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The pharmacokinetics and protein binding of propofol were studied in ten patients with cirrhosis and in ten control patients undergoing elective surgery. All patients received 2.5 mg.kg-1 propofol as an intravenous bolus injection for the induction of anesthesia. Whole blood propofol concentrations were measured at intervals up to 12 h, using a high-performance liquid chromatography (HPLC) technique. Propofol protein binding was estimated by equilibrium dialysis 10 min after injection of propofol. Individual propofol profiles for all patients were best described by a three-compartment open mammillary model. Rapid and slow propofol distribution half-times were observed, followed by an elimination phase with a half-time of 4-5 h. Propofol total body clearance was reduced (1.99 +/- 0.68 l.min-1) in the patients with cirrhosis but did not differ significantly from that in the control patients (2.30 +/- 0.61 l.min-1). The apparent volume of distribution at steady state (Vdss) was similar in the two groups. No significant difference in elimination half-life was observed between the two groups. Propofol was extensively bound (mean: 97-98%) to the plasma protein of both cirrhotic and control groups. This study shows that propofol pharmacokinetics and protein binding of propofol following a single intravenous bolus dose were not markedly affected by uncomplicated cirrhosis of the liver.

Two chromatographic methods which allow the measurement of 2-phenylbutyric acid in serum are described: a gas chromatographic, after silylation, and a reversed-phase high-performance liquid chromatographic. The liquid chromatography with a fluorescent detection, after derivatization by 4-bromomethyl-7-methoxycoumarin, is ten times more sensitive than gas chromatography and 50 ng/ml can be measured in biological liquids.

The pharmacokinetic profile of 0.2 mg kg-1 midazolam given i.v., for induction of anaesthesia, was compared in young subjects and in those who were over 80 years of age. Thirty-five patients were allocated into four groups according to their sex and age. Plasma samples were drawn before midazolam injection and at regular intervals over 24 h following injection. Plasma midazolam concentrations were measured by electron capture gas-liquid chromatography. Equilibrium dialysis was used to assess the plasma protein binding of midazolam. Distribution volume (Vdss) was significantly increased in elderly subjects when compared to young subjects of the same sex (young vs. elderly males, Vdss = 1.22 +/- 0.31 l kg-1 and 2.47 +/- 0.98 l kg-1 respectively; and young vs. elderly females, Vdss = 0.91 +/- 0.29 l kg-1 and 1.70 +/- 0.78 l kg-1 respectively). Total body clearance was significantly reduced in elderly males compared with young males (5.60 +/- 1.77 ml min-1 kg-1 vs. 8.10 +/- 3.58 ml min-1 kg-1). No significant difference in clearance was found between young and elderly females (6.08 +/- 2.04 ml min-1 kg-1 vs. 9.14 +/- 3.36 ml min-1 kg-1). As a consequence, elimination half-life (T1/2E) was significantly prolonged in elderly compared to young males (8.52 +/- 5.4 h vs. 2.77 +/- 0.80 h). In contrast, T1/2E was unchanged in elderly compared to young females (2.99 +/- 0.86 h vs. 2.86 +/- 1.04 h). Midazolam plasma protein binding was not influenced by age and sex.

Fast atom bombardment-tandem mass spectrometry was used to identify molecular species of paf-acether (paf) produced by human polymorphonuclear neutrophils. Using this biological material, normal phase high performance liquid chromatography was necessary prior to the fast atom bombardment-tandem mass spectrometry step. Gas liquid chromatography/electron capture detection after hydrolysis with phospholipase C and conversion to heptafluorobutyrate derivatives was used to confirm the results. The results indicated the presence of mainly 1-O-hexadecyl/octadecyl-2-acetyl-sn-glycero-3-phosphocholine, acyl analogs of paf and only trace amounts of other alkyl analogs of paf. We did not detect the 2-propionyl analog of paf. Moreover, supplementation of human polymorphonuclear neutrophils with sodium propionate did not result in formation of the 2-propionyl analog of paf.

Pentamidine concentrations were determined in plasma after a single aerosolization of 4 mg/kg pentamidine base on 18 patients breathing spontaneously (Group I) and in eight patients receiving mechanical ventilation (Group II). All the patients had documented pneumocystosis. Large interindividual variations in concentrations appeared, especially in Group I. Low concentrations were observed in Group I: Cmax = 65.6 +/- 9.4 micrograms/L (mean +/- SEM), contrasting with high levels in Group II: Cmax = 215.8 +/- 49.8 micrograms/L (mean +/- SEM). Consequently, the mean area under the curve from zero to 4 h was 2.6-fold higher in Group II than in Group I. These findings underline the risk of dose-related pentamidine toxicity in ventilated patients treated with aerosolized pentamidine and the interest of plasma pentamidine monitoring.

A 2g single dose of cefotiam was given by rapid intravenous injection to 17 patients undergoing total hip replacement as a prophylaxis. The concentrations of the antibiotic in plasma and femoral head (cancellous bone, cortical bone and capsule) were measured at different time (40 to 250 minutes) following the injection of the drug. Evaluation was done by liquid chromatography. Mean antibiotic concentrations were 70.5 micrograms/ml, 41.4 micrograms/g, 16.9 micrograms/g and 8.1 micrograms/g respectively in plasma, capsule, cancellous and cortical bones. 240 minutes following the injection, mean concentrations of cefotiam were higher than 2.3 micrograms/ml in plasma and 1.8 micrograms/g in bone. Diffusion in cancellous bone is twofold high as in cortical bone and elimination half lif is higher in bone than in plasma (248.8 minutes versus 59.6 minutes in plasma). These results suggest that a 2g intravenous bolus injection of cefotiam given at the induction of anaesthesia should provide an effective prophylaxis during total hip replacement.

18 patients with myocardial infarction complicated by severe ventricular arrhythmias (polymorphic VEBs or bigeminy = 5; VT = 11; VF = 2) were treated with antiarrhythmics which were stopped after 24 hours (intravenous infusion of mexiletine 0.5 mg/kg/hr after a loading dose). This treatment resulted in one failure (recurrent VF) and 17 successes, after increasing the dose in 3 cases of VT. After stopping treatment, 72% of patients had no further arrhythmia. 5 cases had recurrent VT within 72 hours, which was controlled by oral mexiletine in 4 cases. The ejection fraction was significantly decreased in the group with recurrent VT. Plasma assays were of little help. Stopping the antiarrhythmic treatment after 24 hours does not therefore present any particular risks and can be proposed even in cases with severe arrhythmias.

The ofloxacin diffusion was investigated in 13 cirrhotic patients with spontaneous bacterial peritonitis. Plasma and ascitic samples were collected at times H1, H31 and H8 after a first dose of 200 mg per os, in these 13 patients, after 4.5 or 6 days of 200 mg per os each 8 hours in 9 out of them. After the first dose, the plasmatic and ascitic concentrations, measured by High Performance Liquid Chromatography (HPLC), were between 0 and 3.62 mg/l, 0 and 1.95 mg/l respectively. The steady state concentrations are higher than the MIC'S for the organisms most commonly involved, comparable in the plasma and the ascitic fluid is good and suggest the interest of its use in this indication.

The aim of this study was to determine the influence of 24 h of ranitidine treatment on gastric bacterial flora and N-nitroso compound formation. Nitrate, nitrite levels, N-nitroso compound concentration were measured and bacterial flora was studied in the fasting and postprandial gastric juice of four healthy men under placebo and ranitidine treatment (150 mg. bid). The pH of seventy-five per cent of the gastric juice samples was over 4 when the patients received their ranitidine treatment. While the mean intragastric concentrations of nitrate, nitrite, N-nitroso compounds and counts of nitrate-reducing organisms were not significantly altered by ranitidine, there was a statistically significant rise in the number of total bacteria. During ranitidine treatment, the nitrite/nitrate ratio was positively correlated with intragastric pH and with the nitrate-reducing organism count of the placebo period. These results suggest that the reduction of nitrate to nitrite required the combination of two factors: a high count of nitrate-reducing organisms before treatment and a high intragastric pH.

The authors describe a method of simultaneous estimation of phenobarbitone and valproic acid in the blood. After extraction with ether, these substances were estimated by high performance liquid chromatography. They were separated on a mu Bondapack C18 column. The detection involved a colorimetric procedure based on variation in colour of a solution of bromocresol purple. The technic used is simple, its reproducibility is satisfactory (coefficients of variation of 7.6% for phenobarbitone and 2.3% for valproic acid). The sensitivity was 13.8 mumol/l for phenobarbitone and 11.1 mumol/l for valproic acid. Parallel estimations by gas chromatography led to comparable results. This method is of interest in the supervision of anticonvulsant treatments, especially in pediatrics.

Previous studies have described a pharmacokinetic interaction between probenecid, a uricosuric drug, and oxipurinol, the major metabolite of allopurinol. In single dose studies, no interaction was found to occur between benzbromarone, another uricosuric agent, and oxipurinol. A cross over study was conducted in 12 volunteers to compare the kinetics of allopurinol and oxipurinol following treatment for 7 days with allopurinol alone or combined with benzbromarone 20 or 100 mg. The pharmacokinetic parameters of allopurinol were not modified by the uricosuric therapy, but those of oxipurinol were markedly altered by concurrent administration even of the lower dose of benzbromarone; the average plasma level fell by 30% and the renal elimination rate was increased by 50%. A parallel increase in the renal elimination rate of uric acid was observed (significant only with the higher dose of benzbromarone) and a positive linear correlation between the fractional excretion of uric acid and that of oxipurinol was established.

This study was designed to: (1) determine plasma midazolam concentrations producing adequate sedation in ICU patients; (2) establish an intravenous regimen to provide continuous sedation and rapid recovery after discontinuation of infusion. Initially, 13 ICU patients were given midazolam as a bolus injection, 0.20 mg.kg-1 over 30 s in order to define the midazolam plasma concentration corresponding to an adequate level of sedation. The optimal level was reached in a mean time of 61 +/- 26 min and the mean corresponding midazolam plasma concentration was 163 +/- 62 ng.ml-1. Estimations of the main pharmacokinetic parameters (elimination half life: 230 +/- 102 min, total body clearance: 520 +/- 283 ml.min-1, total volume of distribution: 2.23 +/- 1.15 l.kg-1) showed no marked differences with normal patients. From those variables, an infusion regimen (loading dose and maintenance rate) to provide long term (24 to 80 h) sedation was derived in 9 patients. The mean loading dose was 0.33 +/- 0.18 mg.kg-1 over 30 min and the mean continuous infusion dose was 0.06 +/- 0.02 mg.kg-1.h-1. The mean midazolam plasma concentration during infusion was 215 +/- 61 ng.ml-1, and the mean midazolam plasma concentration at the end of infusion was 199 +/- 93 ng.ml-1. The level of sedation was considered as optimal in most patients throughout the study. After discontinuation of infusion, the mean time for normalization of the mental state was 97 min.

Pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, were assessed in 10 chronic uremic patients treated by maintenance hemodialysis in comparison with 10 normal subjects. All subjects ingested a single dose of 1 g of pyrazinamide, the patients receiving the drug immediately after the end of a dialysis session. Bioavailability of pyrazinamide was only slightly increased in patients, its dialysis extraction coefficient being 55.3%. In contrast, pyrazinoic acid has an elimination rate-dependent metabolism with a bioavailability markedly increased in patients and a dialysis extraction coefficient of 59.8%. These data may lead to recommendations of a reduction in the dosage of pyrazinamide in dialysis patients. However, administering the usual dosage of the drug at the end of each dialysis session seems preferable to the daily administration of a reduced dosage.

The effects of induction of anesthesia with diazepam and midazolam on baroreflex control of heart rate and on plasma levels of catecholamines were investigated in this study. Group 1 subjects (n = 10) received diazepam, 0.4 mg/kg. Group 2 subjects (n = 10) received midazolam, 0.3 mg/kg. Baroreflex function was assessed using a pressor test (phenylephrine). In addition, samples for subsequent determination of plasma norepinephrine and epinephrine levels and plasma diazepam or midazolam concentrations were collected before and 5, 10, and 15 min after intravenous drug administration. The pressor baroreflex slope declined significantly after diazepam or midazolam administration with the maximal changes (-45 and -43%, respectively) observed when plasma diazepam or midazolam concentrations were the highest. Norepinephrine plasma concentrations decreased at each measurement with both drugs. In contrast, epinephrine concentration decreased only after midazolam. The authors conclude that diazepam or midazolam used for induction of anesthesia results in a transient depression of baroreflex function and a sustained decrease of sympathetic tone. This study also indicates that the depression of arterial baroreflex heart rate responses under diazepam or midazolam anesthesia are less pronounced than the depression of baroreflex responses reported by other investigators with potent inhalational anesthetics. However, this disruptive effect of diazepam and midazolam on sympathetic control of circulation might induce a limited ability to compensate for hemodynamic alterations related to hypovolemia.