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PubMed1980

[Comparative study of the therapeutic effect of antiangina agents].

The therapeutic effect of obsidan (25 to 250 mg/24 h), cordanum (75 to 300 mg/24 h), nitropenton (30 mg/24 h), combination of obsidan with nitropenton, prenylamin (180 mg/24 h), stenopril (180 mg/24 h), cordaron (600 mg/24h) and corvaton (4 mg/24 h) was studied according to clinical asessment in 127 patients with stenocardia and in 44 of them by loading tests (veloergometry or treadmill). According to the clinical assessment -- very good (abating of stenocardia paroxysms) and good effect (less frequent paroxysms nitroglycerin necessary every one-two days) was established in 82 per cent of those treated with obsidan, in 78 per cent of the treated with cordanum, in 86 per cent of those treated with the combination obsidan with nitropenton, in 44 per cent of the treated with nitropenton, in 42 per cent of the treated with prenylamin, in 46 per cent pf the treated with stenopril, in 7 out of 9 patients treated with cordaron as well as in 7 out of 9 patients treated with corvaton. According to the data from the loading tests--very good (increase of capacity, not limited by pain and ST depression) and good effect (considerable increase of capacity but limited by pain and ST depression) was found in 77 per cent of the patients administered obsidan, in 67 per cent of those administered cardanum and in 33 per cent of the patients administered tenopril and prenylamin. Beta--blockers significantly excel the therapeutic effect of stenopril, prenylanin and nitropenton, both according to clinical assessment (P < 0,02 to p < 0,001) and to the data from the loading tests (P < 0,02). Beta-blockers dosage was individually determined but 80 per cent of the patients with a favourable effect by obsidan or cordanum had received 60-120 mg/24 h and 150 mg/24 h respectively. The individual effect of the patients is presented so that even the small number of cases observed with cordaron and corvaton treatment shows it reasonable to include new preparations in antianginose treatment.

Aged↗

PubMed1993

Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs.

OBJECTIVE: To test the hypothesis that female prevalence is greater than expected among reported cases of torsades de pointes associated with cardiovascular drugs that prolong cardiac repolarization. DATA SOURCES: A MEDLINE search of the English-language literature for the period of 1980 through 1992, using the terms torsade de pointes, polymorphic ventricular tachycardia, atypical ventricular tachycardia, proarrhythmia, and drug-induced ventricular tachycardia, supplemented by pertinent references (dating back to 1964) from the reviewed articles and by personal communications with researchers involved in this field. STUDY SELECTION: Ninety-three articles were identified describing at least one case of polymorphic ventricular tachycardia (with gender specified) associated with quinidine, procainamide hydrochloride, disopyramide, amiodarone, sotalol hydrochloride, bepridil hydrochloride, or prenylamine. A total of 332 patients were included in the analysis following application of prospectively defined criteria (eg, corrected QT [QTc] interval of 0.45 second or greater while receiving drug). DATA EXTRACTION: Clinical and electrocardiographic descriptors were extracted for analysis. Expected female prevalence for torsades de pointes associated with quinidine, procainamide, disopyramide, and aminodarone was conservatively estimated from gender-specific data reported for antiarrhythmic drug prescriptions in 1986, as derived from the National Disease and Therapeutic Index, a large pharmaceutical database; expected female prevalence for torsades de pointes associated with sotalol, bepridil, and prenylamine was assumed to be 50% or less since these agents are prescribed for male-predominant cardiovascular conditions. RESULTS: Women made up 70% (95% confidence interval, 64% to 75%) of the 332 reported cases of cardiovascular-drug-related torsades de pointes, and a female prevalence exceeding 50% was observed in 20 (83%) of 24 studies having at least four included cases. When analyzed according to various descriptors, women still constituted the majority (range, 51% to 94% of torsades de pointes cases), irrespective of the presence or absence of underlying coronary artery or rheumatic heart disease, left ventricular dysfunction, type of underlying arrhythmia, hypokalemia, hypomagnesemia, bradycardia, concomitant digoxin treatment, or level of QTc at baseline or while receiving drug. When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide. CONCLUSIONS: These findings strongly suggest that women are more prone than men to develop torsades de pointes during administration of cardiovascular drugs that prolong cardiac repolarization. The pathophysiological basis for, and therapeutic implications of, this gender disparity should be further investigated.

Adolescent↗

PubMed1995

The importance of calcium-related effects on energetics at hypothermia: effects of membrane-channel antagonists on energy metabolism of rat liver.

During normothermic metabolism, the active pumping of Ca2+ across the cell membrane, mitochondria, and specialized sequestration organelles accounts for a large proportion of total energy expenditure in the cell. This study was designed to determine the effects of Ca2+ channel antagonists (chlorpromazine, verapamil, nifedipine, prenylamine, and nisoldipine) on energy metabolism and levels of glycolytic substrate (glucose) and anaerobic endproduct (lactate) during cold ischemia in rat livers. We hypothesized that if the passive channels were blocked during cold ischemia, then the ATP requirement of active ion pumping would be reduced and ATP levels and energy charge ratios would remain higher throughout the ischemic period; thus, viability of the liver would also be increased after prolonged ischemia. The most positive effect on energy metabolism was observed in the chlorpromazine-treated livers, followed by verapamil treatment. In the chlorpromazine treatment, total adenylate (TA) contents were 0.5-1.0 mumol/g (P < 0.05) higher than the sham group for most of the 24-h time course. Energy charge (EC) ratios were 0.05-0.07 higher than the sham values up to 4-10 h ischemia. Verapamil treatment was less effective, but still exhibited positive effects on TA levels at several time points (20 min, 10 h, and 24 h) throughout the entire 24-h period. In both of these groups, TA values by 24 h ischemia were similar to levels at 10 h in the sham group (3.1 mumol/g), thus showing a considerable effect in maintaining adenylate levels. Despite similar pharmacological antagonist activities, ATP levels in the nifedipine, prenylamine, and nisoldipine treatment groups were 1.0-1.5 mumol/g (P < 0.05) less than the corresponding sham group (without Ca2+ antagonists) over the first 1 h ischemia. The decreases in high energy adenylate levels were reflected in lower EC ratios in these three groups; values were 0.06-0.17 (P < 0.05) lower than corresponding sham values. Finally, it was an unexpected finding that the sham injection (0.5 mg/kg ethanol+PEG400) resulted in the sustained elevation of ATP, total adenylates, and EC values over the first h; EC ratios remained at initial (t = 0) values (EC = 0.71 +/- 0.01) up to 1 h.

Adenosine Monophosphate↗

PubMed1983

Interaction between calcium and slow channel blocking drugs on atrial rate.

The relationship between extracellular calcium concentration and the chronotropic effect of prenylamine, verapamil and nifedipine was studied in isolated spontaneously beating rat atria. The three slow channel blocking drugs produced a concentration-dependent decrease in atrial rate, though with different relative potencies. The order of potency for decreasing atrial rate, independently of the calcium level (1.0, 3.0, 6.0 or 9.0 mmol/l) was: verapamil greater than nifedipine greater than prenylamine. Increasing calcium from 1.0 to 6.0 and 9.0 mmol/l increased atrial rate from 251 +/- beats . min-1 to 265 +/- 6 beats . min-1 and 285 +/- 9 beats . min-1 (mean +/- 1 standard error) respectively (P less than 0.05). Despite their positive chronotropic effect high calcium levels failed to reverse the negative chronotropic effect of the slow channel blockers. Furthermore, the negative chronotropic effect of both verapamil and nifedipine was enhanced at high calcium levels. Raising calcium from 1.0 to 6.0 mmol/l in the presence of verapamil (1 X 10(-7) mol/l) or nifedipine (3 X 10(-7) mol/l) increased 2-fold the negative chronotropic effect of the calcium channel blockers. In addition, the concentration-effect curves for verapamil and nifedipine shifted to the left by 0.50 +/- 0.14 and 0.50 +/- 0.16 log units, respectively, when calcium increased from 1.0 to 6.0 mmol/l. The data show that increasing calcium may produce positive or negative chronotropic effects depending on whether or not the calcium channels are blocked. This paradoxical effect of calcium ions can be produced either by opposite chronotropic effects on automatic cells or by shifting the pacemaker activity to a group of cells which respond in a different way to an increment of calcium.

Animals↗

PubMed1983

Slow calcium channel blockers and the calcium paradox: comparative studies in the rat with seven drugs.

In studies of the calcium paradox, the isolated perfused rat heart was used to characterize the relationship between myocardial protein leakage and the concentration of calcium antagonist (verapamil and D600) or calcium in the perfusion fluid during a cycle of calcium depletion and repletion. The results indicated a dose-dependency such that protein leakage could be progressively reduced by decreasing the concentration of calcium during calcium repletion and/or by increasing the concentrations of drug. Detailed dose-response studies with seven calcium antagonists (verapamil, D600, nifedipine, terodiline, diltiazem, fendiline and prenylamine) and a calcium concentration of 1.0 mmol/l during a 20 min period of calcium repletion following a 10 min period of calcium depletion revealed complex dose-response characteristics for each drug. In the dose range studied (0 to 40 mumol/l) all drugs with the exception of prenylamine were able to reduce protein leakage by up to 25 to 30% Optimal concentrations for verapamil, nifedipine, D600, diltiazem and terodiline were all between 2.0 and 4.0 mumol/l. With the exception of D600, which provided a constant reduction of protein leakage at all concentrations above this optimum, all drugs exhibited bell-shaped dose-response curves with a loss of efficacy at higher concentrations. Fendiline also had a bell-shaped dose-response curve with 23% as a maximal reduction of leakage; however, the optimal concentration for this drug was 21.0 mumol/l. Additional studies with verapamil revealed that the drug acted during the calcium repletion phase and did not influence events during calcium depletion. Simultaneous use of two drugs, verapamil and nifedipine, at their optimal concentrations failed to improve the reduction in protein leakage over and above that observed with one drug alone.

Animals↗

PubMed1987

Exogenous ATP-stimulated calcium uptake in isolated rat intestinal epithelial cells.

ATP in the extracellular medium is known to stimulate Ca uptake into avian intestinal epithelial cells. We have now demonstrated a similar effect of ATP in mammalian intestinal epithelial cells and have further characterized this effect. Exogenous ATP increased 45Ca uptake 2-6 fold in isolated rat small intestinal epithelial cells, with a maximal effect at 1 mM and an ED50 of 290 microM. A strict structural requirement for nucleotide-stimulated 45Ca uptake was observed. ADP was much less effective than ATP and gamma-thio-ATP, and 5'-AMP, cyclic AMP, adenosine, non-adenine nucleotides, non-hydrolyzable ATP analogs and ATP analogs with ring substitutions at the 8 position were inactive. Prenylamine (100 microM) completely inhibited ATP-stimulated 45Ca uptake, while verapamil (100 microM) had only a small effect. In the intact intestine, ATP increased short-circuit current (Isc) when added to the mucosal side of the tissue. This effect was reduced by 10 microM and abolished by 100 microM prenylamine. The effect of ATP on Isc was markedly reduced in Cl-free solutions and in reduced-Ca solutions. Serosal and mucosal addition of the nonhydrolyzable ATP analog, beta, gamma-methylene-ATP, and serosal addition of ATP had little or no effect on Isc. The similarities between the effects of ATP in isolated cells and in the intact intestine suggest that the effect of ATP on Isc may be at least partially mediated through stimulation of Ca uptake into the epithelial cells.

Adenosine Triphosphate↗

PubMed1986

Antithrombotics in view of thrombosis models.

Two highly sensitive models of arterial and venous thrombosis forming with the test of endothelial stability a complementary system with a maximum stress on the role of vascular lesion were used to test a series of four antithrombotic drugs (heparin, acetylsalicylic acid, dipyridamole, sulfinpyrazone) and four drugs with other indications but with an antithrombotic activity in experiment (prenylamine, troxerutin, ketanserin and pizotifen). All drugs, except heparin, were given orally. Whereas heparin, aspirin and prenylamine had mixed effects on both arterial thrombosis (i.e. mostly on platelet functions) as well as on endothelial stability, ketanserin and pizotifen had a predominant effect on the former while dipyridamole, troxerutin and sulfinpyrazone influenced mostly the latter function.

Animals↗

PubMed1977

The haemodynamic and metabolic effects of MG 8926, a prospective antidysrhythmic and antianginal agent.

1 The antidysrhythmic, haemodynamic and metabolic effects of a new prospective antianginal and antidysrhythmic agent, N-(3-3-dipenylpropyl)-alpha-methyl-beta-cyclohexylethylamine hydrochloride (MG 8926), have been compared with the chemically related substance, prenylamine, in anaesthetized greyhounds and guinea-pigs. 2 When given intravenously 20 min beforehand, both MG 8926 and prenylamine (5 mg/kg) significantly suppressed the early dysrhythmias induced by coronary artery ligation in anaesthetized greyhounds. At a dose of 1 mg/kg, MG 8926 also protected anaesthetized guinea-pigs from dysrhythmias induced by ouabain infusions. 3 In dogs pretreated with MG 8926, metabolic changes indicative of myocardial ischaemia (increased PCO2 and potassium efflux, decreased oxygen content and pH) were less marked than those occurring in control animals. 4 Evidence was obtained that MG 8926, when given either before or after coronary occlusion, was capable of decreasing the severity of myocardial ischaemia as assessed by ST-segment changes in epicardial electrocardiograms.

Animals↗

PubMed1984

Two types of calmodulin antagonists: a structurally related interaction.

The ability of several calmodulin (CaM) antagonists, such as N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) and trifluoperazine, to displace [3H]-W-7 from CaM correlated with the inhibition of Ca2+-CaM-dependent phosphodiesterase (PDE) by these agents. These antagonists also suppressed the increase in fluorescence of n-phenyl-1-naphthylamine (NPN) by complex formation with CaM in the presence of Ca2+. However, the ability of some CaM antagonists, such as prenylamine and butaclamol, to displace [3H]-W-7 from CaM did not correlate with the inhibition of Ca2+-PDE. These antagonists enhanced the increase in fluorescence of NPN by complex formation with CaM in the presence of Ca2+. In a study employing 1H-nuclear magnetic resonance, the spectrum changes of the aromatic region of CaM induced by prenylamine were significantly more marked than the changes induced by W-7. These findings suggest two types of CaM antagonists. The compounds in each of the groups appear to have common molecular structures.

Animals↗

PubMed1984

Hoe 263, a new substance with calcium channel antagonistic activity.

Hoe 263 inhibited the contraction of the potassium-depolarized pulmonary artery of the guinea pig. In this experiment it was slightly more active than verapamil. The calcium uptake of the potassium-depolarized pulmonary artery was inhibited by Hoe 263 more effectively than by prenylamine. The upstroke velocity of the potassium-depolarized papillary muscle of the guinea pig was depressed with similar concentrations of Hoe 263 and verapamil. In the (3H)-nitrendipine binding test, Hoe 263 was effective at similar concentrations as prenylamine and verapamil. The positive inotropic effect of K-strophanthin was depressed by Hoe 263 at concentrations which were comparable with those necessary for verapamil.

Animals↗

PubMed1975

Restriction of isoproterenol-induced myocardial Ca uptake and necrotization in rats by a new Ca-antagonistic compound (ethyl-4-(3,4,5-trimethoxycinnamoyl) piperazinyl acetate (Vascordil)).

As shown in previous investigations overdoses of isoproterenol produce an abundant myocardial Ca uptake, followed by high energy phosphate breakdown, mitochondrial damage and, eventually, cardiac fibre necrotization. Conversely Ca antagonistic compounds such as verapamil, D 600 or prenylamine which reduce the transmembrane Ca influx into the heart muscle cells, can prevent high energy phosphate deficiency and cardiac lesions. Ethyl-4-(3,4,5-trimethoxycinnamoyl) poperazinyl acetate (Vascoril) is another compound which, according to our tracer studies, interferes with transmembrane Ca uptake into the myocardium. As expected the rat hearts were also protected by Vascoril against isoproterenol-induced metabolic disorders and structural alterations. Equiprotective subcutaneous doses, as studied on the right ventricular myocardium of rats, were 600 mg/kg Vascoril, 250 mg/kg prenylamine, 17 mg/kg verapamil or 10 mg/kg D 600.

Animals↗

PubMed1991

Effect of Ca2+ antagonists on isolated rabbit detrusor muscle.

Ca(2+)-antagonists change the contractility of isolated detrusor smooth muscle of rabbit influencing the translocation of intra- and extra-cellular Ca2+. This observation might be of clinical importance in the treatment of disorders of urinary bladder function. During field stimulation of different segments of isolated rabbit bladder it was found that the specific Ca(2+)-antagonist nifedipine and verapamil and the non-selective Ca(2+)-antagonist fendiline, prenylamine and cinnarizine blocked the contractions induced by field stimulus to different extent, which decreased from the bladder towards the bladder base (fundus). The highest rate of blocking effect was produced by nifedipine followed by verapamil, prenylamine and fendiline, respectively. Cinnarizine exerted the lowest effect. The change in amplitude and frequency of spontaneous peristalsis was similar in its tendency to the blockade of the field stimulus induced contraction.

Animals↗

PubMed1987

Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-alpha-benzoate and 3H-tetracaine.

The effects of antianginal drugs, especially arylalkylamines and structurally related derivatives, on 3H-batrachotoxinin-A 20-alpha-benzoate (3H-BTX-B) binding and on 3H-tetracaine binding were studied on rat synaptosomal and heart membrane preparations. The effect of the same drugs on the Na+ influx induced by protoveratrine B was studied on the rat synaptosomal preparation. Antianginal drugs tested inhibited 3H-BTX-B binding in rat synaptosomes, arylalkylamine derivatives being the most potent: IC50 values were 27 nM for flunarizine, 32 nM for prenylamine, 79 nM for cinnarizine. Similarly, these drugs were the most potent when tested in cardiac membrane preparations. All the drugs tested were very weak inhibitors of 3H-tetracaine binding (IC50 ranging from 0.01 mM to more than 1 mM) except for guanabenz, which was more potent (IC50:0.3 microM on the synaptosomal preparation). The various drugs tested inhibited the 22Na+ influx induced by protoveratrine B, with IC50 values ranging from 15 microM (prenylamine) to 110 microM (verapamil), with the exception of nifedipine which had an IC50 of more than 0.1 mM. The inhibition of 22Na+ influx correlated well with the inhibition of 3H-BTX-B binding. These findings suggest that some antianginal drugs, especially the arylalkylamines may have, in addition to their calcium antagonist activity, direct effects on sodium channels.

Angina Pectoris↗

PubMed1994

Kainic acid and 4-aminopyridine seizure models in mice: evaluation of efficacy of anti-epileptic agents and calcium antagonists.

Seizures may be induced in mice in response to stimulation of subtypes of glutamate receptors by kainic acid or inhibition of certain voltage-dependent potassium channels by 4-aminopyridine (4-AP). The anti-seizure efficacy of intraperitoneally administered anticonvulsants and Ca++ antagonists to CF-1 mice was tested using these models. The order of potency for prevention of kainate convulsions and the subsequent lethality was: dihydropyridine Ca++ antagonists (nicardipine, nisoldipine > nitrendipine > nifedipine > nimodipine) followed by verapamil > prenylamine > diltiazem > flunarizine > remacemide HCl > ethosuximide > valproate. In the 4-AP model the order of potency to prevent hind limb tonic extension was: MK801(+/-) > lamotrigine > phenytoin, phenobarbital > carbamazepine > FPL 12495AA (the desglycine metabolite of remacemide HCl), remacemide HCl > flunarizine > prenylamine >>> valproate. Therefore, compounds that limit activation of kainate receptors and voltage-operated linked calcium channels are active in the kainate model. Agents effective against maximal electroshock appear to be effective in the 4-AP model.

4-Aminopyridine↗

PubMed1987

Effects of Ca2+-channel antagonists on nucleoside and nucleobase transport in human erythrocytes and cultured mammalian cells.

Lidoflazine strongly inhibited the equilibrium exchange of uridine in human erythrocytes (Ki approximately 16 nM). Uridine zero-trans influx was similarly inhibited by lidoflazine in cultured HeLa cells (IC50 approximately to 80 nM), whereas P388 mouse leukemia and Novikoff rat hepatoma cells were three orders of magnitude more resistant (IC50 greater than 50 microM). Uridine transport was also inhibited by nifedipine, verapamil, diltiazem, prenylamine and trifluoperazine, but only at similarly high concentrations in both human erythrocytes and the cell lines. IC50 values ranged from about 10 microM for nifedipine and about 20 microM for verapamil to more than 100 microM for diltiazem, prenylamine and trifluoperazine. The concentrations required for inhibition of nucleoside transport are several orders higher than those blocking Ca2+ channels. Lidoflazine competitively inhibited the binding of nitrobenzylthioinosine to high-affinity sites in human erythrocytes, but did not inhibit the dissociation of nitrobenzylthioinosine from these sites on the transporter as is observed with dipyridamole and dilazep.

Animals↗

PubMed1986

Localization of a felodipine (dihydropyridine) binding site on calmodulin.

The fluorescent dihydropyridine calcium antagonist drug felodipine binds to calmodulin (CaM) in a Ca2+-dependent manner. Its binding can be regulated by the interaction of CaM antagonist drugs through allosteric mechanisms [Mills, J.S., & Johnson, J.D. (1985) Biochemistry 24, 4897]. Here, we have examined the binding of a nonspecific hydrophobic fluorescent probe molecule TNS (toluidinylnaphthalenesulfonate) and of felodipine to CAM and several of its proteolytic fragments. While TNS interacts with sites on both the amino-terminal half of the protein [proteolytic fragment TR1C (1-77)] and carboxy-terminal half [proteolytic fragment TR2C (78-148)], felodipine binding shows more selectivity. It binds in a Ca2+-dependent manner to the proteolytic fragments TM1 (1-106) and TR2E (1-90) but exhibits only weak affinity for TR1C (1-77) and TR2C (78-148). Furthermore, felodipine exhibits selectivity over TNS and trifluoperazine (TFP) in blocking the tryptic cleavage between residues 77 and 78. These studies indicate a selective binding of felodipine to a hydrophobic site existing in residues 1-90 and suggest that productive binding requires amino acids in the region 78-90. Although the felodipine binding site is preserved in fragment 1-106, the allosteric interactions between the prenylamine and the felodipine binding sites that are observed with intact CaM are not observed in this fragment. Rather, prenylamine simply displaces felodipine from its binding site on this fragment. Our results are consistent with calmodulin containing not less than two allosterically related hydrophobic drug binding sites. One of these sites (felodipine) appears to be localized in region 1-90 and the other one in region 78-148.

Animals↗

PubMed1996

Effects of calcium channel blockers on steroidogenesis stimulated by ACTH and cAMP in isolated rat adrenal cells.

The effects of the calcium channel blockers verapamil, diltiazem, prenylamine and nifedipine on the ACTH- and cAMP-mediated pathway for steroidogenesis in a suspension solution of isolated rat adrenal cells were studied. Steroidogenesis stimulated by ACTH (10(-10) M) or cAMP (10(-3) M) was not inhibited by nifedipine (10(-4) M), but was strongly inhibited in a concentration-dependent manner by verapamil, diltiazem and prenylamine (10(-5) to 10(-4) M).

Adrenal Glands↗

PubMed1983

A unitary mechanism of calcium antagonist drug action.

[3H]Nitrendipine binding to drug receptor sites associated with calcium channels is allosterically regulated by a diverse group of calcium channel antagonists. Verapamil, D-600 (methoxyverapamil), tiapamil, lidoflazine, flunarizine, cinnarizine, and prenylamine all reduce [3H]nitrendipine binding affinity. By contrast, diltiazem, a benzothiazepine calcium channel antagonist, enhances [3H]nitrendipine binding. All these drug effects involve a single site allosterically linked to the [3H]nitrendipine binding site. Inhibition of [3H]nitrendipine binding by prenylamine, lidoflazine, or tiapamil is reversed by D-600 and diltiazem, which alone respectively slightly reduce or enhance [3H]nitrendipine binding. Diltiazem reverses the inhibition of [3H]nitrendipine binding by D-600. Our prediction that drugs allosterically regulating [3H]nitrendipine binding should be calcium antagonists is confirmed by calcium antagonism in guinea pig ileum observed with the antihistamine dimethindene, the neuroleptics thioridazine and mesoridazine, and the anticholinergic biperiden.

Binding, Competitive↗