[Cytomegalovirus cystitis and AIDS. The value of deep bladder biopsy. Apropos of a case]. / Cystite à cytomégalovirus et SIDA. Intérêt des biopsies vésicales profondes. A propos d'une observation.

In the light of a case of CMV cystitis in an HIV 1-sero-positive patient suffering from disabling bladder pain, refractory to the usual treatments, the authors describe the mechanism of infection, the diagnostic approach, and especially the value of deep bladder biopsies by resection, as the endoscopic appearance is not pathognomonic and CMV was only detected in the deep muscle layer.

[Pulmonary involvement of Bourneville's tuberous sclerosis. The value of early detection. A familial form]. / Les atteintes pulmonaires de la sclérose tubéreuse de Bourneville. Intérêts du dépistage précoce. A propos d'une forme familiale.

Pulmonary disease is very rare during the course of tuberous sclerosis of Bourneville (STB). The authors report two cases of STB with pulmonary involvement occurring in the same family, mother and daughter. Both presented with typical cutaneous manifestations of the disease and bilateral renal angiomyolipomas. In the daughter, the early pulmonary diagnosis was made by computed tomographic examination (TDM) which showed the images of the cyst very sharply, although the pulmonary radiograph was normal. Prolonged follow up with pulmonary function tests is important. Lung function tests were very abnormal in the mother with a frank diminution of the TLCO and hypoxia at rest. In the daughter, they revealed the development of obstructive airways disease. Bronchoalveolar lavage was carried out in both the mother and daughter and showed intra-alveolar haemorrhage (with a ground glass appearance on computed tomography in the mother). Pulmonary lymphangiomyomatosis (LPM) and STB with pulmonary involvement are clinical disorders which are anatomically closely related. If the value of hormonal treatment has been shown during the course of LMP, their efficacy in STB is variable.

[Hemoptysis disclosing a plasma cell granuloma with intra-bronchial involvement]. / Hémoptysies révélant un granulome plasmocytaire avec bourgeon endo-bronchique.

The authors report a case of a plasma cell granuloma in a young woman of 19 with a past history of congenital rubella, presenting with repeated small haemoptyses related to a pedunculated endo-bronchial tumour. The diagnosis was only made per-operatively, permitting an effective excision.

[Prolonged mechanical nasal ventilation. Apropos of 27 case of myopathy]. / Ventilation mécanique prolongée par voie nasale. A propos de 27 cas de myopathie.

We report the results of a retrospective study of a group of 27 patients with a myopathy who were ventilated at home using a nasal mask over a period of 5 years. Twelve patients were ventilated in a preventive fashion before any orthopaedic surgical intervention and 15 out of necessity because of respiratory failure and/or hypercapnia. There was a statistically significant improvement in the PaO2 while the PaCO2 remained stable. The vital capacity (CV) was unaltered. Side effects were relatively frequent but did not lead to this method of ventilation being stopped. One patient died from a very advanced cardio-myopathy after having stopped his own assisted ventilation. Another patient died at home of bronchial congestion. One patient had a tracheotomy after 3 years of ventilation. The treatment was judged overall as positive amongst the 19 patients who responded to a questionnaire anonymously. We are able to confirm the efficacy of this mode of ventilation by the nasal route as much therapeutically as prophylactically, which is against the recently reported results in a multi-centre study.

[Chemotherapy of extensive digestive cancers with 5-fluorouracil: relation between the clinical response and plasma clearance of the drug]. / Chimiothérapie des cancers digestifs étendus par le 5-fluorouracile: relations entre la réponse clinique et la clairance plasmatique du médicament.

This study was designed to establish a possible relationship between the pharmacokinetics of 5-FU and response to treatment. Thirteen patients with advanced, histologically proven malignancies of the gastrointestinal tract were studied. 5-FU, at a single weekly dose of 15 mg/kg, was given in bolus or as an 8-h infusion to every patient. Plasma clearance of 5-FU after an i.v. bolus injection of 15 mg/kg was individually determined and found to vary widely among patients (from 0.39 to 2.55 l/min). A clearance greater than or equal to 0.86 l/min was seen in all the patients who did not respond to treatment. All patients (except one) with a partial response or a stable disease had a clearance less than or equal to 0.72 l/min. The mean clearance of non-responders (1.40 +/- 0.21 l/min) was significantly greater (P less than 0.02) than that of partial responders or patients with stable disease (0.73 +/- 0.15 l/min). These preliminary results deserve further investigation on a larger number of patients, before plasma levels of 5-FU may be accepted as an indication of response to chemotherapy.

Quantitative analysis of 5-fluorouracil and 5,6-dihydrofluorouracil in plasma by gas chromatography mass spectrometry.

5-Fluorouracil and 5,6-dihydro-5-fluorouracil were analysed in the plasma of patients by combined gas chromatography mass spectrometry. 5-Bromouracil was the internal standard. After extraction from plasma with an isopropanol-diethyl ether mixture (20/80) the components were pentylated and the derivatives produced extracted into diethyl ether. Electron impact mass spectrometry was used for the simultaneous quantitative determinations of 5-fluorouracil and 5,6-dihydro-5-fluorouracil (detection limit 10 ng ml-1 5-fluorouracil, 80 ng ml-1 5,6-dihydro-5-fluorouracil). Chemical ionization was utilized to measure 5,6-dihydro-5-fluorouracil concentrations less than 80 ng ml-1 (sensitivity 10 ng ml-1). The biological applicability of these two techniques was demonstrated by analysing plasma samples from patients after administration of 5-fluorouracil or 5'-deoxyfluorouridine by intravenous injections and infusions.

[Pharmacokinetics of intravenous mezlocillin in patients with normal and impaired renal function (author's transl)]. / Etude pharmacocinétique de la mezlocilline intraveineuse chez des malades à fonction rénale normale et chez des insuffisants rénaux.

The pharmacokinetics of mezlocillin after intravenous infusion of 5 g over 30 minutes was compared in 15 patients divided into 3 groups. Group I patients had normal renal function, group II patients had moderate chronic renal impairment and group III patients were under haemodialysis. Plasma mezlocillin levels were measured by the microbiological method. Plasma kinetic values were calculated from a linear two-compartment model, using global estimation of macroconstants by the non-linear least square method. The elimination half-life was 1.19 +/- 0.107 h in group I patients 1.98 +/- 0.19 h in group II patients and 2.34 +/- 0.11 h in group III patients. Renal impairment did not significantly alter the apparent volume of distribution but influenced the total plasma clearance which was 139 +/- 9 ml/min, 87 +/- 9 ml/min and 61 +/- 8 ml/min in groups I, II and III patients respectively. There was a slight decrease of V1 (central compartment) and a noticeable increase of V2 (peripheral compartment), depending on the degree of renal impairment. The total volume of distribution (V1 + V2) remained relatively constant between 12 and 14 litres. Homogeneous results were obtained in each group of patients, thus confirming the regularity of the mezlocillin kinetic model at the dose administered. This should enable dosage adjustment according to renal function, as assessed by laboratory criteria.

Pharmacokinetic study of Cis-dichlorodiammine platinum II, in children after rapid infusion.

This study involves 3 children ranging from 10 to 13 years and an eight-month-old infant who received Cis-DDP (30-100 mg/m2) every fourth week by means of a short-term infusion (20-35 minutes). Platinum levels in plasma and urine were determined by flameless atomic absorption spectrophotometry. The decrease in total plasma platinum is triphasic, consistent with the distribution expected for a 3 compartment model. In the elimination phase, the half-life values are high and vary between 149 and 541 hours. The total plasma clearances are extremely low and range from 0.027 to 0.187 litre/hour. The urinary excretion of platinum during the first 5 and 7 days respectively, in two children following administration of Cis-DDP results in large platinum concentrations (40-71 mg/litre) in the first urine excreted from each child. The cumulative urinary platinum excretion in the first twelve hours is high i. e. 27.2 to 32.5% of the administered dose but them it does not exceed 50% even after 5 days. These results confirm that after a short-term infusion of Cis-DDP in a single dose, the kidneys are suddenly subjected to platinum in high concentrations. In order to minimize the nephrotoxicity of this platinum complex, while maintaining sufficient plasma levels to ensure its anti-neoplastic activity, we recommend a schedule consisting of fractionated doses.

[Clinical pharmacokinetics of flunitrazepam (Nacrozep) in intensive care patient (preliminary results)]. / Pharmacocinétique clinique du flunitrazépam (Narcozep) chez de malades en réanimation (résultats préliminaires).

A protocol of repeated I. V. injections of flunitrazepam was constructed by mathematical simulation on the basis of pharmacokinetic data obtained from single intravenous injections given to healthy subjects. This protocol would given serum blood levels equal to 15 ng . ml-1, rapidly and compatible with long term artificial ventilation, thanks to the pharmacological action of flunitrazepam. Four patients in the ICU benefited from this protocol. The levels desired were not reached but in two cases out of four it was possible to continue artificial ventilation without the addition of any other drug. Furthermore it was possible to show that the three compartment model developed from healthy subjects remains valid in pathological circumstances. A second protocol based on pharmacokinetic data from four patients should allow us to obtain the objective aimed at.

Advantages and limitations of pharmacokinetic studies in the rationalization of anticancer therapy: methotrexate and 5-FU.

The use of pharmacokinetic studies for individual dose regimen adjustments in anticancer therapy is considered. The example of methotrexate in the treatment of head and neck tumors demonstrates the validity of this approach. Moreover, the importance of biotransformations of this antimetabolite is confirmed using a high pressure liquid chromatography assay. The example of 5-FU outlines the analytical and mathematical difficulties rendering this approach unlikely for routine use. Some preliminary relations between pharmacokinetic parameters (plasma clearance) and clinical response are presented. The determination of the main plasma metabolic 5-6 dihydro 5-FU by GC/MS and its possible role in the nonlinear pharmacokinetics of the drug in therapeutic failure are discussed.

High-dose methotrexate: preliminary evaluation of a pharmacokinetic approach.

Clinical pharmacologic studies have been carried out in patients with head and neck tumors following 36-h continuous infusions of high-dose MTX (1.5 g/m2). The results indicated considerable variation in the amount of MTX in the blood of individual patients. To control these variations, a modified protocol was set up to try to attain the same MTX blood level in all subjects. The protocol has a pharmacokinetic basis and involves determination of the MTX kinetics in each patient. The information thus obtained allows us to compute a 36-h infusion dose so that the MTX plasma levels never exceed a threshold beyond which there is a risk of toxicity to the host. The computation is validated by taking a blood sample 6 h after the beginning of the infusion. If the MTX concentration is higher than its expected value, the infusion rate can then be immediately reduced. Analytical methods that will allow such a computation, the results of the clinical application of this pharmacokinetic approach, and some implications of such a method are discussed.

Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics.

An analytic method, sensitive to 5 ng/ml and specific, has been set up for the determination of unchanged 5-fluorouracil in human plasma, using gas chromatography--mass spectrometry. Its applications to the pharmacokinetic study of unchanged 5-Fluorouracil in man following an intravenous bolus, 8 hours infusion and oral administration confirmed the non-linearity of the kinetic model. (The clearances obtained with an infusion--from 5 to 60 1/min--are 10 to 60 times higher than the ones observed with a bolus--from 0.5 to 1.4 1/min.) The bioavailability of the oral form seems to be about 60 per cent and the absorption appears to be very fast. A attempt to search a mathematical non-linear model of the 5-Fluorouracil kinetics, using computer simulation, is presented.