Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes.

We compared the cytotoxic effect of coumarin and its derivatives, 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acetic acid (OHPAA) and o-coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10(-5) and 5 x 10(-5) M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10(-4) M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10(-4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decreased in the presence of SKF 525-A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species-dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.

[Physical and pharmacokinetic properties of anesthetics and sedatives used in neuroanesthesia and resuscitation]. / Propriétés physiques et pharmacocinétiques des substances anesthésiques et sédatives utilisées en neuroanesthésie et réanimation.

Pharmacokinetics of anesthetic drugs are widely influenced by their physical properties. Lipo-solubility is the most important characteristic. This parameter conditions tissue diffusion and subsequently potency and duration of action drugs Distribution is unequal in the different compartments of the body. The concept of effective compartment allows a best understanding of relationship between concentration, intensity and duration of action of anesthetic drugs. Constant intravenous infusion route of anesthetic drugs administration requires to be discussed.

[Adjusting the dosage of netilmicin from two measurements. Program validation]. / Adaptation des posologies de la nétilmicine à partir de deux points. Validation d'un programme.

The aim of this study is to give to clinicians a well validated usefull tool allowing an increase of safety in the monitoring of netilmicin. During the first administration of the drug, two plasmatic concentrations are measured, and input in a preprogrammed hand-held calculator. A posology and a rythm of administration are returned by the calculator. After six days of this dosage regiment, the peak and the valley concentrations are compared with those previously given by the computer as values at equilibrium. No significant difference can be observed. There is no change in plasmatic creatinine level from the first to the sixth day of treatment. So, a preprogrammed hand-held computer can be convenient and safe to monitor netilmicin.

Solid phase extraction and HPLC determination of spiramycin in plasma and vitreous concentrations.

A method for extracting spiramycin by an octadecylsilica cartridge is described for plasma or vitreous samples. The macrolide antibiotic is then measured by reversed-phase HPLC with UV detection. The limit of detection is estimated to be 50 ng/mL. The coefficient of variation for the procedure is 6.1% and 5.2% for the range of concentrations 0.2 micrograms/mL and 10 micrograms/mL respectively. By this method, pharmacokinetic profiles were performed for five adult patients. Spiramycin could be accurately measured in the vitreous humour, allowing the determination of antibiotic at its site of action.

Pharmacokinetics of amineptine after single-dose, repeated treatment and study of the at-risk populations.

In this paper, three different studies are discussed. First, pharmacokinetics of the tricyclic antidepressant amineptine (Survector) and its main metabolite were investigated in young healthy adults. Amineptine was rapidly absorbed. Mean peak plasma concentrations of amineptine and its metabolite occurred 1 and 1.5 h, respectively, after drug administration. The mean apparent volume of distribution was large: 2.4 L/kg. Elimination was rapid. T 1/2 (half-life) was 0.8 h for amineptine and 2.5 h for the metabolite. The mean apparent plasma clearance of amineptine was high (124.8 L/h). In a second study in young patients, no change in pharmacokinetic parameters was observed after a 10-day course of repeated treatment with the drug. Finally, pharmacokinetics of amineptine and its main metabolite were studied in elderly patients on day 1 and after a repeated administration for 15 days. There was no significant age-linked change in the pharmacokinetics of amineptine even if half-life and area under the curve of the metabolite were all greater in the elderly subjects than in young adults. Pharmacokinetic parameters of amineptine and its metabolite were not affected by repeated administration over 15 days. The pharmacokinetic characteristics of amineptine in elderly subjects do not necessitate any dosage alteration for this population.

Study of doxorubicin photodegradation in plasma, urine and cell culture medium by HPLC.

An HPLC method was used to monitor the chemical stability of doxorubicin-HCl (DXR) to light in plasma, urine and cell culture medium at room temperature. The results indicated that DXR was very unstable in cell culture medium and urine when exposed to light. It was more stable in plasma under the same conditions. In all the cases, the decrease in the amount of DXR is greatly dependent on light intensity (no noticeable degradation was observed after 8 h in the dark). These observations may be important for the correct interpretation of the effects and the toxicity of doxorubicin on cells incubated in cell medium, and for determination of urinary or plasma pharmacokinetic parameters.

[Midazolam used for intramuscular premedication in locoregional anesthesia in urology. Usefulness of late premedication]. / Le mizadolam en prémédication intra-musculaire dans l'anesthésie loco-régionale en urologie. Utilité d'une prémédication tardive.

Midazolam was used as an intramuscular premedication combined with atropine in a population of 100 patients receiving loco-regional anaesthesia for urologic procedures. Two different dosages were given according to age: 0.10 mg/kg for patients over 50 years, 0.15 mg/kg for those under 50. This premedication was always effected just before the patient's transport to surgery. We observe the quality of anxiety relief (85%), sedation (82%), anterograde amnesia. These results confirm that midazolam is a suitable drug for late premedication by the intramuscular route. It is a potent drug with regular short-lasting action, which lead us to suggest its use in ambulatory anaesthesia.

[Pharmacokinetics of ceftriaxone in intensive care]. / Pharmacocinétique de la ceftriaxone en réanimation.

Pharmacokinetic parameters of ceftriaxone were studied on day 1 and 5 in 21 patients admitted in an ICU for severe infections. All patients received a single daily infusion of 2 g of ceftriaxone during 15 minutes. We have determined the ratio to the daily dose of serum ceftriaxone concentrations (peak level and trough level) and of areas under the curve. According to renal function and the existence of cholestasis, the results of our study showed: 1) In patients with creatinine clearance greater than 10 ml/mn and without cholestasis, a single daily infusion of 2 g ceftriaxone achieves therapeutic blood levels without any accumulation phenomenon. 2) In patients requiring hemodialysis without cholestasis, the period between two 2 g doses should be prolonged to 48 h. 3) Marked cholestasis and creatinine clearance greater than 10 ml/mn prolong the elimination half-life of ceftriaxone leading to an interval extension of the single dose of 2 g. Further investigations are needed in the latter situation.

Changes in intra-ocular pressure in the elderly during anaesthesia with propofol.

Variations in intra-ocular pressure during anaesthesia were studied in two groups of 15 elderly patients selected randomly. The groups were not significantly different with regard to age, sex, weight or ASA classification. The first group received intravenous propofol as a bolus followed by a continuous infusion. The second group received a bolus of thiopentone followed by maintenance with enflurane. Intra-ocular pressure, heart rate and arterial pressure were measured before and after induction, after intubation and at the end of the operation. Overall, compared with baseline values, the results showed a decrease in intra-ocular pressure of 31% in group 1 and 17% in group 2, and a decrease in systolic arterial pressure of 14% in both groups.

[Kinetics of tobramycin in newborn infants in intensive care]. / Cinétique de la tobramycine chez le nouveau-né en réanimation.

Maximal and minimal tobramycin concentrations were studied in 16 preterm and 4 fullterm neonates on the last day of a four-day course of tobramycin (infusion of 2 mg/kg twice a day). Maximal concentrations were under 6 mg/l in all patients and minimal concentrations were above 2 mg/l in one-third of the preterm babies. Next, tobramycin pharmacokinetic parameters were studied in 4 fullterm and 4 preterm neonates following a first infusion of 2 mg/kg. Half-life was 4 hours in term babies and 7.75 hours in preterm babies. Mean clearance was 0.118 l/h/kg and 0.06 l/h/kg in fullterm and preterm babies respectively (significant difference). Our results show that the 2 mg/kg dosage is too low and that, in preterm neonates, the 12-hour interval between infusions is too short.

[Phenobarbital in the newborn (author's transl)]. / Problèmes posés par l'utilisation orale du phénobarbital chez le nouveau-né.

Neonates with severe cerebral damage are usually given phenobarbital. The authors study the various means of administration and the influence of term and concomitant mannitol administration on the plasma levels of the drug. They recommend the intravenous administration of a load dose and show that phenobarbital blood levels are significantly less in prematures or in children who have been given mannitol.

[Transthoracic electrical impedance plethysmography and thermodilution: comparative evaluation of two methods for cardiac output measurement in man]. / Pléthysmographie électrique d'impédance et thermodilution. Etude comparative chez l'homme de deux méthodes de mesure du débit cardiaque.

The measurement of cardiac output by electrical impedance plethysmography (non invasive technic) seems to be attractive but is still the subject of a certain number of critics. The authors have tried to compare it with a method which validity is well documented, the thermodilution. By these two methods, 87 measures of cardiac output have been performed in 14 hospitalized patients in intensive care, attained of various affections but exempts of cardiac or pulmonary lesions and in stable hemodynamic state. The stroke volume measured by electrical impedance plethysmography is calculated using Kubicek's formula: SV = Q (L2/Zo2) (dz/dt min) t. Results were as follows: absence of significative difference between the coefficients of variation of each series of measures (coefficient of mean variation, 5,6 +/- 3,4 p. cent for impedance and 3,8 +/- 3,2 p. cent for thermodilution); absence of significative difference between the mean values of cardiac output (7,59 +/- 2,69 l . min-1 for impedance and 7,72 +/- 1,99 l . min-1 for thermodilution); highly significant correlation between values for cardiac output obtained for each of these two methods )r = 0,804; n = 87; p less than 0,001). The authors conclude that in patients in intensive care whose pulmonary or cardiovascular system is not in critical situation, the electrical impedance plethysmography appear as a secure method for cardiac output measurement. However its generalisation still require other works.

[Massive poisoning by paraquat with early death (19 hours). Apropos of a case with ultrastructure study]. / Intoxication massive par le paraquat avec décès précoce (19 H). A propos d'un cas avec étude ultrastructurale.

The authors report a case of a forty-years-old woman who died nineteen hours after ingestion of a massive dose of Paraquat (about 125 ml of Gramoxone, 52 g of Paraquat) with vomitings, anuria and cardiac arrest. Early autopsy (less than two hours after death) showed necrotizing esophagitis, ulcerative gastritis, tubular nephritis, congestion of lung, interstitial myocarditis which could explain the heart failure. The ultrastructural study of lung showed interstitial edema associated with minimal endothelial changes but important epithelial cell necrosis of both pneumocytes. These findings are very similar to experimental studies of massive Paraquat poisoning emphasizing the early involvement of pneumocyte II.

[Problems in the treatment of a patient with longstanding epilepsy (author's transl)]. / Problèmes thérapeutiques chez une épileptique ancienne.

The case of a female patient with longstanding epilepsy is reported. Many problems in achieving a satisfactory therapeutic regimen were encountered. They originated in storage of phenobarbital, which had been prescribed since childhood, interference between phenobarbital, dipropylacetic acid, and phenylhydantoins. Some pharmacokinetic principles are reviewed in the light of this clinical experience.

[Measurement of cardiac output by electrical impedance plethysmography during respiration and in apnea]. / Mesure du débit cardiaque par pléthysmographie électrique d'impédance au cours de la respiration et en apné.

The measurement of cardiac output by electrical impedance plethysmography (non-invasive technique) may be disturbed by a certain number of factors, including respiration. The authors sought to demonstrate that this factor could be eliminated during measurement calculations. By this method, in 18 adult subjects with coronary artery disease, 50 measurements during respiration and 50 measurements in apnoea (paired measurements) of stroke volume and of cardiac output were performed. Stroke volume was calculated using Kubicek's formula: SV = P(L2/Zo2) (dz/dt min)t Results were as follows: highly significant correlation between values for stroke volume obtained during respiration and in apnoea (r ;.9767; n=50; P < 0.001); highly significant correlation between values for cardiac output obtained under the same conditions (r = 0.9744; n=50; P < 0.001). The authors conclude that with the limits of certain technical conditions of measurement, respiration does not disturb measurements of stroke volume and of cardiac output by electrical impedance plethysmography.