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C Libersa

Publications and source records attributed to C Libersa.

At least 19 recordsLinked to original sources
PubMed1992

High-performance liquid chromatographic assay for amiodarone N-deethylation in microsomes of rat liver.

A reversed-phase high-performance liquid chromatographic assay using ultraviolet detection is described for determining the production of the major N-dealkylated metabolite of amiodarone in rat liver microsomes. The principal advantages of this method are its simple sample preparation (protein precipitation by acetonitrile), low detection limit for N-desethylamiodarone (0.05 mumol/l) and relatively short analysis time (16 min). Its analytical applicability is demonstrated by the comparison of the kinetic parameters (maximum velocity and Michaelis-Menten constant) between Sprague-Dawley and Dark-Agouti rats.

Amiodarone↗
PubMed1991

Single-dose quinidine treatment inhibits mexiletine oxidation in extensive metabolizers of debrisoquine.

Urinary elimination of unchanged mexiletine, p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and mexiletine N-glucuronide conjugate (MGC) was investigated before and after treatment with quinidine. All subjects were phenotyped as extensive metabolizers for debrisoquine oxidation. The total recovery of mexiletine and metabolites was significantly reduced after quinidine pretreatment. It is concluded that pretreatment with a very low dose of quinidine inhibits markedly the elimination of both major mexiletine metabolites (PHM and HMM) and likely decreases the overall elimination of mexiletine. That should lead to changes in mexiletine disposition and have clinical consequences during combination therapy with both drugs.

Debrisoquin↗
PubMed1991

The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation.

1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O-demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4-hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = -0.83; P = 0.006 and rs = -0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine-type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Wenckebach periods in sinoatrial block: experimental and clinical evidence.

The reality of sinoatrial Wenckebach periods (WP) has been suggested, but not proven, in the literature. We report experimental and clinical data showing WP in sinoatrial blocks. Experimental sinoatrial blocks were induced by superfusion of bepridil (10(-5) M) in 15 preparations of isolated rabbit right atria. Different types of block were observed, including Blumberger I block, i.e., sinoatrial WP. The recordings showed that the typical pattern of Blumberger type IA block and sinoatrial WP may be due to transient acceleration of the sinus rate, without change in the increment. We also observed sinoatrial WP in a 72-year-old patient on direct recordings of the sinus node (SN) electrical activity. In this case, transient acceleration of the sinus rate also seemed to be involved in the genesis of sinoatrial WP. Analysis of these clinical and experimental data showed similarities that may explain the mechanism of the WP. Usually type IA Blumberger block is said to involve a decrease in the sinoatrial increment to explain the atrial sequence (decrease in PP interval followed by a pause shorter than twice the value of the preceding cycle, then a cycle longer than the one preceding the pause). In fact, this pattern can be observed when the acceleration of the higher structure, the SN, induces block within the lower structure, i.e., the atrium.

Action Potentials↗
PubMed1991

[Prolongation of the CAST study.Is it justified to consider another trial?].

A possible prolongation of the CAST would be another trial of the same type, (CAST II), designed for high risk patients (1 year mortality over 20%). The aim of this study would be to confirm the hypothesis that the ratio efficacy/undesirable side effects of antiarrhythmic drugs is beneficial in this type of patient. The most important selection criteria would be an ejection fraction of less than 40%, the presence of repetitive arrhythmias, especially ventricular tachycardia on Holter monitoring and the recording of late ventricular potentials on surface averaging ECG. The patients would be included at about the 20th day after myocardial infarction in order to exclude as much as possible unstable coronary artery disease and ventricular arrhythmias on successive Holter recordings because this would make interpretation of the efficacy of antiarrhythmic drugs impossible. The ideal number of patients would be about 5,000 but this is unrealistic because the trial would only include high risk cases and there would be difficulties in recruiting this number even in a multicenter trial. During follow-up of 2 to 3 years, the surveillance of the therapeutic efficacy of the antiarrhythmics would have to be better than in the CAST. The most delicate methodological problem would be the randomization of patients as the formation of a placebo group is unethical in high risk coronary patients with severe or malignant ventricular arrhythmias. The use of the only proved cardioprotector drugs, the betablockers, in all these high risk patients would be one solution, even if it might introduce a bias in the results.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1991

[Prognostic value and development of late potentials after aortocoronary bypass. A prospective study of 100 patients].

Ventricular late potentials are post-infarction markers of the risk of ventricular tachycardia and sudden death. In order to assess their prognostic value and evolution after coronary bypass surgery, 100 patients underwent signal-averaged electrocardiographic recordings 24 hours before and 9 days after surgery, and were then prospectively followed up for 40 +/- 8 months. Patients who displayed late ventricular potentials underwent an additional recording at 5 months with 24 hour Holter monitoring. The average age of the patients was 57.0 +/- 8.4 years; 55 had previous myocardial infarction; 32 had triple vessel disease; the mean left ventricular ejection fraction was 59.7 +/- 12.4%. Ventricular late potentials were recorded in 17 patients before surgery and their left ventricular ejection fraction was significantly lower (51.4 +/- 11.5% vs 61.4 +/- 11.9%: p less than 0.05). There was one operative death in a patient with late ventricular potentials. After surgery, late ventricular potentials were only recorded in 6 patients: at the 9th postoperative day in 3 cases and at the 5th postoperative day in 3 cases. Ventricular late potentials appeared postoperatively in 5 patients, 4 of whom had suffered perioperative myocardial infarction. The recordings became normal at the 5th month in 2 of these 5 patients. Holter monitoring at the 5th month compared with a control group, showed a significant correlation between left ventricular potentials and frequent repetitive or polymorphic ventricular extrasystoles. The 40 month survival rate was excellent: 2 patients were lost to follow-up; there were 3 cardiac deaths, one of which was sudden and 4 non-cardiac deaths. All patients with late ventricular potentials were still alive. These results show that late ventricular potentials persist after coronary bypass surgery in 2/3 of patients; their prognostic significance is not obvious. The low incidence of postoperative sudden death could be attributed to the favourable overall effects of revascularisation rather than on the arrhythmogenic substrate.

Adult↗
PubMed1991

[Unwanted cardiovascular effects of anti-arrhythmia agents].

Antiarrhythmic drugs can cause many undesirable side effects affecting a number of organs and functions. Of those which affect the cardiovascular system, the proarrhythmic and negative inotropic effects are the most serious. Proarrhythmic effects, suggested by an aggravation of an arrhythmia or the induction of a previously undocumented arrhythmia, may be favorised by the presence of an arrhythmogenic substrate (unidirectional lock, delayed conduction, dual conduction pathways, low thresholds of depolarisation or fibrillation, presence of zones of hyperautomaticity...), "triggering" mechanisms (extrasystoles, variations of heart rate, after-depolarisation) and by changes in the cardiac environment (variations of autonomic nervous tone and hormonal changes, electrolytic or metabolic disorders...). An antiarrhythmic may have a beneficial action on one of these factors (for example, suppression of extrasystoles) but an aggravating effect on others (for example, an increase in the heart rate, creation of zones of reentry). This probably explains the fact that, for the moment, only molecules which have multifactorial modes of action have been shown to be beneficial in arrhythmias after myocardial infarction. Negative inotropic effects may be directly responsible for a deterioration in the hemodynamic status of patients on antiarrhythmics and indirectly responsible for aggravating arrhythmia by altering the anatomical substrate, so favorising proarrhythmic effects. The negative inotropic action may be related to ionic mechanisms (lowering intracellular calcium concentration due to blockade of the sodium channel by Class I antiarrhythmics) or to indirect mechanisms (reduced sympathetic tone, non-specific beta inhibition, calcium channel blockade, decreased left ventricular compliance, vasoconstrictor effects...).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1991

[Circumferential laser thermo-exclusion of post-infarction ventricular tachycardia. Apropos of 11 cases].

Circumferential laser thermoexclusion was assessed in the treatment of postinfarction ventricular tachycardia resistant to drug therapy in 11 patients between December 1986 and April 1989. There were 10 men and 1 woman with an average age of 63.7 +/- 5.6 years whose ventricular tachycardia occurred 10.7 +/- 7.5 years after infarction. All had left ventricular aneurysm or an akinetic plaque. Circumferential thermoexclusion was carried out by Mesnildrey's method, systematically associated with resection of the aneurysm or, when this was not feasible, with coronary revascularisation. Programmed ventricular stimulation was performed before and after surgery in 8 patients. Sustained ventricular tachycardia remained inducible in 4 patients after surgery but the prescription of antiarrhythmic drugs in 2 of these cases resulted in tachycardia becoming non-inducible. The increase in the left ventricular ejection fraction after surgery was not statistically significant (36.9 +/- 9.4% to 44.4 +/- 12.8%). After an average follow-up of 16.7 +/- 10.6 months, there were 2 cardiac deaths not related to arrhythmias (18%), 1 early at the 20th postoperative day and 1 late, 10 months after surgery. There were 2 recurrences of tachycardia (18%) controlled by antiarrhythmic therapy. Late ventricular potentials were recorded in 9 out of the 11 patients before surgery but in only 3 of these cases (33%) after surgery. Circumferential laser thermoexclusion guided visually in the border zone of the infarct scar would seem to be a simple, safe, rapid and therefore attractive, surgical antiarrhythmic technique, the efficacy of which should be evaluated by programmed ventricular stimulation. This should be undertaken on a large scale in order to define the indications and results of this method.

Aged↗
PubMed1990

Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes.

The cytochrome P-450dbl isozyme (P-450bdl) is responsible for the genetic sparteine-debrisoquine type polymorphism of drug oxidation in humans. To investigate the relationship between mexiletine oxidation and the activity of this isozyme, cross-inhibition studies were performed in human liver microsomes with mexiletine and dextromethorphan, a prototype substrate for P-450dbl. The formation of hydroxymethylmexiletine and p-hydroxymexiletine, two major mexiletine metabolites, was competitively inhibited by dextromethorphan. Mexiletine competitively inhibited the high affinity component of dextromethorphan O-demethylation. In addition, there was a good agreement between the apparent Km values for the formation of both mexiletine metabolites and the high affinity component of dextromethorphan O-demethylation and their respective apparent Ki values. Several drugs were tested for their ability to inhibit mexiletine oxidation. Quinidine, quinine, propafenone, oxprenolol, propranolol, ajmaline, desipramine, imipramine, chlorpromazine and amitryptiline were competitive inhibitors for the formation of hydroxymethylmexiletine and p-hydroxymexiletine as for prototype reactions of the sparteine-debrisoquine type polymorphism. Amobarbital, valproic acid, ethosuximide, caffeine, theophylline, disopyramide and phenytoin, known to be non-inhibitors of P-450dbl activity, were found not to inhibit the formation of these mexiletine metabolites. Moreover, the formation of both metabolites was strongly inhibited by an antiserum containing anti-liver/kidney microsomes antibodies type I (anti-LKMI) directed against P-450dbl. These data suggest that the formation of two major metabolites of mexiletine is predominantly catalysed by the genetically variable human liver P-450dbl.

Binding, Competitive↗
PubMed1990

In-vitro and in-vivo electrophysiologic effects of encainide.

The intracellular electrophysiologic effects of encainide (E) and its main metabolite, O-desmethyl-encainide (ODE), were studied in guinea-pig papillary muscle preparations and related to the in-vivo electrophysiologic effects observed after intravenous (IV) infusion of E in 11 patients undergoing electrophysiologic study (EPS). At equipotent concentrations of E and ODE, frequency-dependent reductions in Vmax studied at pacing rates of 30-180 beats/min ranged from -11.5% to -53%, with maximum reductions of -53% and -47%, respectively at the highest frequency. The kinetics of onset of use-dependent Vmax reduction were slower for ODE than for E at each studied pacing rate. The kinetics of total recovery from use-dependent block were still slower (120 seconds for E and 300 seconds for ODE at a 90 beats/min pacing rate). These in-vitro electrophysiologic data could explain the marked alterations in intraventricular and atrioventricular conduction observed in humans 60 minutes after IV administration of 1 mg/kg of E over a 15-minute period. The QRS, PA, AH, and HV intervals were significantly increased (p less than 0.01) and the Wenckebach cycle length was increased by 8% (p less than 0.05). Blood pressure, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval was already increased 2 minutes after drug administration, while AH was not increased until 15 minutes after drug administration. There was a positive correlation between the increase of the AH interval and the blood level of ODE.

Anilides↗
PubMed1989

Effect of quinidine on the dextromethorphan O-demethylase activity of microsomal fractions from human liver.

1. The kinetics of dextromethorphan O-demethylation were measured in microsomes prepared from five human livers, both in the absence and in the presence of quinidine. 2. For each liver and over the concentration range of dextromethorphan examined (4.2-3400 microM), this reaction involved an enzymatic component of high affinity, with an apparent Michaelis-Menten constant (Km) of 4.6 +/- 1.8 microM (mean +/- s.d.) and a maximum velocity (Vmax) of 4.2 +/- 3.5 nmol mg-1 h-1 (mean +/- s.d.). 3. Quinidine was a potent and competitive inhibitor of the activity of this component (mean Ki +/- s.d. of 0.025 +/- 0.008 microM) as it is for other oxidation reactions which have already been found to co-segregate with the debrisoquine-type polymorphism. 4. With microsomes from four of the five livers studied, there was evidence of a second enzymatic component of activity characterized by a similar Vmax and about 20-fold higher Km compared with the high affinity component. The activity of this low affinity component was unaffected by quinidine in the concentrations studied.

Chromatography, High Pressure Liquid↗
PubMed1987

Propafenone versus disopyramide: a double-blind randomized crossover trial in patients presenting chronic ventricular arrhythmias.

In vitro and in vivo electrophysiological studies have shown that propafenone could be classified as a class I antiarrhythmic agent. The aim of this study was to investigate the short-term antiarrhythmic efficacy and safety of propafenone in 10 patients compared to disopyramide in a double-blind randomized protocol. Included patients suffered from ventricular arrhythmias with at least 60 ventricular premature beats (VPB) per hour refractory to at least two other antiarrhythmic agents. At the end of the control period and of the two treatment periods during which patients received either propafenone (300 mg three times a day) or disopyramide (200 mg three times a day), clinical examination, Holter recordings, electrocardiogram, and clinical laboratory tests were performed. The PR interval and the QRS interval were significantly increased with propafenone, but not with disopyramide. The cQT interval was not significantly changed by either propafenone or disopyramide. Heart rate was decreased with propafenone (p less than 0.05) with no change in the diurnal/nocturnal circadian ratio variation. Heart rate was significantly decreased with disopyramide only during the day. Five of nine patients in the propafenone group and two of nine patients in the disopyramide group showed a reduction in ventricular premature beats greater than 80%. Total resolution of severe arrhythmias (repetitive events) was seen in 5 of 8 patients with propafenone; 2 of 8 with disopyramide. Adverse events, when they occurred, were mild (visual disturbances, epigastric discomfort, changes in taste perception, transient atrioventricular block with propafenone, and photophobia with disopyramide), and did not require reduction or discontinuation of study drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

[Raynaud's phenomenon and finger necrosis after treatment of ovarian seminoma with bleomycin, vinblastine and 5-fluorouracil].

Bleomycin is sometimes at the origin of a Raynaud's phenomenon (RP). From the literature, there does not seem to exist a dose-dependent relationship. The phenomenon occurs early or late and often is resistant to various medications. The possible physiopathological mechanisms are: direct vascular toxicity, hypersensitivity vascularization, alteration of platelets activity, alteration of Willebrand's factor, and as predisposing factors: association to periwinkle alkaloids or hypomagnesemia.

Adult↗
PubMed1986

[Ventricular extrasystole. Which should be treated and how?].

The decision of whether or not to treat a ventricular extrasystole depends in the first instance on the benign or severe nature of the disorder, and on whether there is subjacent cardiopathy. The results of 24-hour Holter monitoring, exercise tolerance tests and clinical and echographic examinations will define the pathological character of a ventricular extrasystole and will indicate any subjacent cardiopathy. Electrophysiological exploration with programmed stimulation should be reserved for so-called lethal cases of arrhythmia, such as attacks of sustained ventricular tachycardia. Ischemic cardiopathy is by far the most frequent cause of ventricular extrasystoles. The two major risks of sudden death after myocardial infarction are due to left ventricular dysfunction and repetitive and/or complex ventricular extrasystoles, as well as to attacks of ventricular tachycardia. Heart patients presenting these disorders must receive urgent treatment with antiarrhythmics. Isolated, monomorphic ventricular extrasystoles are also treated in heart patients at risk if their frequency is greater than 10 per hour, measured by 24-hour Holter monitoring. In the absence of subjacent cardiopathies, the therapeutic indications are much less well defined. Approximately five per cent of subjects in a normal population present ventricular extrasystoles, the frequency of which, however, rarely exceeds 100 per 24 hours. Repetitive phenomena are only seen in 10 per cent of cases. Attacks of ventricular tachycardia are almost never seen. Ventricular extrasystoles that develop in apparently normal hearts, but which do not fulfill the above criteria, can be considered abnormal. Nevertheless, there is no categorical proof that these ventricular extrasystoles represent any risk, notably of sudden death.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗