PubMed Health⌕ Search

Biomedical subjects

C Libersa

Publications and source records attributed to C Libersa.

At least 37 records · Page 2Linked to original sources
PubMed1995

Octreotide effects on orthostatic hypotension in patients with multiple system atrophy: a controlled study of acute administration.

In nine patients with orthostatic hypotension due to multiple system atrophy, the effects of octreotide (100 micrograms s.c.), a somatostatin analogue, on blood pressure (BP), heart rate (HR), and norepinephrine (NE) plasma levels after 60 degrees head up tilt test were evaluated by a randomly controlled study. Octreotide increased supine BP, tilt-test duration (+28%), and delay to obtain minimal BP during the 60 degrees head up tilt (+50%). Octreotide changed neither HR nor NE plasma levels.

Aged↗
PubMed1994

Genetic polymorphism of cytochrome P450 2D6 in idiopathic Parkinson disease and diffuse Lewy body disease.

We investigated genetic polymorphism of the cytochrome P450 CYP 2D6 gene in 105 caucasian patients with idiopathic Parkinson's disease (IPD) and 15 patients with diffuse Lewy body disease (DLBD). The mutations of the CYP 2D6 gene associated with the poor metabolizer (PM) phenotype of the debrisoquine/sparteine polymorphism were analyzed in DNA by a polymerase chain reaction (PCR)-based DNA amplification combined with Xba I restriction fragment length polymorphism (RFLP) analysis. The rate of genotypically defined PM and the frequencies of the mutation D6-B were not significantly different in IPD and DLBD patients. This study fails to find a relationship between CYP 2D6 impairment and neuropathological lesions diffusion in IPD and DLBD. This study cannot exclude involvement of neuronal expression of CYP 2D6.

Aged↗
PubMed1994

Octreotide in the management of orthostatic hypotension in multiple system atrophy: pilot trial of chronic administration.

The aim of the study was to determine the potential effect of octreotide chronic administration on the functional prognosis of patients suffering from multiple system atrophy (MSA) with orthostatic hypotension (OH). Five patients received octreotide (100 micrograms s.c. injections t.i.d.) during 6 months in an open trial. Patients experienced functional improvement after 6 months of treatment. All of them continued to receive octreotide after the 6-month evaluation period (mean duration: 12 months).

Aged↗
PubMed1993

Amiodarone N-deethylation in human liver microsomes: involvement of cytochrome P450 3A enzymes (first report).

Experiments were conducted on three different human liver samples to identify the cytochrome P450 isozyme which is involved in the biotransformation of the class III antiarrhythmic agent, amiodarone, into its major metabolite, desethylamiodarone (DEA). The classic P450 inhibitors, SKF 525A, metyrapone, and carbon monoxide provided a significant reduction in the in vitro formation of DEA by human hepatic microsomes. Amiodarone N-deethylase activities expressed by intrinsic clearance values were similar in all the livers used, although two livers were genotyped as extensive and one as a poor metabolizer for the cytochrome P450 CYP2D6 gene. DEA production was strongly inhibited (more than 80%) by the anti-P450 3A4 antibody, but not by anti-LKM1-positive serum. It seems therefore that the P450 3A subfamily is certainly implicated in human hepatic amiodarone N-deethylation.

Amiodarone↗
PubMed1993

Acute electrophysiological effects of intravenous milnacipran, a new antidepressant agent.

Milnacipran is a new antidepressant agent selected from a series of cycloproprane derivatives. The aim of this study was to investigate the acute electrophysiological effects and the tolerance of intravenous administration of this drug in 10 patients without any abnormality as shown in an electrophysiological study done for various complaints. Milnacipran was given over a 30-min period at doses of 0.2 mg/kg (2 patients), 0.4 mg/kg (2 patients) and 0.8 mg/kg (6 patients). The most significant alterations observed in this study were increases in heart rate (average of maximal increase: +19.5% at 50 min, P = 0.06) and systolic blood pressure (average of maximal increase: +21.5% at 10 min, P < 0.005), and decreases in the functional refractory period of the atrium (-3%, P < 0.05), the atrioventricular node (-9%, P < 0.005) and the effective refractory period of the right ventricle (-10.8%, P < 0.05) at 50 min. The sinus node function was improved in nine patients but depressed in one patient with previous slight baseline sinus node alterations. Milnacipran being devoid of both anticholinergic and monoamine oxidase inhibition activities, these alterations could be related to inhibition of noradrenaline uptake leading to an increase of adrenergic activities. No other ECG or electrophysiological parameters were significantly altered. Five of the 10 patients reported transient nausea, four of them for the highest dosage (0.8 mg/kg) and at the moment of peak of milnacipran plasma level. In conclusion, electrophysiological effects of intravenous milnacipran are negligible. These findings differ from those, well described in the literature, for imipramine-like antidepressant agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Effects of acute and chronic administration of acebutolol on the right ventricular effective refractory period in conscious dogs.

beta-Adrenergic blocking drugs are effective in reducing sudden cardiac death after acute myocardial infarction but the precise mechanism of this effect is unclear. We investigated the acute and chronic effects of acebutolol, a beta-adrenergic blocker, on electrocardiographic parameters, diastolic excitability threshold (DET), and right ventricular effective refractory period (RVERP) in chronically instrumented conscious dogs. These parameters were determined during spontaneous sinus rhythm and at a fixed pacing rate (200 beats/min). Acebutolol (0.5, 1, and 5 mg/kg i.v.) decreased the heart rate (HR) (by 23, 26, and 24%, respectively) without effects on any electrocardiographic parameters or on the DET. The maximal increases in ERP were 4.7, 7, and 7.8%, respectively, during pacing and 8.5, 13.3, and 10.3%, respectively, during sinus rhythm. Acebutolol, 10 mg/kg/day P.O. for 6 weeks, reduced the HR from the third day onward without altering the PR, QRS, QT, or QTc intervals or the DET. The increase in ERP was significant from the third day (14%) during pacing and from the seventh day (15.5%) during sinus rhythm. The degree of prolongation of the ERP subsequently remained stable during the 6 weeks of treatment. The ERP returned to the baseline value 7 days after acebutolol withdrawal. This increase in ERP, which was more marked during chronic oral treatment, could contribute to the documented protective effect of the beta-blocking drugs against sudden cardiac death after myocardial infarction.

Acebutolol↗
PubMed1993

Stereoselective hydroxylation of mexiletine in human liver microsomes: implication of P450IID6--a preliminary report.

Mexiletine, a class Ib antiarrhythmic drug, is used clinically as a racemic mixture of two enantiomers. Aromatic and aliphatic hydroxylation are the two major metabolic steps. In the liver, this metabolism is catalyzed by the cytochrome P450IID6, an isoenzyme of cytochrome P450 due to genetic polymorphism in humans. In the present study, the metabolism of the two stereoisomers was compared in vitro in human liver microsomes. Parahydroxylation (aromatic hydroxylation) is favored for S(+)-mexiletine with a mean intrinsic clearance higher than for R(-)-mexiletine. The R(-) enantiomer exhibits a threefold higher mean Vmax value for aliphatic hydroxylation than S(+)-mexiletine. We showed that (i) the high-affinity component of dextrometorphan O-demethylation was competitively inhibited by R(-)- and S(+)-mexiletine and that (ii) hydroxylations of the two enantiomers were very strongly competitively inhibited by quinidine. Hydroxylation reactions of mexiletine exhibit stereoselectivity in vitro in human liver microsomes and are catalyzed by P450IID6.

Cytochrome P-450 CYP2D6↗
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↗