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Biomedical subjects

P Jaillon

Publications and source records attributed to P Jaillon.

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

Relevance of intrinsic sympathomimetic activity for beta blockers.

Intrinsic sympathomimetic activity (ISA) characterizes a group of beta blockers that are able to stimulate beta-adrenergic receptors (agonist effect) and to oppose the stimulating effects of catecholamines (antagonist effect) in a competitive way. Partial agonists are ligands that elicit a submaximal response when bound to beta receptors at maximal occupancy. In the isolated rat atrium, acebutolol produces a maximal stimulatory effect that is only 17 +/- 8% of the maximal effect induced by the full beta agonist isoproterenol. The presence of ISA results in less resting bradycardia and less of a reduction in cardiac output than is observed with beta blockers without ISA. In the long term, partial beta agonists may produce arterial vasodilation and increase arterial compliance, possibly leading to additional beneficial effects in the treatment of hypertension. beta blockers with ISA do not have adverse effects on plasma lipoproteins during long-term treatment; in addition, the presence of ISA could counteract the up-regulation of beta adrenoceptors often observed with beta blockers without ISA. Finally, the presence of ISA has been a conflicting issue for the use of such beta blockers in secondary prevention after myocardial infarction. However, the impressive results of the Acebutolol Prevention of Secondary Infarction trial in high-risk patients after myocardial infarction show that acebutolol, a beta blocker with moderate partial agonist activity, can be effective in decreasing the postinfarction mortality rate. By exhibiting a strikingly different hemodynamic profile from that of beta blockers without ISA, the partial beta agonists form an intriguing pharmacologic class of drugs for which prospective clinical trials should be extensively pursued.

Acebutolol↗
PubMed1990

Effects of bepridil and CERM 4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers.

Bepridil is a calcium antagonist that prolongs the duration of ventricular repolarization, whereas CERM 4205, another calcium antagonist, seems to be devoid of any effect on QT interval. The aim of this study was to compare the effects of bepridil and CERM 4205 on the QT-RR relation at different heart rates during rest and exercise and the results of pharmacologic tests designed to vary neurovegetative tone. Twelve healthy men (21 to 37 years) participated in a placebo-controlled, randomized, crossover, double-blind study and received either bepridil (200 mg/day twice daily) or CERM 4205 (200 mg/day twice daily), or matching placebo during three 14-day treatment periods at 2-week intervals. Bepridil, but not CERM 4205, caused a significant prolongation of resting QT interval. The RR-QT relation was monoexponential for all subjects during resting and exercising physiologic conditions and remained unchanged after 14 days with placebo or CERM 4205. Bepridil significantly shifted the relation upward, resulting in a rate-dependent QT prolongation that predominated during bradycardia. After isoprenaline, QT no longer adapted to changes in heart rate, whereas atropine resulted in a rate-dependent shortening in QT. These results suggest that bepridil and CERM 4205 exert different effects on ventricular repolarization, since only bepridil significantly prolonged QT duration. Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia.

Adult↗
PubMed1990

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers.

The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg.kg-1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg.kg-1 i.v. of dl-sotalol. There was no significant difference in the disposition of the d-enantiomer and the racemate. The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l.h-1.kg-1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).

Administration, Oral↗
PubMed1990

Pharmacokinetics and metabolism of encainide.

The metabolism of encainide occurs in the liver and is polymorphically distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine. Over 90% of patients are extensive metabolizers (EM) in whom the oral bioavailability of encainide is only 30% because of extensive first-pass metabolism. In EMs, elimination t1/2 is about 2.5 hours, with a systemic clearance of 1.8 l/min. The plasma concentrations of the major metabolites O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethyl-encainide (3-MODE) are higher than those of encainide and have antiarrhythmic activity. The remaining patients (less than 10%) are poor metabolizers (PM), in whom the oral bioavailability is near 88% with an elimination t1/2 of 8-11 hours and a systemic clearance of 0.2 l/min. Encainide plasma concentrations are 10- to 20-fold higher than in EMs, but considerably less ODE and no 3-MODE is formed by the PMs. The conversion to the N-desmethyl-encainide (NDE) metabolite seems to be similar in both metabolizer groups, and plasma protein binding of encainide of 70-78% is also similar. During long-term treatment, the antiarrhythmic metabolites of encainide accumulate in the plasma, so that the relationships between the effect and plasma concentration on encainide, ODE, and 3-MODE are not always obvious. Minimally effective plasma concentrations appear to be approximately 300 ng/ml of encainide, 35 ng/ml of ODE, and 100 ng/ml of 3-MODE. Dose adjustment is necessary in patients with decreased kidney function, but not in patients with cirrhosis, in whom the plasma levels of metabolites appear to be comparable to those in normal subjects.

Anilides↗
PubMed1990

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients.

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.

Administration, Oral↗
PubMed1990

Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

Administration, Oral↗
PubMed1990

Pharmacokinetic characteristics of bornaprolol in healthy volunteers.

1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240, 480, 960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (C1), 207 l for volume of distribution (V beta), 2.6 h for elimination half-life (t1/2 beta). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 60 l/h for C1, 1500 l for V beta, 20 h for t1/2 beta. Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-10 min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.

Adrenergic beta-Antagonists↗
PubMed1990

Healthy volunteers data bank: where and how?

In order to improve safety for healthy volunteers to be included in phase I clinical trials, a national data bank will be set up and controlled by the French Ministry of Health. Each investigator responsible for an agreed phase I center will have a personal access code to the central computer in order to consult the national registry before including any healthy volunteer in a study. If the volunteer has already participated in a recent study, the investigator will find 2 important pieces of information in the data bank: the duration of the safety period following the preceding trial and during which the subject is not allowed to participate in another study; the total amount of money received by the subject during the last 12 months in grants for phase I studies; this amount will be limited by the Ministry of Health. This healthy volunteer data bank will decrease the risk of drug interaction and will improve safety in phase I trials. However, many practical and ethical problems remain to be solved.

Databases, Factual↗
PubMed1989

Recent antiarrhythmic drugs.

Clinical failure of antiarrhythmic drugs often occurs in practice. Therefore, there is a need for new, effective and long-acting drugs with a wide therapeutic range and a low level of toxicity. Most new class I compounds block the fast sodium ion inward current of myocardial cells. According to their effects on the recovery kinetics of the sodium ion channel, these drugs are classified into 3 groups: IA (intermediate--cibenzoline, pirmenol, hydroxy-3-S-dihydroquinidine, quinacainol); IB (fast--tocainide, moricizine); IC (slow--flecainide, encainide, propafenone, lorcainide, indecainide, recainam and penticainide). Class IC drugs greatly depress intracardiac conduction and are the most potent antiarrhythmic compounds able to suppress ventricular premature beats. However, it is doubtful that long-term suppression of ventricular arrhythmias will improve survival of the patients. Some new drugs have been developed belonging to other classes: class II, esmolol, a new ultrashort-acting beta blocker; class III, N-acetyl-procainamide and sotalol, which prolong duration of the action potential and increase ventricular refractoriness; class IV, the mixed sodium ion-calcium ion-potassium ion antagonist, bepridil. The pharmacologic properties and the clinical effects of these new antiarrhythmic drugs are reviewed. However, future therapeutic trends will depend on the results of large multicenter clinical secondary prevention trials such as the Cardiac Arrhythmia Suppression Trial. New antiarrhythmic drugs with original electrophysiologic profiles and minimal adverse effects must prove their ability not only to suppress arrhythmias but also to reduce sudden cardiac death rate.

Animals↗
PubMed1989

Physiologic relation between cardiac cycle and QT duration in healthy volunteers.

To determine the relation between QT duration and RR interval on the electrocardiogram, 2 studies were undertaken in 23 young healthy volunteers (mean age 24 years). In study 1, the electrocardiogram (paper speed at 50 mm/s, 800 measurements/subject) was recorded in 11 subjects (5 men, 6 women) at rest, during dynamic exercise and after rapid intravenous injections of isoproterenol (0.2 to 12.8 micrograms), before and after intravenous atropine (2 mg). In study 2, the QT-RR relation was studied at rest and during exercise in 12 subjects (6 men, 6 women) before and after oral propranolol (80 mg). The results confirmed a monoexponential individual relation of the QT and RR intervals during rest and exercise: QT = A-B.Exp (-k.RR). By pooling the RR-QT plots from the 11 subjects in study 1, we found that the measured QT interval = 425-676.Exp (-3.7.10(-3) RR. During isoproterenol-induced tachycardia, QT either did not change or increased and this may indicate an increase in temporal dispersion of ventricular repolarization. Atropine-induced tachycardia produced changes similar to those resulting from exercise testing. Propranolol did not change the QT-RR relation despite a lengthening in RR intervals. These results suggest that physiologic QT-RR adaptation is mainly under parasympathetic control.

Adrenergic beta-Agonists↗
PubMed1989

Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients.

Nalbuphine is a new agonist and antagonist opioid analgesic agent that undergoes an important hepatic metabolism. In this study, we compared the pharmacokinetics of intravenous and oral nalbuphine in three groups of subjects: group I consisted of 14 children from 1 1/2 to 5 years of age (group IA) and from 5 through 8 1/2 years of age (group IB), group II consisted of 9 healthy male volunteers from 23 to 32 years of age, and group III consisted of 9 elderly patients from 65 to 90 years of age. All subjects and patients had normal hepatic and renal functions. The children received an intravenous injection of nalbuphine (0.2 mg/kg), and the subjects and patients in groups II and III received, at random, 10 mg intravenous injections and 30 mg oral doses of nalbuphine on two separate occasions. The distribution of nalbuphine was not modified with age. Elimination half-life (t1/2) was significantly shorter in group I (0.9 hour) than it was in group II (1.9 hours) and in group III (2.3 hours). Systemic clearance of nalbuphine decreased significantly with age. Absolute bioavailability of nalbuphine increased from F = 12% in group II to 46.3% in group III (p less than 0.01). These findings suggest that doses and rates of administration of nalbuphine should be adapted in younger patients and in elderly patients.

Administration, Oral↗
PubMed1989

Pharmacokinetics of amoxycillin/clavulanic acid in serum and ascitic fluid in cirrhotic patients.

A combination of amoxycillin and clavulanic acid (Augmentin) might be useful for first-line treatment of spontaneous bacterial peritonitis in patients with cirrhosis. We have studied the pharmacokinetics of amoxycillin/clavulanic acid in serum and ascitic fluid of six cirrhotic patients. A total of 66 simultaneous serum and ascitic samples were analysed. Following iv injection of 1 g amoxycillin plus 0.2 g clavulanic acid, the ascites to serum AUC ratio was 1.38 for amoxycillin and 1.01 for clavulanic acid, indicating a good distribution of these drugs into the ascitic fluid. In this study, experimental data were fitted to a three compartment body model which revealed that the prolonged serum half-lives of amoxycillin (274 min) and clavulanic acid (200 min) were probably due to the slow return from the ascitic compartment.

Adult↗
PubMed1989

Effects of falipamil (AQ-A 39) on heart rate and blood pressure in resting and exercising healthy volunteers.

Falipamil (AQ-A 39) is a new verapamil derivative which exerts antitachycardic effects by a direct action on the sinus node. Its effects on heart rate (HR), blood pressure (BP) and ECG intervals were studied in 12 healthy volunteers, at rest and during bicycle exercise tests. In a double-blind, cross-over, single-dose study, the effects of falipamil (100 and 200 mg) during 8-h post-dosing were compared with those of placebo. Falipamil did not modify resting HR, BP, and electrocardiogram (ECG) intervals significantly. Maximal exercise HR significantly decreased by 5.3 +/- 2.9 (SD)% and 11.2 +/- 3.6% 2 h after the 100- and 200-mg dose respectively, whereas placebo had no effect. Exercise BP was not significantly modified by falipamil. The slopes of HR-workload relationships significantly decreased with falipamil. Peak plasma concentrations of falipamil occurred 1-1.5 h after absorption, and the falipamil-induced decrease in exercise HR over 8 h postdosing was proportional to falipamil plasma concentrations. These results suggest that falipamil decreases HR at exercise in normal subjects and may exert antianginal effects in patients with myocardial ischemia.

Adult↗
PubMed1989

Comparative hemodynamic study of a new aminosteroid: LND-623 with its 20 alpha-isomer: LND-369, and with digoxin and digoxigenin-rhamnoside in the anesthetized dog.

Hemodynamic effects of LND-623, a new aminosteroid lacking the C17 lactone ring and the C14 hydroxyl group common to the natural glycosides, were studied in the pentobarbital-anesthetized dog and compared to those of its 20 alpha-isomer LND-369 and of digoxin and digoxigenin-rhamnoside (DRh). Twenty-four mongrel dogs were divided into 4 groups. Group I received either LND-623 or saline on study day 1 and the other drug or saline 1 wk later. Saline was replaced by digoxin in group II, digoxigenin-rhamnoside in group III, and LND-369 in group IV. All drugs except LND-369 were infused as 3.10(-9) mol.kg-1.min-1 over 20 minutes. LND-369 was infused at twice the dose. LND-623 increased left ventricular dP/dt for at least 3 h with a peak at end-infusion or 15 min later, accompanied by a transient vasopressor effect. LND-369 induced, at twice the dose, an inotropic effect of comparable magnitude but of shorter duration. Inversely, it provoked a more marked and prolonged vasopressor effect than its 20 beta-isomer, LND-623. Maximal digoxin inotropic effect occurred later but was of comparable magnitude to that induced by LND-623. Its vasopressor effects reached a plateau rapidly and remained sustained until min 200. Digoxigenin-rhamnoside inotropic but not vasopressor effects are weaker than those of LND-623. It is concluded that LND-623, although lacking the most common structural features of the natural cardiac glycosides, provoked rapid and sustained inotropic activities with transient vasopressor effects. These time-course effects differ from digoxin, and these differences are unrelated to their sugar-moiety characteristics. LND-623 inotropic effect is twice as potent as its 20 alpha-isomer.

Anesthesia↗
PubMed1989

Pharmacokinetics and effects on exercise heart rate of PK 11195 (52028 RP), an antagonist of peripheral benzodiazepine receptors, in healthy volunteers.

PK 11195 (or 52028 RP; 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide), an antagonist of the peripheral-type benzodiazepine receptors which are coupled to calcium channels, was administered to 10 healthy volunteers in order to study the pharmacokinetics and cardiovascular effects of the drug. PK 11195 was randomly administered intravenously (10 mg) and orally in three single dosages (100, 200 and 400 mg). Placebo was only given orally. Heart rate and blood pressure were recorded at rest and during exercise tests which were performed at 0, 1, 3, 6 and 24 h after dosing on each study day. The results showed that after IV administration, PK 11195 was rapidly distributed in two or three open compartments. Its elimination T 1/2 was short (3.7 +/- 3.0 h) with high interindividual variability. After oral ingestion the pharmacokinetics of PK 11195 were linear over the range of 100-400 mg single oral doses with a stable absolute bioavailability (33%). T 1/2 elimination was prolonged (7-12 h) and the presence of secondary increases in plasma concentration at 8-10 h and 22-24 h after drug absorption may have been related to enterohepatic cycling. No unchanged PK 11195 could be detected in urine. PK 11195 did not significantly modify heart rate and blood pressure at rest or during exercise and was well tolerated by the subjects. These data suggest a high inter-individual variability in PK 11195 disposition with extensive metabolism in normal exercising volunteers.

Administration, Oral↗
PubMed1989

Evidence of the intact hepatocyte theory in alcoholic cirrhosis.

To improve our understanding of the predominant operational model involved in the decreased clearance in cirrhosis, hepatic clearance, the extraction ratio of indocyanine green, and liver plasma flow were estimated in cirrhosis, either with a method based on the Fick principle or with a pharmacokinetic method assuming a bicompartmental plasma elimination of the dye. The two methods gave similar values for clearance. In contrast, the pharmacokinetic analysis gave significantly (p less than 0.01) lower hepatic plasma flow values and significantly (p less than 0.01) higher extraction values than those obtained with the reference (Fick principle) method. The main finding of this work is that in these cirrhotic patients, as in normal subjects, 'cellular' extraction estimated by the pharmacokinetic method is in the range of 0.60-0.80, whereas the extraction by the entire liver, assessed by the reference method, is low. In chronic liver diseases such as cirrhosis these data support the predominance of the intact hepatocyte theory, which assumes the existence of intrahepatic shunts associated with normally perfused and normally extracting hepatocytes. In acute liver disease, a cellular damage could be superadded.

Adult↗