Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects.

OBJECTIVES: A new, ready-to-use solution for injection of paracetamol (Perfalgan 10 mg/ml) without previous reconstitution has been developed. The aim of the study was to determine the serum concentration profiles of paracetamol after 15 min infusion of Perfalgan 0.5 g and 1 g doses and to demonstrate the bioequivalence between Perfalgan 1 g dose and a marketed reference formulation for injection, propacetamol 2 g (Pro-Dafalgan 2 g) equivalent to 1 g of paracetamol. The secondary objective was to evaluate local tolerance, and clinical and biological safety. METHODS: The study was performed in 24 healthy, male volunteers, according to an open-label, randomized, single-dose, 3-period crossover design, with a 1-week washout period between the doses. Blood samples were taken prior to each administration and at 18 time points within the 24-hour period following the beginning of each infusion. Serum concentrations of paracetamol were determined by validated high-performance liquid chromatography with UV detection. From serum concentration-time data, a non-compartmental pharmacokinetic analysis was performed to calculate Cmax, tmax, AUC(inf), t(1/2), MRT, Cl(T) and Vd. Log-transformed AUC(inf) and Cmax were tested for bioequivalence. The local pain intensity at infusion site was assessed using a 4-point categorical scale from 0 (none) to 3 (severe). The clinical and biological safety was evaluated by physical examination with measurements of vital signs and ECG and laboratory tests including hematology and biochemistry. RESULTS: After infusion of 0.5 g and I g of the new paracetamol solution, C(max) and AUC(inf) increased proportionally with dosage. After dose correction to 1 g of paracetamol, the mean (+/- SD) Cmax ratio was 0.98 +/- 0.24 and 0.94 +/- 0.08 for AUC ratio. Identical t(max) was observed for the 2 paracetamol dosages and 90% confidence intervals for t(1/2), MRT, Cl(T) and V(d) were within the acceptable interval 0.8-1.25. The calculated 90% confidence intervals of the new solution (Perfalgan 1 g) to marketed solution (propacetamol 2 g) ratios were 1.11-1.31 (point estimate 1.20) for C(max) and 1.10-1.16 (point estimate 1.13) for AUC(inf). These values were within the acceptable bioequivalence intervals of 0.75 to 1.33 for Cmax and 0.80-1.25 for AUC(inf). Application site disorders were the most frequently observed adverse events but local pain at infusion site was less reported by subjects after Perfalgan (2%) compared to propacetamol (20%). The clinical and biological safety was good and equivalent for the 3 treatments. CONCLUSION: After administration of paracetamol solution for injection 0.5 g and 1 g, the pharmacokinetics of paracetamol is linear. All results indicate that 1 g of paracetamol administered as Perfalgan 10 mg/ml is bioequivalent to propacetamol 2 g with a better local safety.

Capillary gas chromatographic method for the measurement of small concentrations of monoethylglycinexylidide and lidocaine in plasma.

The major metabolite of lidocaine, monoethylglycinexylidide (MEGX) is currently used as a dynamic marker of liver function. It has been proven, in recent advances, that the determination of MEGX formation after intravenous injection of lidocaine was an effective means of assessing liver dysfunction in critically ill patients. An accurate and sensitive gas chromatographic method has been developed for the determination of small quantities of MEGX formed in such cases. The procedure involves a solid-phase extraction and injection of the extract (splitless mode) into a gas chromatograph equipped with a capillary column and nitrogen-phosphorus detector. The limit of detection is 1 ng/ml and the limit of quantification is 2.5 ng/ml. The response is linear up to 50 ng/ml. The inter- and intra-assay coefficients of variation for MEGX and lidocaine are between 5 and 9%. This method can be used for the determination of small concentrations of MEGX in plasma and could be applied to analysis of small amounts of many other nitrogenous molecules.

Compound heterozygosity Hb S/Hb Hope (beta 136 Gly-->Asp): a pitfall in the newborn screening for sickle cell disease.

The presence of Hb Hope associated with Hb S may represent a pitfall (false positive) in the neonatal detection of sickle cell disease by two of the most widely used analytical methods in screening programmes-isoelectric focusing (IEF) and high performance liquid chromatography (HPLC). This example illustrates the need to improve analytical strategies to avoid unnecessary anxiety and summoning of families often from a cultural background in which testing of the father is difficult to obtain. It is suggested that using two independent HPLC procedures might improve the specificity of the screening strategies. Additionally, simple procedures for detection of the most common mutations of the beta globin gene of DNA extracted from dried blood specimens could be easily developed for the control of abnormal samples. These procedures could be introduced into the analytical strategy.

Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics.

OBJECTIVE: Administration of interleukin-6 partially reproduces the inhibitory effects of the acute-phase response on cytochrome P450-dependent drug metabolism. The aim of the study was to determine whether endogenous cytokine has such an effect in patients treated by cyclosporine, which is metabolized by the cytochrome P4503A subfamily. METHODS: Blood cyclosporine and serum interleukin-6 levels were determined in six patients undergoing bone marrow transplantation, as long as they received cyclosporine by continuous infusion. Two serum acute-phase proteins, C-reactive protein and alpha 1-acid glycoprotein, and two cyclosporine metabolites, AM1 and AM9, were also determined. RESULTS: At the time of marrow infusion, levels of specific markers of inflammation were low. A peak in interleukin-6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C-reactive protein levels. A parallel twofold increase in AM1 concentrations was observed, followed by a three-fold increase in cyclosporine levels, which peaked 4.8 days after interleukin-6. The times of peak cyclosporine and AM1 levels correlated with the time of peak interleukin-6 levels. AM9 was detectable in three patients but concentrations fell when interleukin 6 became detectable. CONCLUSIONS: An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.

Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects.

The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 x 2.5 mg) and long-acting furosemide (2 x 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 +/- 1.6 years and weighing 68.8 +/- 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 +/- 1.04 h after the combination treatment and 2.76 +/- 0.98 h alone, amiloride plasma half-life was respectively 15.7 +/- 4.6 h and 14.6 +/- 3.7 h. The urinary elimination of furosemide was significantly higher in the 2-4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (P less than 0.01) and the potassium excretion was significantly decreased (P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.

[Treatment with sustained theophylline release. Monitoring by salivary assay in children]. / Traitement par théophylline à libération prolongée. Surveillance par dosage salivaire chez l'enfant.

We have tested the possibility of replacing plasma assays by salivary assays of theophylline for the monitoring of sustained-release theophylline therapy in asthmatic children. In a first group of 40 children aged 7.2 +/- 3.3 years (mean +/- SD) treated with sustained-release theophylline in mean daily doses of 18.8 +/- 5 mg/kg, 77 plasma and saliva samples were taken simultaneously 6 hours after the morning dose (6 H). Saliva was collected after mouth-wash and stimulation with 10 mg of citric acid. Assays were performed using the EMIT method. Theophylline plasma concentrations (P) and salivary concentrations (S), both expressed as mumol/l, were found to correlate: P = 1.58 S + 8.7 (P less than 0.0001). In a second group of 33 children, 39 simultaneous samples were taken at 6 H. From the equation previously obtained the plasma concentration corresponding to each salivary concentration was calculated, and the calculated value was compared with the measured value. The difference between the two values was 7.1 +/- 9 mumol/l. On this basis, and because the method is non-invasive and painless, were are now using salivary assays (under strict conditions of collection and measurement) to verify the patients' compliance and to maintain or adjust dosage in asthmatic children.

[Application of a method of analysis using high performance liquid chromatography of isoniazid and acetylisoniazid to determine the phenotype of acetylation]. / Application d'une méthode de dosage de l'isoniazide et de l'acétylisoniazide par chromatographie liquide haute performance à la détermination du phénotype d'acétylation.

The described method is adapted from Moulin to measure plasma levels of isoniazid (INH) and acetylisoniazid (AINH) after extraction, HPLC separation and UV detection (254 nm). INH and AINH plasma levels of 109 patients aged between four months to 87 years were measured, allowing dosage individualization. The ratio of AINH to INH (Rm) three hours after administration was calculated. Rm allows determination of the patient acetylation phenotype: in fast acetylators with INH half-life shorter than 1.8 h, Rm is greater than 0.77 and in slow acetylators with INH half-life longer than 1.8 h, Rm is less than 0.48.

Hemodynamic and pharmacokinetic study of propranolol and atenolol in cirrhosis patients.

The pharmacokinetic properties of propranolol and atenolol were evaluated both in 9 patients with cirrhosis and in 12 healthy subjects. The hemodynamic effects of the drugs were evaluated separately in the cirrhotic patients. Propranolol and atenolol significantly decreased wedged hepatic venous pressure and cardiac output in cirrhotic patients. Propranolol Cmax, tmax and AUC were significantly increased and plasma half-life was significantly prolonged in cirrhotic patients. In contrast, the corresponding pharmacokinetic values of atenolol were not significantly different in cirrhotic patients and in healthy subjects.

Comparison of changes in the characteristics of beta-adrenoceptors and responsiveness of human circulating lymphocytes during and after chronic administration of pindolol and propranolol.

The characteristics of the beta-adrenoceptors (3H-dihydroalprenolol binding) and the beta-adrenergic responsiveness (cyclic AMP response to isoproterenol) were studied in circulating lymphocytes from healthy volunteers before (D 0), on the 22nd day of treatment (D 22) and on the fifth day (D 30) following discontinuation of pindolol 15 mg/day or propranolol 160 mg/day. During pindolol therapy (D 22) the beta-adrenoceptor-affinity towards dihydroalprenolol was unchanged and the beta-adrenoceptor density decreased by 50%, an effect which persisted after drug administration ceased (D 30). The receptor "down-regulation" was accompanied by a parallel decrease in the maximal lymphocyte response to isoproterenol on D 22 and 30, by a shift to the right of the concentration-response curves to isoproterenol on D 22 and 30. In contrast, no significant modification in beta-adrenoceptor density or in the maximal response to isoproterenol was observed during (D 22) or after discontinuation (D 30) or propranolol therapy; the beta-adrenoceptor affinity for dihydroalprenolol and the sensitivity of the lymphocyte response to isoproterenol were markedly reduced on D 22 but not on D 30. It is concluded that the lymphocyte beta-adrenoceptor "down regulation" and the parallel beta-adrenergic desensitization induced by chronic pindolol therapy are both due to the intrinsic sympathomimetic activity of this drug.