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Biomedical subjects

C Funck-Brentano

Publications and source records attributed to C Funck-Brentano.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization.

OBJECTIVES: To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and QTc prolongation on the surface electrocardiogram after oral and intravenous administration. METHODS: Ten healthy volunteers received a single dose of 0.5 mg dofetilide orally and intravenously (over 30 minutes) in a randomized crossover study. The QTc interval versus dofetilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques. RESULTS: Dofetilide absolute bioavailability and systemic clearance were 92% +/- 9% and 0.35 +/- 0.05 L/hr/kg, respectively. Mean maximum increase in QTc interval duration was 99 msec (27%) and 61 msec (16%) after intravenous and oral administration, respectively. A counterclockwise hysteresis loop between dofetilide plasma concentrations and QTc interval duration was observed after intravenous infusions in all subjects, whereas direct linear relationships were observed after oral administrations in eight of 10 subjects. Pharmacokinetic-pharmacodynamic modeling showed the consistency of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (Emax) model and data obtained after intravenous infusion, mean maximum QTc prolongation (Emax) was 121 +/- 57 msec and mean dofetilide plasma concentration associated with half the maximum effect (EC50) was 2.2 +/- 0.6 ng/ml. Pharmacokinetic-pharmacodynamic modeling was useful in detecting the maximum effect and in describing the plasma concentration versus effect relationship during intravenous infusion of dofetilide but was otherwise not superior to analyses performed with postdistribution data. CONCLUSION: We conclude that dofetilide prolongs QTc interval duration in a concentration-dependent manner in normal volunteers during sinus rhythm and that pharmacokinetic-pharmacodynamic modeling is useful for examination of maximum QTc prolongation induced by dofetilide.

Administration, Oral↗
PubMed1995

Comparison of chloroguanide and mephenytoin for the in vivo assessment of genetically determined CYP2C19 activity in humans.

OBJECTIVES: The main objective of this study was to examine the relations between chloroguanide (proguanil) and mephenytoin metabolic ratios to determine whether or not chloroguanide could replace mephenytoin as a probe for the indirect in vivo measurement of CYP2C19 activity. An additional objective was to examine the interactions between chloroguanide, omeprazole, and mephenytoin, which are three substrates of CYP2C19. METHODS: Twenty healthy volunteers received 200 mg chloroguanide orally on three separate occasions in an open, randomized-sequence crossover design: once alone, once 2 hours before the oral administration of 100 mg mephenytoin, and once after oral administration for 7 days of 40 mg/day omeprazole. During one additional period, 100 mg mephenytoin was administered orally. The chloroguanide to cycloguanil ratio was determined in plasma 4 hours after drug administration; it was determined in urine collected over 4, 8, and 24 hours. The mephenytoin hydroxylation index was also measured in urine. RESULTS: All subjects were extensive metabolizers of chloroguanide and mephenytoin. We found no correlation between the mephenytoin hydroxylation index and the chloroguanide to cycloguanil ratio in any of the urine samples collected or in plasma. In the presence of chloroguanide, mephenytoin hydroxylation index increased from a baseline value of 1.2 +/- 0.2 to 1.7 +/- 1.0 (p < 0.05). In the presence of omeprazole, the chloroguanide to cycloguanil metabolic ratio in 24-hour urine increased from 2.2 +/- 1.0 to 5.6 +/- 3.2 (p < 0.001). CONCLUSION: Chloroguanide inhibits the CYP2C19-dependent 4'-hydroxylation of mephenytoin. The bioactivation of chloroguanide to cycloguanil is inhibited by the CYP2C19 substrate omeprazole. However, the chloroguanide to cycloguanil metabolic ratio does not reflect the same array of S-mephenytoin hydroxylase activities found in extensive metabolizers as that show by the mephenytoin hydroxylation index.

Adult↗
PubMed1994

Comparison of tolerance to intravenous nitroglycerin during nicorandil and intermittent nitroglycerin patch in healthy volunteers.

BACKGROUND: Nitrate tolerance is associated with a loss in the hemodynamic response to nitrate during repeated administration. Nicorandil is a new potassium channel agonist with additional nitrate properties. The aim of this study was to determine whether 7-day nicorandil (10 mg orally twice a day) administration attenuates the response to single-dose intravenous nitroglycerin (0.45 mg over 1 minute) in comparison with 7-day intermittent nitroglycerin patch administration (10 mg for 16 of 24 hours). METHODS: This was an open, randomized crossover study performed in 12 healthy volunteers. Blood pressure, heart rate, and their oscillations were measured with use of a noninvasive device. Low-frequency oscillations (66 to 129 mHz) of blood pressure reflect sympathetic activity. Reflex sympathetic activation was measured as after versus before intravenous nitroglycerin difference in low frequency oscillations of blood pressure and heart rate on day 0 and day 7 of each treatment period. Measurements after single-dose intravenous nitroglycerin included the maximum decrease in systolic blood pressure and maximum increase in heart rate and sympathetic activation. Tolerance in each group was assessed as the difference in each parameter between day 7 and day 0. RESULTS: Attenuation of the intravenous nitroglycerin-induced decrease in systolic blood pressure (day 7 - day 0) was - 10 +/- 10 mm Hg during use of the nitroglycerin patch and -2 +/- 11 mm Hg during nicorandil (p = 0.03). Similarly, the change in low frequency oscillations of systolic blood pressure was -79 +/- 144 mm Hg-Hz-1/2 during nitroglycerin administration and 60 +/- 139 mm Hg-Hz-1/2 during nicorandil administration (p = 0.04). CONCLUSION: These results indicate that 7-day administration of nicorandil does not attenuate single-dose intravenous nitroglycerin-induced hemodynamic changes or sympathetic activation. In healthy volunteers and at this dosage (10 mg twice a day), cross tolerance between nicorandil and nitroglycerin does not occur.

Administration, Cutaneous↗
PubMed1994

Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone.

We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady-state disposition kinetics and the electrocardiographic effects of flecainide at two doses and during combination with amiodarone. Seven extensive and five poor metabolizers of dextromethorphan were studied during a three-period crossover study. All subjects received 50 mg flecainide every 12 hours, alone or together with 200 mg amiodarone every 12 hours, and 100 mg flecainide every 12 hours for 5 days. Mean steady-state plasma concentration of flecainide and QRS change from predrug value did not differ significantly among extensive and poor metabolizer subjects during each study period. Except for a shortened elimination half-life and nonlinear kinetics in extensive metabolizer subjects, phenotype had no significant influence on flecainide pharmacokinetics. Combination with amiodarone resulted in an increase in mean flecainide plasma concentration and effect in subjects with both phenotypes. Our findings indicate that CYP2D6 phenotype predicts flecainide nonlinear kinetics and flecainide half-life but has no influence on electrocardiographic effects during repeated administration of flecainide or on the extent of the amiodarone-flecainide interaction.

Administration, Oral↗
PubMed1994

Relationships between acute and chronic beta-blocking effects of bisoprolol in healthy volunteers: a practical approach to predict intensity of beta-blockade.

Bisoprolol is a selective beta 1-adrenoceptor antagonist devoid of partial agonist activity that can be used for treatment of chronic and acute myocardial ischemia. In this condition, it is important to demonstrate that a stable beta-blocking effect at steady state can be predicted by a mathematical model determined by plasma concentration-effect relationship after an acute intravenous (i.v.) dose. This relation was studied in 10 healthy volunteers in a double-blind, randomized, cross-over, placebo-controlled study after a 5-min i.v. infusion of bisoprolol (5 mg) or placebo. Standardized exercise tests were recorded at different times for 48 h after infusion with simultaneous bisoprolol assay (high-performance liquid chromatography, HPLC) in plasma. After a 1-week interval, subjects received oral bisoprolol (10 mg once daily) for 5 days and exercise tests were repeated on day 5 before and 2, 3, and 4 h after dosing, with bisoprolol plasma level determined simultaneously. In the acute period, bisoprolol significantly decreased exercise heart rate (HR: peak effect -20.5 +/- 4%) as compared with placebo. There was a direct relationship (no hysteresis) between beta-blockade and plasma concentrations with a sigmoid (7 subjects) or a linear (3 subjects) best-fit model. After repeated bisoprolol administration, steady-state plasma levels were achieved and 88% of the observed decreases in exercise HR were within the 95% confidence interval (CI) for individual prediction. These data suggest that bisoprolol-induced beta-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.

Adult↗
PubMed1994

Clinical evaluation of pain during subcutaneous injections of low molecular weight heparins in healthy volunteers.

In order to compare the intensity and the duration of the pain following the subcutaneous injection of low molecular weight heparins, 0.4 ml nadroparin, 0.4 ml enoxaparin and 0.4 ml placebo (NaCl 0.9%) were administered at 1 week intervals to 12 healthy volunteers in a randomised, double-blind, three-period study. Pain was assessed by visual analogue and verbal category scales. Based on visual analogue scale scores, nadroparin resulted in significantly less pain than enoxaprin at 1 and 5 min after injection (6.2 +/- 2.6 mm vs 21.9 +/- 5.9 mm; P < 0.05 and 3.5 + 1.5 mm vs 14.3 +/- 4 mm; P < 0.05, respectively, mean +/- s.e. mean). Similar results were obtained using verbal category scale. Confidence interval testing for difference between groups showed that nadroparin injection resulted in less pain than enoxaparin at 1 min (-15.8: -31.2 to -0.4 mm).

Adult↗
PubMed1994

Reproducibility of non-invasive measurement and of short-term variability of blood pressure and heart rate in healthy volunteers.

1. Spectral analyses of blood pressure and heart rate oscillations are increasingly used to assess the influences of diseases and drugs on the autonomic nervous system. Such influences can only be interpreted in view of the spontaneous variability of these oscillations. We therefore studied the reproducibility of power spectral analyses of blood pressure and heart rate fluctuations measured by a non-invasive finger plethysmographic method in 24 healthy volunteers. 2. Intra-observer reproducibility was assessed from measurements obtained on 3 consecutive days and 1 month later in each subject. Inter-observer reproducibility was assessed by comparing measurements made by two observers on one occasion. 3. There was no significant difference in standard haemodynamic and spectral analysis parameters (low frequency: 60-130 mHz and high frequency: respiration rate +/- 30 mHz) measured on 3 consecutive days and 1 month later in each subject. The standard deviation of differences between systolic blood pressure or heart rate oscillations on different occasions was in the 150-200 and 50-100 mm Hg Hz-1/2 or beats min-1 Hz-1/2 range for low frequency and high frequency oscillations respectively. Similar results were found when inter-observer reproducibility was considered. 4. From these results, we derived a sample-size table giving the number of subjects to be included in studies of cross-over or parallel design in order to detect a non-random difference in spectral analysis parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Rapid development of nitrate tolerance in healthy volunteers: assessment using spectral analysis of short-term blood pressure and heart rate variability.

Nitrate tolerance is characterized by a loss of nitroglycerin (NTG) vasodilating and hypotensive effects during continuous administration, but is difficult to detect clinically. We hypothesized that the decrease in arterial blood pressure (BP) and the reflex sympathetic activation and tachycardia due to baroreflex deactivation associated with rapid intravenous (i.v.) infusion of NTG would be decreased during continuous NTG patch therapy as a result of tolerance to transdermal NTG. Sympathetic activation was measured as the change in amplitude of low-frequency (66-129 mHz) oscillations in BP and heart rate (HR) recorded by a noninvasive method. Eleven healthy male volunteers received rapid i.v. infusion of 0.45 mg NTG in 1 min on 3 consecutive days: before NTG patch, after 22.5 h of patch therapy, and 22.5 h after patch removal. The maximum decrease in systolic BP (SBP) and maximum reflex tachycardia as well as the sympathetic activation produced by i.v. NTG were compared during each of the three study periods. The maximum decrease in SBP was 38 +/- 8 mm Hg before NTG patch and 27 +/- 15 mm Hg during NTG patch (p < 0.05), with return to baseline values (37 +/- 13 mm Hg) after patch removal. There was no significant change in amplitude of reflex tachycardia among study periods. However, low-frequency oscillations in SBP increased by 40 +/- 31% in the absence of NTG patch and by only 9 +/- 35% after 22.5 h of patch therapy (p < 0.05). Patch removal resulted in a significant rebound increase in these oscillations (70 +/- 51%; p < 0.05 vs. baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Rate-corrected QT interval: techniques and limitations.

The duration of the QT interval on the surface electrocardiogram represents the time required for all ventricular depolarization and repolarization processes to occur. Among the many physiologic and pathologic factors that contribute to the QT interval, heart rate plays a major role. Several approaches have been used to correct the QT interval, all of which take into account the heart rate at which the interval is measured. The simplest and most common approach to correcting the QT interval is to divide its value by the square root of the preceding RR interval expressed in seconds, i.e., by using Bazett's formula. This calculation provides a corrected QT (QTc) interval that represents the QT interval normalized for a heart rate of 60 beats/min. However, several studies have shown that Bazett's correction formula is not optimal. Fridericia's cube-root formula has been shown to perform better in correcting the QT interval for heart rate. Other formulas require the measurement of several QT-RR pairs at various heart rates to obtain a reliable QTc interval and are therefore not easily usable. Any correction formula is likely to introduce an error in assessing the QTc interval. Although the importance of this error should not be minimized, the corrected QT interval remains useful in assessing the effects of drugs on the duration of repolarization. For this purpose, Fridericia's cube-root formula is preferable to Bazett's square-root formula.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrocardiography↗
PubMed1993

d-sotalol reduces heart rate in vivo through a beta-adrenergic receptor-independent mechanism.

d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

Adult↗
PubMed1993

Pharmacokinetic and pharmacodynamic profiles of d-sotalol and d,l-sotalol.

d,l-Sotalol is a racemic drug composed of equimolar amounts of d-(+)-sotalol and l-(-)-sotalol. The l-(-)-enantiomer has both beta-blocking (class II) activity and potassium-channel-blocking (class III) properties. The d-(+)-enantiomer has class III properties similar to those of l-sotalol. However, the affinity of d-sotalol for beta-adrenergic receptors is 30 to 60 times lower than the affinity of l-sotalol. The pharmacokinetics of d,l-sotalol are linear. Following oral administration, absorption and bioavailability are almost complete; apparent elimination half-life ranges from 7 to 18 hours. More than 80% of racemic sotalol elimination occurs by renal excretion of unchanged drug. Sotalol is not metabolized, nor is it significantly bound to plasma proteins. Thus, steady-state plasma concentration is reached within 3 days of treatment onset in patients without renal insufficiency. Dosage of sotalol should be adjusted to creatinine clearance. The pharmacokinetic profile of d-sotalol is similar to that of the racemate. Plasma concentrations of racemic sotalol associated with beta-adrenergic blockade are similar to those associated with its class III actions. QT interval prolongation with d,l-sotalol is dose- and concentration-dependent and decreases at rapid heart rates. Also, QT interval prolongation at a given plasma concentration during repeated dosing tends to be less pronounced than QT prolongation at the same plasma concentration during single dosing. The class III actions of d-sotalol in the sinus node are associated with slowing of sinus heart rate, whereas additional beta blockade contributes to the decrease in heart rate observed with l- or d,l sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

Pharmacokinetics and platelet antiaggregating effects of beraprost, an oral stable prostacyclin analogue, in healthy volunteers.

Beraprost sodium (BPS) is an orally stable analogue of prostacyclin that inhibits adenylate-cyclase-dependent platelet aggregation and is proposed for treatment of chronic arterial occlusion. To determine the duration and intensity of platelet antiaggregation with BPS, 12 healthy, nonsmoking, male white volunteers participated in a double-blind, dose-escalating design with randomized placebo, placebo-controlled, cross-over study. After overnight fasting, single (20, 40, 60 micrograms and placebo) and repeated [20, 40, 60 micrograms and placebo) and repeated [20, 40, 60 micrograms and placebo three times daily (t.i.d.) for 3 days] oral doses of BPS were administered. Mean percentage of inhibition of ADP-induced aggregation normalized to placebo was measured for 8 h after drug administration and related to plasma concentrations (Cp) of the active enantiomer (APS 314d). BPS 40 and 60 micrograms decreased platelet aggregation 1 h after single doses, and 0.5 h and 1 h after repeated doses. BPS 20 micrograms had no significant effect. APS 314d pharmacokinetics was linear, and its terminal half-life (t 1/2) ranged from 0.50 +/- 0.21 to 0.91 +/- 0.27 h (mean +/- SD) independently of BPS dose. Antiaggregating effects were poorly related to Cp of APS 314d (r2 < or = 0.2). Some subjects complained of moderate postdrug absorption headaches (7 of 12 after single and 8 of 12 after repeated doses) and flushes (6 of 12 and 7 of 12, respectively). These data indicate that orally active prostacyclin BPS (40 or 60 micrograms) exerts its maximal antiaggregating effects between 0.5 and 1 h.

Administration, Oral↗
PubMed1993

CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans.

The metabolism of dextromethorphan, a drug used to probe genetically determined CYP2D6 activity has been investigated in vivo and in vitro. In vitro, kinetic parameters were determined in adult microsomes: Km for the O-demethylation was much lower than for N-demethylation (7 versus 650 microM) but Vmax was comparable. Fetal liver microsomes actively catalysed the N-demethylation of dextromethorphan, with kinetic parameters (Vmax and Km) quite similar in fetal and adult microsomal preparations while the O-demethylation did not exceed 5% of adult activity. In microsomes, the N-demethylation was inhibited by antibodies raised against CYP3A subfamily members although fetal microsomes were much less sensitive to immunoinhibition than adult microsomes. In vivo, urinary excretion of dextromethorphan and its three demethylated metabolites was examined in 155 adult volunteers and compared between extensive (n = 144, 92.9%) and poor (n = 11, 7.1%) metabolizers. The O-demethylation to dextrorphan is the rate-limiting step of metabolism. In 2D6 poor metabolizers, the N-demethylation to 3-methoxymorphinan is slightly higher than in 2D6 extensive metabolizers but does not compensate defective O-demethylation. The frequency distribution histograms of dextromethorphan/dextrorphan and 3-methoxymorphinan/3-hydroxymorphinan metabolic ratios appeared bimodally distributed, reflecting the participation of CYP2D6 in the O-demethylation reaction. They clearly differed from the random distribution of dextromethorphan/3-methoxymorphinan, and dextrorphan/3-hydroxymorphinan ratios among the population. These data clearly suggest that the N-demethylation of dextromethorphan is dependent on CYP3A and that both CYP2D6 and CYP3A are involved in the overall metabolism of dextromethorphan.

Adult↗
PubMed1993

Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination.

1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine concentration and beta-adrenoceptor blocking effects did not differ between the phenotypes and were not influenced by metoprolol. We conclude that beta-adrenoceptor blockade during repeated dosing with metoprolol is more pronounced in poor than in extensive metaboliser subjects, that nicardipine decreases a CYP2D6-independent route of metoprolol elimination but does not increase beta-adrenoceptor blockade during repeated dosing with metoprolol.

Adrenergic beta-Antagonists↗
PubMed1993

Rate-dependence of class III actions in the heart.

The pharmacodynamics of many antiarrhythmic drugs are altered by heart rate. The ability of sodium channel blockers to decrease conduction velocity (class I action) is more pronounced with rapid heart rates. Drugs with class III action increase action potential duration and refractoriness in the heart. Most drugs with class III actions, currently being developed, produce their action by blocking one or several of the potassium channels responsible for repolarization. In vitro and in vivo studies have shown that their ability to increase repolarization time is less pronounced, or even disappears, at rapid pacing or heart rates. This so called 'inverse' rate-dependence of class III action is a characteristic of all drugs currently used in man except amiodarone, for which prolongation of repolarization time persists to a limited extent with rapid heart rates. It has been suggested that one possible mechanism of the inverse rate-dependence of class III action is related to the preferential binding of drugs to the potassium channels in the closed, polarized state. An inverse rate-dependence of class III action has also been found on prolongation of refractoriness. However, preliminary studies suggest that the positive inotropism of class III drugs not only persists but may increase with rapid heart rates. The clinical consequences of this phenomenon remain unclear, especially in view of the fact that the rate-dependence of class III action on dispersion of repolarization has not been specifically studied and that class III actions tend to decrease in ischemic tissues. However, the increase of action prolongation at slow heart rates may contribute to the bradycardia-dependent development of torsades de pointes arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Mishaps with anti-arrhythmic agents used to reduce mortality after infarction].

The presence of isolated and/or repetitive ventricular arrhythmias following myocardial infarction identifies a group of patients at increased risk of death. The availability of anti-arrhythmic drugs, noticeably drugs with class I activity, efficient at suppressing arrhythmias has led to the hope that their administration could reduce post-myocardial infarction mortality. However, this hypothesis has not been confirmed. The Cardiac Arrhythmia Suppression Trial, which was designed to have the power to test the hypothesis that suppression of ventricular arrhythmias is associated with a decrease in mortality following myocardial infarction, even showed an increase in mortality with two drugs with class I activity. Several meta-analyses have confirmed that administration of class I antiarrhythmic drugs is of no clinical benefit in patients with non sustained ventricular arrhythmias following myocardial infarction. Ongoings studies are testing the hypothesis that such benefit could exist with amiodarone. The clinical benefit of beta-blockers, in terms of reduction of both total and sudden death post-myocardial infarction, has been clearly documented and mandates their administration in this setting. Futures studies of anti-arrhythmic drugs will have to focus on groups of patients at increased risk of arrhythmic death.

Amiodarone↗
PubMed1992

Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects.

We examined the influence of toloxatone, a new reversible monoamine oxidase-A inhibitor used in the treatment of depression, on tyramine-induced pressor effect in healthy volunteers. The maximum increase in systolic blood pressure produced by four single oral doses of tyramine administered during a meal and ranging from 100 mg to 800 mg was compared during repeated (3 to 5 days) administration of placebo, 200 mg toloxatone three times a day and 400 mg toloxatone three times a day in a single-blind, three-period crossover study. Toloxatone by itself had no significant influence on blood pressure. During administration of toloxatone, no significant increase in tyramine-induced increase in systolic blood pressure was observed for tyramine doses of 200 mg or less that are consistently higher than those associated with normal food intake. However, toloxatone increased the tyramine-induced increase in blood pressure after 400 mg tyramine (400 mg toloxatone three times a day) and 800 mg tyramine (200 mg toloxatone three times a day and 400 mg toloxatone three times a day). This pharmacodynamic interaction could be explained by an increase in tyramine systemic bioavailability in the presence of toloxatone. It is concluded that interaction between tyramine in meals and toloxatone is unlikely to occur in patients after long-term administration of the drug at therapeutic dosages.

Administration, Oral↗