by the drug. However, there was a reduced incidence of spontaneous angina and nitroglycerin usage during the month on prenylamine by contrast with either month on placebo (p <0.05).

Angina Pectoris↗

PubMed1983

Negative inotropic effect of verapamil, nifedipine and prenylamine and its reversal by calcium or isoproterenol.

The type of antagonism between verapamil, nifedipine or prenylamine and calcium or isoproterenol on myocardial contractility, was investigated in cat papillary muscles. Dose response curves to calcium or to isoproterenol were performed in the absence and presence of a single dose of either verapamil, nifedipine or prenylamine. Non significantly different maximum values of tension (T) and maximal rate of rise of tension (+dT/dtmax) were obtained at the "plateau" of the dose responses curves to calcium in the absence and presence of the slow channel inhibitors. The (Ca2+)50, i.e. the calcium concentration necessary to obtain 50% of the maximal effect (T or +dT/dtmax), was significantly greater in the presence of the calcium channel blockers (Lineweaver-Burk method). The decrease in time to peak tension (TTP) associated with the negative inotropic effect of calcium channel blockers was also completely off-set by the addition of extra calcium. A Shild plot with a slope close to the unity confirmed simple competitive antagonism between calcium and nifedipine or prenylamine but not between calcium and verapamil. Isoproterenol was unable to completely overcome the negative inotropic effect of verapamil 10(-5) M and nifedipine 5 X 10(-7) M on T and +dT/dtmax. In addition, it enhanced the decrease in TTP produced by these two calcium entry blockers. The results do not support the view of a competitive antagonism between isoproterenol and verapamil or nifedipine on myocardial contractility. They also indicate that in restoring the decrease in myocardial contractility produced by calcium channel blockers, it is not the same to add extra calcium than isoproterenol.

Animals↗

PubMed1977

Metabolism of DL-[14C]prenylamine in man.

Following oral administration of DL-[14C]prenylamine, about 40% of the dose administered was excreted in urine within 10 days. Less than 0.1% of the dose was excreted as unchanged prenylamine. The drug was extensively metabolized to at least 20 to 25 metabolites. The structure of 12 metabolites could be elucidated by means of g.c.m.s. Ring hydroxylation and further methylation of the phenolic metabolites are the main metabolic pathways involved. A substantial part of the drug and/or its metabolites is metabolized via cleavage of the C--N--C bond, giving rise to amphetamine and diphenylpropylamine which are further metabolized by aromatic and sidechain hydroxylation.

Adult↗

PubMed1985

Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase.

The effect of four slow Ca2+ channel blockers (felodipine, nifedipine, prenylamine and bepridil) that possess the ability to bind to calmodulin (CaM) section and to inhibit myosin light chain kinase (MLCK) on CaM-regulated Ca2+ pumping ATPase of cardiac sarcolemma (SL) and brain cyclic AMP phosphodiesterase (PDE) was studied. The ability of these drugs to inhibit Ca2+ pumping ATPase correlated with their inhibitory effect on CaM-activated Ca2+-dependent PDE. Nifedipine was unable to inhibit markedly both enzymes. Prenylamine also was a weak inhibitor, which was unexpected because of its CaM binding potency. Felodipine (10-50 microM) and bepridil (50 microM) markedly reduced activities of SL Ca2+ pumping ATPase and PDE. Striking differences were, however, demonstrated when Ca2+ and CaM concentrations, respectively, were increased. Previously it was reported that inhibition of the SL Ca2+ pumping ATPase by the CaM antagonist calmidazolium could be overcome by increasing Ca2+ concentrations (J. M. J. Lamers and J. T. Stinis, Cell Calcium 4, 281-294, 1983). Felodipine (10-50 microM) in the present study, appeared to be equipotent with calmidazolium in reducing Ca2+ pumping ATPase, but increasing Ca2+ up to 12.2 microM could not counteract this effect. Felodipine (2-10 microM) also inhibited brain PDE noncompetitively with respect to CaM contrary to the competitive effectors calmidazolium and bepridil. On the other hand, bepridil (10-20 microM) decreased or increased Ca2+ pumping ATPase activity depending on the Ca2+ concentration (0.29 and 12.2 microM, respectively) used. These findings suggest at least two types of CaM antagonists, which can be discriminated on basis of their inhibition patterns of PDE and heart SL Ca2+ pumping ATPase.

Animals↗

PubMed1984

Acute coronary artery occlusion-reperfusion arrhythmias in pigs: antiarrhythmic and antifibrillatory evaluation of verapamil, nifedipine, prenylamine and propranolol.

The antiarrhythmic activity of the calcium entry blockers, verapamil, nifedipine and prenylamine, was assessed against arrhythmias occurring during 20 min of acute occlusion, or upon rapid reperfusion of the left anterior descending coronary artery (LAD) in anesthetized pigs. Propranolol, which may indirectly reduce calcium entry by blocking the facilitory action of catecholamines on slow channel conductance, was also evaluated for antiarrhythmic activity in this acute arrhythmia model. Only verapamil (0.2 mg/kg i.v.) reduced both the number of arrhythmias occurring during LAD occlusion and the incidence of ventricular fibrillation (VF) occurring after occlusion and reperfusion. Although both nifedipine (0.04-0.2 mg/kg i.v.) and propranolol (1-2 mg/kg i.v.) produced a slight but significant (P less than 0.05) dose-dependent decrease in the incidence of VF during the occlusion period only, this protection was accompanied by a significant increase in ectopic activity. The increase in ectopic activity produced by propranolol (1.0 mg/kg i.v.) persisted even in combination with verapamil (0.2 mg/kg i.v.) which given alone decreased the ectopic frequency. Prenylamine up to 5 mg/kg was without significant antiarrhythmic or antifibrillatory activity. However, unlike verapamil and nifedipine, this drug produced only slight changes in heart rate or blood pressure which suggested the presence of only minimal calcium entry blocking action on myocardial and vascular tissue at the doses we employed. Because the relative antifibrillatory efficacies of verapamil and nifedipine paralleled the relative efficacies reported for depression of atrioventricular conduction, this may implicate the slow inward current channel in the etiology of VF occurring during acute myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Prenylamine and the myocardial response to ischaemia and reperfusion: effects of acute and chronic treatment.

The ability of prenylamine gluconate (Segontin) to influence the extent of myocardial ischaemic injury was investigated in the isolated 'working' rat heart preparation. The drug was administered either acutely alone (4 microM litre-1 in the perfusion medium) or chronically plus acutely in which case animals were pre-treated (10 mg kg-1 day-1 orally) for 10 days and the drug was then also added (4 microM litre-1) to the perfusate. Acute administration alone resulted in a small reduction in spontaneous functional performance in the aerobic isolated heart in comparison with gluconate treated controls. It also increased the percentage of hearts able to recover functional activity after a period of severe ischaemia and decreased ischaemia induced injury as assessed by enzyme leakage. In contrast to the acute results the combination of chronic and acute administration of prenylamine did not significantly alter spontaneous cardiac function. Although a small increase in the number of hearts that recovered function was apparent, there was a concomitant decrease in post-ischaemic functional performance with no reduction of ischaemia induced enzyme leakage.

Animals↗

PubMed1989

Enantioselective disposition of R-(-)- and S-(+)-prenylamine in the rat.

The disposition of R- and S-prenylamine was investigated in male Wistar rats after i.v. and p.o. dosage of 2 mg/kg racemic prenylamine. Concentrations of the enantiomers were determined in plasma, lung, heart, spleen, liver kidney and muscle tissue within a period of 5 h after dosage. In addition, plasma protein binding was assayed in vitro with racemic drug and found to be similar for the two enantiomers. Except for plasma samples after i.v. administration the concentrations of the S-enantiomer exceeded those of the R-enantiomer.

Administration, Oral↗