Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Article in English | MEDLINE | ID: mdl-15151172

ABSTRACT

The pharmacokinetics of immediate (IR) and modified release (MR) trimetazidine (TMZ) in dogs and pigs, have been compared under single dose conditions, then predicted at steady-state under conditions mimicking an actual human pharmacokinetic study. In both animal species, the MR tablet has demonstrated sustained release properties, as assessed by delayed time to peak and increased mean absorption times. Multiple dose simulations in dogs revealed a delayed time to peak (3.0 vs. 1.0 h), a decrease in peak plasma concentration (544 vs. 659 microg/L), an increase in trough concentrations (115 vs. 63 microg/L), a decrease in peak-trough fluctuation (141 vs. 193%), and an increase in plateau time (5.5 vs. 4.9 h). Qualitatively similar changes were simulated in pigs. These properties have then been verified in humans where a TMZ MR 35 mg b.i.d regimen did provide similar total exposure, increased plateau time (11 vs. 4 h), decreased peak-trough fluctuation (86 vs. 121%), a 31% increase in trough concentrations, and no increase in inter-individual variability as compared to a TMZ IR 20 mg t.i.d. regimen. Furthermore, the TMZ MR 35 mg b.i.d. regimen is likely to result in improved patient compliance and better patient anti-ischemic protection in the early morning.


Subject(s)
Trimetazidine/administration & dosage , Trimetazidine/pharmacokinetics , Administration, Oral , Adult , Animals , Chemistry, Pharmaceutical , Cross-Over Studies , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Dogs , Drug Evaluation, Preclinical/methods , Humans , Male , Species Specificity , Swine
2.
Clin Pharmacol Ther ; 69(3): 122-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11240976

ABSTRACT

OBJECTIVE: Our objective was to compare the sympathetic modulation induced by oral administration of a single dose of 20 mg of standard nifedipine, of 10 mg of amlodipine, and of 100 mg of mibefradil. METHODS: Sixteen healthy male volunteers participated in this double-blind, randomized, placebo-controlled, crossover four-period study. The sympathetic modulation induced by treatments was evaluated during 24 hours after drug administration by neurohormonal dosages, hemodynamic parameter measurements, and spectral analysis of heart rate and blood pressure. RESULTS: We observed a significant (P <.05) decrease in diastolic blood pressure 1 hour after the administration of nifedipine (62 +/- 9 to 59 +/- 5 mm Hg) with concomitant increases in heart rate (59 +/- 5 to 74 +/- 8 bpm) and neurohormones (53 +/- 18 to 83 +/- 50 pg/mL for aldosterone, 157 +/- 56 to 282 +/- 119 pg/mL for norepinephrine, and 9.8 +/- 5.5 to 40.2 +/- 97.1 pg/mL for active renin). No significant modification of these parameters was observed with amlodipine and mibefradil, except an isolated increase of norepinephrine plasma level 2 hours after the administration of mibefradil (133.1 +/- 67.1 to 210.9 +/- 92.5 pg/mL). The spectral analysis over 24 hours of Mayer waves of systolic blood pressure did not show any significant change over time in the different groups. When the analysis was performed during the first 4 hours after treatment administration, we observed a decrease of Mayer waves of systolic blood pressure with nifedipine (2.21 +/- 1.45 mm Hg(2) versus 3.53 +/- 1.85 mm Hg(2) with placebo). These results indicate that oral single doses of mibefradil and amlodipine do not induce baroreflex-mediated clinical changes in healthy volunteers. The single oral dose of nifedipine resulted in a marked increase in sympathetic tone and a decrease in systolic blood pressure variability early after oral administration. CONCLUSION: Mibefradil, the nondihydropyridine calcium antagonist, exerts much less sympathetic stimulation than nifedipine.


Subject(s)
Amlodipine/pharmacology , Calcium Channel Blockers/pharmacology , Hemodynamics/drug effects , Mibefradil/pharmacology , Nifedipine/pharmacology , Sympathetic Nervous System/drug effects , Administration, Oral , Adult , Aldosterone/blood , Cross-Over Studies , Double-Blind Method , Electrocardiography/drug effects , Epinephrine/blood , Humans , Male
3.
Clin Pharmacol Ther ; 68(6): 658-66, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11180026

ABSTRACT

BACKGROUND: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers. METHODS: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral doses (400 mg and 800 mg) of moxifloxacin or placebo. At the time of expected moxifloxacin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT interval and the corresponding RR interval value were measured within a wide range of RR intervals in each subject. RESULTS: ANOVA showed that both moxifloxacin doses increased mean QT intervals compared with placebo. The mean QT interval duration at RR = 1000 ms was 379 +/- 24 ms during placebo, 394 +/- 33 ms during moxifloxacin 400 mg (P < .05), and 396 +/- 28 ms during moxifloxacin 800 mg (P < .05). Moxifloxacin-induced QT interval prolongation remained significant at all tested heart rates. The increase in QT interval duration relative to placebo remained between 2.3% +/- 2.8% and 4.5% + 3.8% across the range of RR intervals tested. CONCLUSION: Moxifloxacin prolongs QT interval duration. The amplitude of this effect is small, and the risk of moxifloxacin-induced torsades de pointes is expected to be minimal when the drug is administered at the recommended dose of 400 mg/d. However, moxifloxacin should not be used in patients with predisposing factors of torsades de pointes such as electrolyte disturbances and bradycardia or during coadministration of proarrhythmic drugs.


Subject(s)
Anti-Infective Agents/adverse effects , Aza Compounds , Fluoroquinolones , Quinolines , Ventricular Function/drug effects , Administration, Oral , Adult , Anti-Infective Agents/blood , Anti-Infective Agents/pharmacokinetics , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Electrocardiography/drug effects , Exercise Test/drug effects , Female , Heart Conduction System/drug effects , Heart Conduction System/physiology , Humans , Infusions, Intravenous , Male , Moxifloxacin , Placebos , Ventricular Function/physiology
4.
Fundam Clin Pharmacol ; 13(4): 501-7, 1999.
Article in English | MEDLINE | ID: mdl-10456293

ABSTRACT

The present trial was planned to study the effects of smoking on short-term variability of blood pressure and on haemodynamic parameters after an overnight cessation and after one day of repeated smoking in healthy cigarette smoking volunteers, compared to a control group of non-smokers who were not asked to smoke. 40 healthy male volunteers, 20 smokers and 20 non-smokers, participated in an open study with two period of measurements over a single day (morning and afternoon). Blood pressure and heart rate were measured using standard and finger recordings over 6 min before and 10 min after smoking one cigarette (in smokers only). During the two periods, smokers were asked to smoke 4 cm of a cigarette containing 1 mg of nicotine in 2 min, and a blood sample was taken for a plasma nicotine assay. In the smoking group, smoking the first cigarette of the day caused a significant increase of systolic blood pressure (+7%), diastolic blood pressure (+10%) and heart rate (+25%). The blood pressure variability in the frequency range of the Mayer waves (66-129 mHz) was increased after an overnight cessation of smoking in the smoking group in comparison to the non-smokers, and decreased significantly after the first cigarette of the day (7.1 +/- 4.0 to 3.2 +/- 1.8 mmHg2; P < 0.01). The changes observed in the afternoon after continuous smoking were significantly less important (3.8 +/- 1.9 to 3.2 +/- 1.9 mmHg2; NS). In the non-smoking group, the different parameters remained stable between the different measurements. These results suggest that an overnight cessation of smoking in smoking subjects is associated with a increase in sympathetic activity to the vascular system in the morning, which is released by smoking the first cigarette. This effect of smoking is reduced in the afternoon after a continuous nicotinic impregnation.


Subject(s)
Blood Pressure , Smoking/physiopathology , Adult , Heart Rate , Humans , Male , Nicotine/blood , Smoking/blood , Smoking Cessation
5.
Br J Clin Pharmacol ; 44(4): 403-9, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9354317

ABSTRACT

AIMS: Tedisamil is a new blocker of K+ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a beta-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests. METHODS: The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers. RESULTS: This study showed that tedisamil exerted a significant (P<0.05) bradycardic action at rest (-10 beats min(-1); 95% CI: -6 to -15 beats min(-1)) similar to atenolol (-14 beats min(-1); -11 to -17) and drug combination (-9 beats min(-1); -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (-42 beats min(-1); -37 to -47) and combination (-47 beats min(-1); -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000 ms, but not at RR<700 ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation. CONCLUSIONS: These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Anti-Arrhythmia Agents/pharmacology , Atenolol/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cyclopropanes/pharmacology , Electrocardiography/drug effects , Heart Rate/drug effects , Adrenergic beta-Antagonists/pharmacokinetics , Adult , Anti-Arrhythmia Agents/adverse effects , Anti-Arrhythmia Agents/pharmacokinetics , Area Under Curve , Atenolol/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cyclopropanes/adverse effects , Cyclopropanes/pharmacokinetics , Diarrhea/chemically induced , Drug Combinations , Exercise Test , Half-Life , Humans , Male , Metabolic Clearance Rate
6.
Circulation ; 94(7): 1592-9, 1996 Oct 01.
Article in English | MEDLINE | ID: mdl-8840849

ABSTRACT

BACKGROUND: The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects. METHODS AND RESULTS: Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax-QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P < .01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P < .05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate. CONCLUSIONS: Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.


Subject(s)
Electrocardiography , Heart Rate/drug effects , Phenethylamines/pharmacology , Physical Exertion , Sulfonamides/pharmacology , Adult , Anti-Arrhythmia Agents/pharmacology , Cross-Over Studies , Double-Blind Method , Humans , Male , Osmolar Concentration , Phenethylamines/blood , Reaction Time/drug effects , Sulfonamides/blood , Time Factors
7.
Br J Clin Pharmacol ; 42(3): 394-7, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8877033

ABSTRACT

Sertraline is a serotonin reuptake inhibitor. The enhancement of serotoninergic transmission is associated with antidepressant activity. In order to determine the pharmacokinetics of sertraline in patients with chronic stable hepatic insufficiency, 10 patients were matched (age, weight, sex) with 10 healthy subjects in an open study. Each participant received a single capsule containing the equivalent of 100 mg sertraline base. Blood samples were taken during 264 h after administration for measurement of plasma concentrations of sertraline. The results confirm that the oral clearance of sertraline is reduced with a 1.7-fold increase in Cmax and a significant prolongation in elimination half-life in hepatically impaired patients.


Subject(s)
1-Naphthylamine/analogs & derivatives , Antidepressive Agents/pharmacokinetics , Liver Cirrhosis/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , 1-Naphthylamine/pharmacokinetics , Adult , Aged , Female , Humans , Male , Middle Aged , Sertraline
8.
Br J Clin Pharmacol ; 41(6): 499-503, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8799513

ABSTRACT

1. Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate-dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes. 2. A double-blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400 mg) on the QT interval at various heart rates. 3. 12-lead ECGs were recorded at rest and during exercise tests 5 h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT-RR curve fitting. 4. Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate-dependence of QT interval prolongation was observed. 5. Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.


Subject(s)
Anti-Infective Agents/pharmacology , Fluoroquinolones , Heart Rate/drug effects , Quinolones/pharmacology , Ventricular Function/drug effects , Administration, Oral , Adult , Anti-Infective Agents/adverse effects , Double-Blind Method , Electrocardiography , Exercise Test , Humans , Male , Quinolones/administration & dosage , Quinolones/adverse effects , Quinolones/blood
9.
J Cardiovasc Pharmacol ; 22(5): 711-6, 1993 Nov.
Article in English | MEDLINE | ID: mdl-7506323

ABSTRACT

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.


Subject(s)
Epoprostenol/analogs & derivatives , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation/drug effects , Administration, Oral , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Epoprostenol/blood , Epoprostenol/pharmacokinetics , Epoprostenol/pharmacology , Half-Life , Humans , Intestinal Absorption , Male , Platelet Aggregation Inhibitors/blood
SELECTION OF CITATIONS
SEARCH DETAIL
...