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.

[Biomarkers for toxicity and metabolic abnormalities of the main severe poisonings. Clinical and toxicologic symptoms. Conservative determination]. / Biomarqueurs de toxicité et anomalies métaboliques dans les principales intoxications graves. Symptomatologie clinique et toxique. Le prélèvement conservatoire.

The members of the joint group "Toxicology and Clinical Biology" of the French Society of Clinical Biology (SFBC), the French Society of Analytical Toxicology (SFTA), and the Society of Clinical Toxicology (STC), suggest guidelines to meet the requirements of clinical biologists who are not specialized in toxicology. Based on good laboratory practice they propose a number of guidelines. Three synthetic tables have been established. They are not only toxicity biomarkers and metabolic disorders associated with the main severe intoxications, but also clinical signs that are observed during these intoxications, finally biological sampling as a precautionary measure. The table also takes into account approximately fifty xenobiotics: main clinical signs emergency, identification or quantification of the suspected product, useful biological markers, therapeutic, quantitations necessary to take into consideration patient care, and poison antidotes, are described. Recommendations regarding medical and forensic techniques are also proposed by the group. It is also necessary to collect and store biological samples when the individual patients are in charge. These samples will be analyzed or not depending on the individual case history.

Use of midodrine (Gutron) to treat permanent hypotension in a chronic hemodialysis patient.

Chronic hypotension, infrequent though possible in chronic renal failure patients on hemodialysis, has harmful consequences on their physical state and hence general well-being. These patients often experience acute intradialytic manifestations while non-pharmacologic interventions as pharmacologic agents are sometimes insufficient to improve symptoms. Well tolerated, midodrine appears to be a suitable and effective agent as it raises blood pressure significantly via its effect on peripheral alpha-adrenergic receptors. The authors describe their use of midodrine in a dialysis patient for the longest period of time reported up to now, documented by a pharmacokinetic study, confirming long-term both clinical efficacy and safety of the drug.

[Simultaneous quantitative determination of amprenavir and indinavir in human plasma by high-performance liquid chromatography]. / Détermination simultanée de la concentration plasmatique de l'amprénavir et de l'indinavir par chromatographie liquide haute performance.

A reversed-phase high-performance liquid chromatographic assay for the determination of the HIV protease inhibitors amprenavir (Agenerase) and indinavir (Crixivan) in human plasma is described, using a mobile phase consisting of 0.50 M phosphate buffer (adjusted to pH 5,5) - Milli-Q water - acetonitrile (120: 1,080: 800, v/v/v). A solid-phase extraction using C18 extraction columns (Discovery columns 100 mg, 1 ml Supelco) and a liquid-liquid extraction with 0.5 ml hydrogenocarbonate/carbonate buffer (adjusted to pH 10.6) and 6 ml methyl ter-butyl ether have been compared. The liquid-liquid extraction has been chosen to be easier and cheaper. The method has been validated over the range of 60 to 3,000 ng/ml for amprenavir and 20 to 3,000 ng/ml for indinavir using a 0.5 ml sample volume. The specificity, linearity, accuracy and precision have been studied. The limit of detection was respectively for amprenavir and indinavir 15 and 4 ng, and the limit of quantification was 60 and 20 ng/ml. Stability tests under various conditions were performed. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of amprenavir in HIV-infected patients. The trough plasma concentrations average has been determined in patients treated by amprenavir and indinavir for seven months.

[Midodrine (Gutron) treatment of permanent arterial hypotension in a chronic hemodialysis patient]. / Traitement par midodrine (Gutron) de l'hypotension artérielle permanente d'un patient hémodialysé chronique.

Chronic hypotension, although unfrequent in uremic patients on hemodialysis, accentuates the deterioration of patients physical state and thus, their general well-being. These patients often experience acute intradialytic symptoms and respond very poorly to conventional therapies. Well tolerated, midodrine is a suitable and effective choice as it raises blood pressure significantly through its effect on peripheral alpha-adrenergic receptors. The authors report observing the use of midodrine by a dialysis patient during the longest time period published to date, documented by a pharmacokinetic study, and that confirms the excellent results and proves long term tolerance for that drug.

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.

[Impact of the method and timing of administration on the systemic transport of ketoprofen]. / Répercussion du mode et du rythme d'administration sur le passage systémique du kétoprofène.

The pharmacokinetics of the non-steroidal antiinflammatory drugs are influenced by circadian rhythms and ketoprofen (K) absorption by food, to investigate the influence of these two factors, 12 subjects were treated, in random order, orally by a fast release tablet (FR 100 mg), by a fast-slow release tablet (FSR 150 mg) and by an intramuscular solution (i.m. 100 mg). The 3 treatments were administered, with a standardized meal, at 8 h a.m and 8 h p.m, and also at 1 h p.m with FR. The daily dosing was 300 mg by oral administration and 200 mg by i.m. route. Serum concentration profiles of K were determined by HPLC. The pharmacokinetic parameters of K were not modified by the time of intramuscular injection. The oral absorption of K (Tmax) was significantly delayed at 1 h p.m and more even at 8 h p.m. The maximal serum concentration (Cmax) was significantly decreased at 1 h p.m (about 50%, p < 0.001) and also at 8 h p.m. The oral bioavailability, evaluated by the area under the K serum concentration curve, was not modified, those of FSR was significantly lower than FR (6%, p < 0.05). This study shows that the time of K administration delayed the Tmax and food decreased the Cmax without loss of bioavailability.

Metabolism of quinine in children with global malnutrition.

Malnutrition and malaria are two important public health problems in Africa. Quinine is one of the major treatments of chloroquine-resistant malaria. Although some authors have shown that quinine clearance is decreased in kwashiorkor, this type of malnutrition is caused by protein deficiency that differs from global protein-energy malnutrition. In rats, hepatic metabolism of many drugs is decreased in protein deficiency and increased in global food restriction. Several studies have found that human hepatic metabolism of many drugs is decreased in kwashiorkor, but, as yet, no study has focused on human global energy-protein malnutrition. Thus, as quinine is a drug with a narrow therapeutic index, we compared the pharmacokinetics of quinine in two groups. One group included children with global malnutrition and the other was a control group of children with normal nutrition. Volume of distribution and plasma concentrations of unbound quinine did not differ between children with global malnutrition and children with normal nutritional status. Clearance was significantly faster, half-life shorter, and concentrations, 12 h after the beginning of treatment, lower in malnourished children compared with control subjects. The ratio between area under the curve of hydroxyquinine (metabolite of quinine in man) and area under the curve of quinine was significantly increased in malnourished children and correlated with mid-arm/ head circumference ratio (marker of malnutrition in children). Thus, as metabolism of quinine is increased in children with global malnutrition, we suggest that the administration interval should be reduced in these children to obtain the same plasma concentrations of quinine found in normally nourished children. A safe and effective dosing strategy is postulated.

Bioequivalence study of alpha-dihydroergocryptine: utility of metabolite evaluation.

Metabolite assessment is an open question in bioequivalence studies. In situations of low absorption, high first-pass metabolism, and intrasubject variability, metabolites may reflect absorption more adequately than the parent drug, and their determination may help decision-making in bioequivalence issues. Treating alpha-dihydroergocryptine (DHECT) as a model, we used both unchanged DHECT and a pool of DHECT metabolites to evaluate the bioequivalence of 2 oral DHECT formulations (reference-R and test-T) in 12 subjects. DHECT and its metabolites were immunoassayed. There was no difference between the 2 formulations in terms of the AUC0-infinity (area under the curve) values determined from unchanged DHECT or DHECT with metabolites profiles: 572 +/- 490 pg/ml.h (R) and 442 +/- 276 pg/ml.h (T) for unchanged DHECT, and 7,141 +/- 2,936 pg/ml.h (R) and 6,941 +/- 1,462 pg/ml.h (R) for DHECT with metabolites. Confidence intervals were within the ranges 0.8-1.25 (AUC0-infinity) and 0.7-1.43 (Cmax) for DHECT with metabolites but not for unchanged DHECT. This study describes a particular case where only measurements on the basis of the metabolites can justify the assumption of bioequivalence.

Clinical pharmacokinetics of lansoprazole.

Lansoprazole, a benzimidazole derivative with antisecretory and antiulcer activities, inhibits the acid pump activity at the final stage of the enzyme process and therefore reduces the acid secretion of parietal cells. Lansoprazole is converted to active metabolites in the acid environment of these cells. It is rapidly absorbed from a gastric acid-resistant formulation and is approximately 97% bound in human plasma. Single dose pharmacokinetics of lansoprazole appear to be linear over the range from 15 to 60mg. Food and time of dose influence absorption after single doses, but do not modify the antisecretory effect of multiple doses. Lansoprazole is extensively metabolised following oral administration into sulphone and 5-hydroxylated metabolites by the cytochrome P450 enzymes CYP3A4 and CYP2C18. Two other metabolites have been identified in plasma: sulphide and hydroxylated sulphone. Mean plasma elimination half-life (t1/2) is between 1.3 and 2.1 hours in healthy volunteers. 15 to 23% of the total dose is found in urine as free and conjugated hydroxylated metabolites, while unchanged lansoprazole is not detected. The pharmacokinetic profile of the drug is not modified by multiple administration. In healthy elderly volunteers, area under the plasma concentration-time curve (AUC) and t1/2 are significantly greater after single administration occurs to the same extent as in young volunteers. Renal failure has no influence on the pharmacokinetics of lansoprazole, but severe hepatic failure causes a significant decrease in clearance and an increase in the AUC and t1/2 of lansoprazole. This is accompanied by modifications in the AUC of metabolites, but severe hepatic failure has minimal effect on accumulation of the drug after multiple administration. The pharmacokinetics of lansoprazole in patients with acid-related disorders do not differ from those in healthy volunteers. Studies of interactions of lansoprazole with warfarin, prednisone, theophylline, phenazone (antipyrine), diazepam, phenytoin and oral contraceptives suggest minimal risk of any clinically significant interaction.

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.

[Evaluation of an immunological new kit used in the toxicological screening of benzodiazepines in hospital emergency care units]. / Evaluation d'une nouvelle trousse immunologique utilisée dans le dépistage toxicologique des benzodiazépines en médecine d'urgence hospitalière.

Benzodiazepines are mostly used for their antianxiety and sedative effects. In recent years, new compounds have been developed with a hypnotic action. Although marked toxicity is uncommon with the use of these compounds, the clinician requires a rapid laboratory report in emergency and intensive care units in case of self-poisoning. To reduce the incidence of false-negative results routinely observed with our enzyme immunoassay kit (Emit tox benzodiazepine), the performance of a new kit (Emit dau benzodiazepine) was evaluated in 57 patients who had taken an overdose of benzodiazepines. Results were compared with those obtained by high performance liquid chromatography (HPLC) using a diode array detector and giving a semi-quantitative result. Seventy-four percent of the patients studied gave readings above the cut-off value, which was consistent with benzodiazepine intoxication, according to the results of the specific HPLC analysis (bromazepam, triazolam, alprazolam and flunitrazepam were clearly identified). No false negatives were obtained in this study with the Emit dau benzodiazepine. Finally, HPLC is unsuitable in the emergency setting; the enzyme multiplied immunoassay technique is the most appropriate method used in cases of self-poisoning with benzodiazepines having a low therapeutic index.

Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects.

Plasma concentrations of lansoprazole and of its sulphone, sulphide and 5-hydroxylated metabolites were determined after oral administration of a single 30 mg dose and after 7 days of treatment with a daily 30 mg dose in 12 elderly subjects (mean age 83 years). Results after a single dose were compared with those from a historical control group of 18 young subjects (mean age 23 years). Mean values of AUC after single dose were 2668 ng ml(-1) h in the young subjects and 5216 ng ml(-1) h in the elderly (P < 0.05). Mean t 1/2z values in young and elderly subjects were 1.4 h and 2.9 h, respectively (P < 0.001). Plasma concentrations of the metabolites were similar in both groups. However, the hydroxylated metabolite of the sulphone was detected only in elderly subjects. Steady state plasma concentrations of lansoprazole were reached after 3 days of dosing with lansoprazole. The accumulation ratio was 1.31 in the elderly subjects.

Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity.

The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis. In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment. In hepatitis patients, the AUC and t1/2 of L were doubled, without any change in Cmax. In cirrhotics tmax was prolonged, the AUC was increased (P < 0.001) and there was prolongation of t1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (Cmax, Rm) and a decrease in the hydroxylated metabolite (Cmax, Rm) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination. Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.

Influence of lansoprazole treatment on diazepam plasma concentrations.

The possible influence of long-term treatment with lansoprazole on the single-dose pharmacokinetics of diazepam was investigated in 12 healthy male volunteers. In this double-blind randomized crossover study, 60 mg lansoprazole or placebo was administered once daily for 10 days. One hour after administration on day 7, 0.1 mg/kg diazepam was administered intravenously, and blood was collected up to 96 hours after the injection for plasma diazepam and desmethyldiazepam measurement. During the placebo session, the plasma elimination half-life, clearance, and volume of distribution of diazepam were 26.0 +/- 1.6 hours, 22.5 +/- 1.1 ml/hr/kg, and 0.82 +/- 0.04 L/kg, respectively. These parameters were not significantly different during the lansoprazole session. The mean plasma concentrations of desmethyldiazepam were similar in both sessions. These findings illustrate that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.

Pharmacokinetics of salbutamol in the pregnant woman after subcutaneous administration with a portable pump.

OBJECTIVE: We sought to determine whether subcutaneous administration of salbutamol resulted in plasma levels comparable to those achieved after intravenous or oral administration. METHODS: Twenty-nine women with preterm labor received subcutaneous infusion of salbutamol through a portable pump. We used three different rates of continuous infusion: a low rate of 3.33 micrograms/minute (20 subjects), an intermediate rate of 6.66 micrograms/minute (four subjects), and a high rate of 9.99 micrograms/minute (five subjects). Plasma salbutamol concentrations were assayed by high-performance liquid chromatography after 48 hours of continuous infusion in the subcutaneous tissue and after bolus injections (184 micrograms in the low-rate group and 368 micrograms in the intermediate- and high-rate groups). RESULTS: Plasma salbutamol concentrations after 48 hours of subcutaneous infusion increased almost linearly with the rate of infusion: 6.29 +/- 1.58, 15.5 +/- 1.0, and 21.7 +/- 4.26 ng/mL in the low-, intermediate-, and high-rate groups, respectively (P less than .001 between the three groups). After bolus injection, maximum plasma concentrations were significantly different between the three groups (P less than .001) and from their respective baseline values (P less than .001): 8.33 +/- 1.9, 18.85 +/- 2.0, and 25.86 +/- 4.8 ng/mL in the low-, intermediate-, and high-rate groups, respectively. CONCLUSION: Subcutaneous tocolysis can provide plasma salbutamol levels similar to the levels obtained orally or intravenously.

[Methods of cyclosporine determination in biological media]. / Méthodes de dosage de la ciclosporine dans les milieux biologiques.

Cyclosporine is an immunosuppressive medicine widely used in all grafts and organ transplantations. Its pharmacokinetic characteristics, especially its intensive metabolism, result in great variability potential between and within patients justifying blood levels' determination in patients treated with this drug. If the biological medium (whole blood) selection is of the utmost importance regarding the quality of the result and its validity, the accuracy of the result compared to the blood levels of the drug will depend on the selection of the determination technic involved. At present, various analytical methodologics are available: the immunological technics involving radioactive or non-radioactive tracers, and HPLC (High Performance Liquid Chromatography) technic. The latter requires good chromatography experience; it takes more time to be implemented due prior extraction of cyclosporine from the biological media. This extraction can be effected with organic solvents or by column chromatography: these various technics will be discussed and compared. This methodology enables one to determine metabolite concentrations. Regarding immunological technics, multiclonal or monoclonal antibodies are available for technics involving fluorescence polarization. However, for radioactive tracings and enzymic tracers, only one specific antibody is available. It is important to take into account the specificity of these antibodies relative to the various metabolites regarding results interpretation, their crossing rate being altered in accordance with antibodies and related pathologies. The validity of these technics will be discussed in words of accuracy and exactitude. The laboratory arrangement, the feasability and cost of the technic are also factors to be taken into consideration. At present selection tends towards to most specific technics.

Plasma assay of salbutamol by means of high-performance liquid chromatography with amperometric determination using a loop column for injection of plasma extracts. Application to the evaluation of subcutaneous administration of salbutamol.

An isocratic high-performance liquid chromatography method with amperometric detection for the assay of plasma salbutamol is described. The plasma extract is injected into the chromatographic system via a loop column. This insures the purification of the injected extracts and allows a simple and rapid liquid-solid extraction procedure. The good reliability, as shown by the low limit of detection (0.5 ng/ml) and a precision ranging between 5 and 10%, has permitted the investigation of a new mode of administration of salbutamol using a portable subcutaneous infusion pump. Our results show that subcutaneous administration yields plasma levels comparable with those obtained after usual intravenous doses.

Determination of lansoprazole and its metabolites in plasma by high-performance liquid chromatography using a loop column.

A high-performance liquid chromatographic method for the simultaneous determination of lansoprazole, a new proton pump inhibitor, and its metabolites in human plasma is described. Lansoprazole, its metabolites and an internal standard were extracted with tert.-butyl methyl ether. Samples were injected using an automatic injector via a loop column, and separation was obtained using a reversed-phase column under isocratic conditions. The absorbance was monitored at 285 and 303 nm. The quantification limit was 2 ng/ml for lansoprazole and 3 or 5 ng/ml for the metabolites. No endogenous compounds were found to interfere. The mean overall recovery was between 75 and 95% for lansoprazole and its metabolites. This method is suitable for pharmacokinetic studies.