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Biomedical subjects

C Funck-Brentano

Publications and source records attributed to C Funck-Brentano.

At least 91 records · Page 5Linked to original sources
PubMed1990

Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias.

A genetically determined pharmacokinetic and pharmacodynamic interaction between quinidine and single doses of encainide in healthy volunteers has previously been described. In subjects with the extensive metabolizer phenotype, quinidine blunted encainide-induced QRS prolongation (a marker of sodium channel block) because it impaired encainide biotransformation to the potent active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide. Therefore, the purpose of this study was to test the hypothesis that quinidine would inhibit sodium channel block (and by inference arrhythmia suppression) during encainide therapy in patients with the extensive metabolizer phenotype. Surprisingly, however, in eight extensive metabolizer patients, the extent of QRS prolongation during chronic encainide therapy was unaltered by quinidine (139 +/- 21 vs. 139 +/- 22 msec) whereas arrhythmia suppression was enhanced (64 +/- 22 to 77 +/- 19%; P = .05). Plasma concentration data demonstrated that although encainide metabolism to ODE was partially impaired by quinidine, subsequent 3-methoxy-O-desmethyl encainide formation from ODE was virtually completely inhibited; thus steady-state plasma ODE remained unchanged whereas plasma encainide increased 10-fold (21 +/- 30 to 240 +/- 118 ng/ml; P less than .05). In contrast, no changes in disposition or in pharmacodynamics were observed in two poor metabolizers. It is concluded that the effect of this drug interaction in patients is determined by differential sensitivities to inhibition by quinidine of encainide O-demethylation and subsequent ODE 3-methoxylation. Evaluation of potential drug interactions should include assessment of possible genetic factors as well as of steady-state effects.

Aged↗
PubMed1989

Improved high-performance liquid chromatographic assay for encainide and its metabolites in human body fluids.

Methods reported previously for the determination of encainide and its metabolites in biological fluids have not been extensively described and evaluated. We report an improved high-performance liquid chromatographic assay for the quantification of these compounds in plasma and urine with complete estimation of the accuracy and reproducibility of the analytical method. The major improvements consist of: (1) the use of ethaverine as an appropriate internal standard; (2) the use of the salting-out technique which improves the extraction recovery for the metabolites of encainide and the sensitivity of the assay; and (3) a shift of the ultraviolet absorption wavelength from 254 to 270 nm to increase the selectivity of the detection.

Anilides↗
PubMed1989

Recainam dose titration and pharmacokinetics in patients with resistant arrhythmias.

Recainam, a new antiarrhythmic drug, was evaluated in 20 patients with drug-resistant stable ventricular arrhythmias. Dosage was increased stepwise every 48 to 72 hours until arrhythmia suppression, side effects, or a predetermined maximal dosage occurred. After a pharmacokinetic evaluation, efficacy was confirmed in a double-blind, crossover protocol. One patient had unusable ambulatory ECG data. There were 14 of 19 patients who responded during dose titration; efficacy was confirmed in 11 of 14. The mean effective dosage and trough plasma concentration were 427 mg every 8 hours and 1.83 micrograms/ml, respectively. One patient withdrew because of nausea. Slowing of intraventricular conduction necessitated dosage reduction in two patients. Plasma half-life was 9.4 +/- 4.1 hours, with renal elimination accounting for 62% of oral clearance. However, 66% of the variability in oral drug clearance was the result of nonrenal elimination. Oral recainam at dosages of 300 to 600 mg every 8 hours is effective in some drug-resistant ventricular arrhythmias and is well tolerated.

Administration, Oral↗
PubMed1989

Pharmacokinetic and pharmacodynamic interaction of N-acetyl procainamide and procainamide in humans.

Procainamide is a sodium channel blocker which prolongs QRS and QTc intervals, yet its major active metabolite, N-acetylprocainamide (NAPA), generally prolongs only QTc and has very different electrophysiologic and antiarrhythmic actions. In greater than 50% of patients receiving chronic treatment with procainamide, plasma concentrations of NAPA exceed those of procainamide. In this study, we examined the hypothesis that NAPA might alter the disposition kinetics or pharmacologic actions of procainamide. Ten patients with frequent ventricular extrasystoles received intravenous (i.v.) infusions of procainamide alone (study day 1), procainamide and NAPA (study day 2), and NAPA alone (study day 3) at least 48 h apart. On study days 1 and 2, procainamide was administered at a constant rate for 4 h. On study days 2 and 3, NAPA was administered as a loading and maintenance infusion designed to reach a target pseudo-equilibrium plasma concentration of 8 micrograms/ml. NAPA increased procainamide elimination half-life (t1/2) from 275 +/- 42 min (mean +/- SD) on day 1 to 340 +/- 74 min on day 2 (p less than 0.01). A significant correlations was noted between the change in procainamide total clearance on day 2 relative to day 1 and the initial procainamide total clearance on day 1 (r = -0.77, p = 0.009). Findings were similar when procainamide fractional urinary excretion was considered (r = -0.89, p = 0.007). NAPA did not alter procainamide-induced QRS prolongation, but potentiated procainamide-induced QTc prolongation. The antiarrhythmic response to procainamide was not significantly altered by NAPA in seven of nine patients. One patient had greater arrhythmia suppression when NAPA and procainamide were combined than when either was administered alone. In one patient, NAPA apparently antagonized procainamide-induced arrhythmia suppression, but this effect was not reproducible. We conclude that accumulation of NAPA during procainamide therapy can alter both procainamide elimination as well as its electrophysiologic actions.

Acecainide↗
PubMed1989

Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.

Adult↗
PubMed1989

Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism.

Encainide biotransformation to its active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide cosegregates with the polymorphic oxidation of debrisoquine. Because quinidine has been reported recently to be a potent inhibitor of the enzyme responsible for this polymorphism (cytochrome P450db1), we tested the hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation. Seven subjects with the extensive and four subjects with the poor metabolism phenotype received encainide (60 mg p.o. and 4.5 mg of [14C]encainide i.v. administered simultaneously) alone and during chronic treatment with low dose quinidine (50 mg q 6 hr) in a randomized, crossover design. In extensive metabolizers, quinidine decreased encainide systemic clearance from 935 +/- 541 to 190 +/- 77 ml/min and encainide nonrenal clearance from 782 +/- 474 to 95 +/- 32 ml/min (both P less than .02). In this population, quinidine significantly increased encainide elimination half-life from 1.8 +/- 1.2 to 7.7 +/- 2.4 hr and fractional urinary recovery of unchanged encainide from 17.5 +/- 7.6 to 47.4 +/- 7.8% (both P less than .001). The extent to which quinidine altered these indices of encainide disposition was highly correlated with the metabolic ratio for debrisoquine oxidation (r = 0.62-0.95). Moreover, poor metabolism and QRS prolongation during encainide were blunted by addition of quinidine; the extent of quinidine-induced reversal of encainide-related ECG changes was also correlated with debrisoquine ratio (r = 0.91). In contrast, in poor metabolizers, quinidine did not change encainide disposition kinetics and neither encainide alone nor encainide plus quinidine significantly altered electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Overview of the clinical pharmacology of antiarrhythmic drugs.

Antiarrhythmic drugs have been recognized to possess 1 or more classes of antiarrhythmic action. This classification scheme is useful, but has major limitations because the available drugs and their metabolites have multiple actions. This report presents an overview of the distinguishing features of the most frequently used agents having class I or III actions. Agents with class I actions are local anesthetic agents that depress the fast inward depolarizing sodium current and thereby slow the rate of the rise of the action potential (phase 0). This category is further divided into classes IA, IB, and IC according to the degree of potency as sodium channel inhibitors, and the individual effects of the drug on action potential, conduction velocity and repolarization. Included in the spectrum of agents with class I action are quinidine, procainamide, disopyramide, lidocaine, tocainide, mexiletine, flecainide, amiodarone, encainide and lorcainide. The antiarrhythmic drugs that exert class III action lengthen repolarization and refractoriness; included in this category are amiodarone, quinidine, bretylium and sotalol. Because of the broad range of effects that antiarrhythmic agents may exert, safe and effective therapy requires a thorough familiarity with the pharmacologic profile of each drug administered and a careful evaluation of the presenting condition and the patient history. In some cases, a multiple drug regimen may be most appropriate. Various combinations such as class IA and IB agents, have been shown to slow conduction synergistically and increase refractoriness while keeping adverse effects to a minimum.

Action Potentials↗
PubMed1988

Rate dependence of ventricular extrasystoles: computer identification and quantitative analysis.

A new computer program was designed to identify and quantify the rate dependence of arrhythmias using 24 hour Holter tape recordings. The program was used in 10 untreated apparently healthy patients with fixed, coupled, isolated monomorphic ventricular extrasystoles. The second cycles of two consecutive sinus cycles were grouped according to whether or not they were followed by a ventricular extrasystole. Each of these sinus cycles was further analysed by cycle length during successive one hour periods. From the number of cycles in each cycle length class, identification and quantification of an upper or lower limit, or both, of cycle length beyond which ventricular extrasystoles disappeared were possible. Upper and lower limits were observed in 10 and eight of the 10 patients respectively. An upper and a lower limit were identifiable (mean(SD) 9.3(5.1) and 8.4(5.8) times per recording respectively). Values of both types of limits varied throughout tape recording. A positive significant correlation was found between the values of upper and lower limits and the mean sinus cycle length during the corresponding hour in nine of the 10 and eight of the eight patients respectively. The type of relation observed suggests that heart rate directly alters limits or that heart rate and limits are under the same influence of the autonomic nervous system. It is concluded (a) that identification and quantification of the rate dependence of arrhythmias is possible using this computer program; and (b) that, in patients with ventricular extrasystoles and apparently normal hearts, upper and lower limits vary and are related to heart rate.

Adolescent↗
PubMed1987

[Efficacy of high doses of molar lactate by the venous route in flecainide poisoning].

Three cases of intoxication by flecainide acetate were characterized by cardiovascular collapse with widening of the QRS complex at electrocardiography. In two of these patients, impairment of liver or renal function probably played a facilitating role. Infusion of molar sodium lactate in high doses resulted in rapid and durable clinical and electrocardiographic improvement. This effect of molar sodium lactate may tentatively be attributed to either displacement of flecainide from its tissue receptor sites, or to a decrease in the effect of flecainide by alteration of its action on the fast sodium channel, or to the beneficial effects of vascular filling.

Adult↗
PubMed1987

Exercise test: arrhythmogenic or antiarrhythmic? Rate-dependency vs. adrenergic-dependency of tachyarrhythmias.

The arrhythmogenic effects of exercise tests are often unpredictable, sometimes paradoxical, and usually poorly reproducible. This explains why they are rather neglected by rhythmologists in studying the mechanisms of arrhythmias and the effects of antiarrhythmic drugs and why their prognostic value is a matter of controversy. At the same time the induced, supposedly ischaemia-related arrhythmias are usually not prevented by revascularization procedures. All these discrepancies are probably explained by the complex interactions between the time-limited stimulation of the sympathetic drive and the arrhythmia mechanisms. During the exercise test the sympathetic drive is increased via the neurogenic and humoral routes, and the post-exercise period is characterized by a vagally-induced deceleration of the heart rate which intervenes in the setting of a persistent high level of sympathetic activity. The arrhythmia components formed by potential triggers (isolated premature beats) and substrates (repetitive activity) do not react in the same way to those different phases. Extrasystoles are mainly rate-dependent, so that they often tend to disappear as the sinus rate accelerates. The repetitive ventricular activity directly depends on the sympathetic drive, but necessitates the presence of the trigger to become manifest. Conceivably, many different situations may result from the complex interplay between these distinct parameters, so that the apparent clinical effect of exercise may be either arrhythmogenic or antiarrhythmic in apparently identical diseases, or even in the same patients.

Arrhythmias, Cardiac↗
PubMed1987

Neurogenic hypertension associated with an excessively high excretion rate of catecholamine metabolites.

A 60 year old hypertensive patient suffered several cerebral infarctions. A phaeochromocytoma was suspected because the excretion rates of vanillylmandelic acid and its methoxy derivatives were raised and the patient had hypertensive crises. No tumour was found, however, by 131mI-iodobenzylguanidine scintigraphy and computed tomography of the abdomen. Moreover, the enhanced orthostatic plasma catecholamine response suggested that the high excretion rates of catecholamine metabolites were more likely to be caused by the syndrome of raised catecholamines after cerebrovascular accidents than a phaeochromocytoma. A phaeochromocytoma should not be diagnosed within several months of cerebral infarction without first excluding the possibility of a hyperadrenergic state induced by cerebral infarction.

Adrenal Gland Neoplasms↗
PubMed1986

Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure.

A patient with congestive heart failure and moderate renal insufficiency developed severe reversible non-oliguric renal failure while on frusemide and enalapril. Renal failure developed when enalapril was given in the presence of pronounced sodium depletion. When positive sodium balance was restored the plasma creatinine concentration began to fall while angiotensin converting enzyme inhibition remained effective and blood pressure was stable. These observations suggest that the degree of sodium depletion plays an important role in the tendency for angiotensin converting enzyme inhibitors to induce renal failure in patients with congestive heart failure and moderate renal insufficiency. Restoration of a positive sodium balance promotes the recovery of renal function after the combined administration of angiotensin converting enzyme inhibitors and diuretics.

Acute Kidney Injury↗
PubMed1985

Regulation of renal cytochrome P-450. Effects of two-thirds hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes.

The possibility of a relationship between hepatic and renal cytochrome P-450 contents was assessed in rats with liver disease. In rats killed 3 days after two-thirds hepatectomy (a model for hepatocellular insufficiency), the total microsomal cytochrome P-450 content of the whole liver was decreased by 60% as compared to that in control rats; renal cytochrome P-450 was increased by 30% while the 7-ethoxycoumarin deethylase activity of kidney microsomes was increased by 80%. In rats killed 7 days after bile duct ligation (a model for cholestasis) or 35 days after bile duct ligation (a model for biliary cirrhosis), hepatic cytochrome P-450 was decreased by 60% and 45%, respectively, while renal cytochrome P-450 content was increased by 50% and 150%, respectively. In contrast, in rats killed 15 days after the last dose of carbon tetrachloride, 1.3 ml/kg twice weekly for 3 months (a model for post-necrotic cirrhosis), both hepatic and renal cytochrome P-450 contents remained unchanged. Phenobarbital (80 mg/kg daily for 3 days) was a poor inducer of renal cytochrome P-450 in sham-operated rats but became a potent inducer of renal cytochrome P-450 in rats with two-thirds hepatectomy. We conclude that renal cytochrome P-450 is increased in three models in which hepatic cytochrome P-450 contents are decreased (two-thirds hepatectomy, cholestasis and biliary cirrhosis), but remains unchanged in a model of severe liver pathology, in which hepatic cytochrome P-450 content is not modified (late, post-necrotic cirrhosis). The hypothetical role of endogenous inducer(s) is discussed.

Animals↗