Search

Glia cell missing (GCM) transcription factors form a small family of transcriptional regulators in metazoans. The prototypical Drosophila GCM protein directs the differentiation of neuron precursor cells into glia cells, whereas mammalian GCM proteins are involved in placenta and parathyroid development. GCM proteins share a highly conserved 150 amino acid residue region responsible for DNA binding, known as the GCM domain. Here we present the crystal structure of the GCM domain from murine GCMa bound to its octameric DNA target site at 2.85 A resolution. The GCM domain exhibits a novel fold consisting of two domains tethered together by one of two structural Zn ions. We observe the novel use of a beta-sheet in DNA recognition, whereby a five- stranded beta-sheet protrudes into the major groove perpendicular to the DNA axis. The structure combined with mutational analysis of the target site and of DNA-contacting residues provides insight into DNA recognition by this new type of Zn-containing DNA-binding domain.

This outbreak of colonization of neonates in a 10-bed pediatric intensive care unit illustrates the probable role of a healthcare worker (HCW) in the transmission of methicillin-resistant Staphylococcus aureus, despite good hygienic practices. It raises the issue of preventive exclusion of HCWs affected by chronic skin disease from high-risk units.

Glial cells missing (GCM) proteins form a small family of transcriptional regulators involved in different developmental processes. They contain a DNA-binding domain that is highly conserved from flies to mice and humans and consists of approximately 150 residues. The GCM domain of the mouse GCM homolog a was expressed in bacteria. Extended X-ray absorption fine structure and particle-induced X-ray emission analysis techniques showed the presence of two Zn atoms with four-fold coordination and cysteine/histidine residues as ligands. Zn atoms can be removed from the GCM domain by the Zn chelator phenanthroline only under denaturating conditions. This suggests that the Zn ions are buried in the interior of the GCM domain and that their removal abolishes DNA-binding because it impairs the structure of the GCM domain. Our results define the GCM domain as a new type of Zn-coordinating, sequence-specific DNA-binding domain.

A novel procedure to specifically quantify low amounts of pipecolic acid and structurally related compounds in several types of biological materials has been characterized. From crude extracts of various types of biological material, the first step was to clear all low-molecular-weight compounds containing primary amino groups by a treatment of nitrous acid. Using a microwave-assisted reaction, the remaining substances containing secondary amino groups were then derivatized with ninhydrin and made soluble in glacial acetic acid. The derivatives produced were resolved by reverse-phase HPLC and detected by spectrophotometry at 570nm. This procedure allowed more rapid determination of pipecolic acid since microwave heating shortened the time needed for derivatization compared with heating at 95 degrees C in a water bath. The complete analysis of the chromogens for pipecolic acid and related substances was achieved in 20min. Under such conditions, the detection threshold for pipecolic acid was about 20pmol. The suitability of the technique was assessed in various biological matrices known to contain significant amounts of this amino acid. The data obtained are in accordance with those available in the literature. To our knowledge, this is the first method using the ninhydrin reaction in a precolumn, microwave-assisted derivatization procedure for detection and determination of heterocyclic alpha-amino acids.

Fetal exposure to valproic acid or carbamazepine increases the risk of neural tube defect (NTD). The risk of a mother having a baby with spina bifida has been estimated at 1-2 p. 100, close to the rate of risk of recurrent cases. No study has evaluated the effect of folic acid in neonates of women treated with valproic acid or carbamazepine although the protective effect against NTD has been proven in other populations. Periconceptional folic acid supplementation, 0.4 to 1 mg/day, for at least one month prior to conception and until the date of the second missed menstrual period or later decreases the incidence of a first occurrence of neural tube defect. Periconceptional folic acid supplementation, 4 mg/day, decreases the recurrence of NTD in women who had previously had a child with NTD. It seems pertinent to recommend periconceptional folic acid supplementation in women treated with carbamazepine or valporic acid. There are very few data in women on which to base a decision to advise taking 4 mg/day (as used in recurrence prevention) or low doses of 0.4 mg/day (used in primary prevention).

A total of 588 blood specimens collected in an emergency unit were screened for benzodiazepines (BZDs) using enzyme-multiplied immunoassay and gas chromatography. Two-hundred eighty-five samples were positive for BZDs, and 303 samples that were negative by EMIT included 20 samples with BZDs detectable by gas-liquid chromatography. A total of 15 BZDs were identified, and the most frequently occurring were nordiazepam, bromazepam, diazepam, and alprazolam. Individual BZDs were found in 74% of cases, but some samples contained two, three, or even four BZDs. There is a risk of missing intoxication by BZDs with low therapeutic range and/or low cross-reactivity (alprazolam, bromazepam, flunitrazepam). There is a risk of misinterpreting a positive result for some BZDs with high therapeutic range and/or high cross-reactivity (nordiazepam), which may reflect a pharmacologically ineffective concentration. A semiquantitative analysis is inappropriate even when the identity of BZD is known. Immunoassays are the only methods presently available for use in emergencies, but physicians must be clearly informed of their limitations and interpret results with caution.

Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 μg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.

The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans.

Brain ageing affects numerous cerebral metabolic pathways such as cerebral glucose consumption or protein synthesis rate. The pharmacological effect of a mixed D1-D2 dopaminergic agonist, piribedil, on this last metabolism is reported. Cerebral Protein Synthesis Rate (CPSR) was measured by the [35S]L-methionine autoradiographic procedure in 38 main brain regions of 11 and 26-month-old Wistar rats after a 2-month treatment per os at 9 and 30 mg/kg/day with piribedil. Mean decrease of CPSR was -21% during the 15-month ageing we followed, with important local variations. Mean CPSR increased with the two treatments, +25% in mature and +35% in aged rats. Treatments restored CPSR of aged rats to the exact mature subjects levels in quite all the brain regions. No dose-effect or asymetrical modification was statistically revealed for the two treatments. Metabolic increases involved particularly central brain gray structures, especially some DA-targeted brain nuclei concerned with behaviour and learning. This effect argued for a general metabotrophic effect of D1-D2 dopamine stimulation of the brain. The original pattern of local ageing of brain protein synthesis in rat was also incidentally reported. This was the first direct report of a wide and effective metabolic activation of CPSR in the brain during ageing by a curative dopaminergic agonist treatment.

The development of chromatography technology, with the increasing availability of easier-to-use mass spectrometers combined with gas chromatography (GC), the use of diode-array or programmable variable-wavelength ultraviolet absorption detectors in conjunction with high-performance liquid chromatography (HPLC), and the availability of scanners capable of reading thin-layer chromatography (TLC) plates in the ultraviolet and visible regions, has made for easier, quicker and more positive identification of cannabis samples that standard analytical laboratories are occasionally required to undertake in the effort to combat drug addiction. At laboratories that do not possess the technique of GC combined with mass spectrometry, which provides an irrefutable identification, the following procedure involving HPLC or TLC techniques may be used: identification of the chromatographic peaks corresponding to each of the three main cannabis constituents-cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN)-by comparison with published data in conjunction with a specific absorption spectrum for each of those constituents obtained between 200 and 300 nm. The collection of the fractions corresponding to the three major cannabinoids at the HPLC system outlet and the cross-checking of their identity in the GC process with flame ionization detection can further corroborate the identification and minimize possible errors due to interference.

MDL 72222, an antagonist of 5HT3 receptors, was labeled with a specific radioactivity of 340-400 mCi/mumol by alkylation of the nor-precursor with [11C]CH3I. The yield of the synthesis, starting from [11C]methyliodide to the purified product and corrected for decay, was good approximately 70-75%. After i.v. injection, [11C]MDL 72222 diffuses readily in the central nervous system but is not detected as metabolites in brain and blood, during 1 h study carried out in rats. The time course and distribution of [11C]MDL 72222 was assessed in various organs (liver, lung, kidney, heart, whole brain) and in blood; the organ uptake was rapid and large; the highest accumulation was found in the lung. The regional brain distribution shows initial uptake and subsequent retention of tracer in favor of the cerebral cortex. The level of brain radioactivity was not reduced by pretreatment with a 1000-fold excess of unlabeled MDL 72222. These results suggest that [11]MDL 72222 is of limited interest for 5HT3 receptor binding studies in brain in vivo, presumably mainly because of large non-specific binding.

Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.

Flumazenil is a specific antagonist of the central benzodiazepine receptor (CBZR). Labelled with 11C, this compound is the reference radioligand for positron emission tomography (PET) study of the CBZR in humans and primates. The time-course of [11C]-flumazenil radioactivity and its main acid metabolite [11C] Ro 15-3890 were reconstructed from the time-course of total radioactivity in plasma after administration with high or low SRA in primates and humans, applying an extraction procedure validated by TLC. The measured pharmacokinetics of [11C]-flumazenil (T1/2 beta = 45.1 +/- 12.3 min, T1/2 alpha = 1.5 +/- 1.5 min; K = 0.14 +/- 0.14 min-1; Vd area = 44.0 +/- 17.0 l; Clp = 40.0 +/- 8.5 l/h) exhibited a very rapid distribution phase followed by fast elimination, with a large volume of distribution; these results were confirmed by HPLC determinations and agree with previously published data on unlabelled flumazenil. Pharmacokinetics of [11C] Ro 15-3890 acid metabolite show that high drug concentrations in the blood are promptly achieved (kf = 0.13 +/- 0.004 min-1), with a very rapid elimination half-life (T1/2m = 4.47 +/- 1.31 min) comparable to that of [11C]-flumazenil. The percentage metabolization of parent compound to the acid [11C] Ro 15-3890 was constant from the 15th minute and was significantly higher in man compared to the monkey. This percentage was increased by prior eating. The other putative metabolites, i.e. labelled [11C] Ro 15-4965 and unlabelled Ro 15-5528, were never observed at detectable concentrations with TLC and HPLC in rabbit, baboon and human blood samples. This pharmacokinetic study of plasma flumazenil may be useful to implement a dynamic method of CBZR quantification using PET and for analysis of pharmacokinetics in brain tissue.

The determination of the percentage of unchanged [11C]Ro 15-1788 with respect to total radioactivity, essential for the pharmacokinetic exploitation of data of blood radioactivity decrease obtained in PET studies, may be carried out with equal results using either an extraction procedure or a TLC method. The analysis of blood samples of various sources (rabbits, baboons, healthy volunteers and anxious patients) and the use of an automatic linear scanner to quantify the radioactive distribution on the TLC plates lead to the conclusion that only [11C]Ro 15-1788 and its acid metabolite [11C]Ro 15-3890 and no other radioactive compound are present in blood at detectable concentration.

A gas chromatographic method using a short, high-resolution capillary column connected to a specific thermoionic detector and requiring a simple and short extraction step without evaporation was developed for the rapid and precise determination of two new hypnotics, zolpidem and zopiclone, in serum at concentrations greater than 5 ng/mL. The assay was linear between 5 and 200 ng/mL, with coefficients of intra- and interassay variation less than 5% for both. The method was validated and then used to analyze zolpidem serum concentrations in nine rabbits after oral administration of 0.5 mg/kg and zopiclone serum concentrations in six patients treated orally with a 7.5-g dose.

The pharmacokinetics of fluconazole given orally (100 mg) or intraperitoneally (50 and 150 mg) were determined in 15 patients with chronic renal failure who were undergoing continuous ambulatory peritoneal dialysis. The half-life (72 to 85 hours) was intermediate between values obtained in healthy volunteers and in patients with renal insufficiency studied during an interhaemodialysis period. The peritoneal clearance, 0.26 to 0.33 L/h, led to an 18% recovery of administered drug in the dialysates after 48 hours. The peritoneal absorption was slow (time to peak plasma concentration 7 hours) but the peritoneal bioavailability was excellent at 87 +/- 5%. The mean concentrations of fluconazole up to 24 hours were 770 and 1900 micrograms/L after single intraperitoneal doses of 50 and 150 mg, respectively. The volume of distribution (40 to 60 L) did not differ from that determined in patients with normal renal function. In the case of fungal peritonitis essentially attributed to Candida spp., a 6-hour intraperitoneal infusion of fluconazole 150 mg every 2 days appears to be a good regimen to rapidly exceed minimum inhibitory concentrations and treat infection without risk of systemic dissemination of fungi or toxicity.

The pharmacokinetics of piperacillin given intravenously (1 or 2 g) to nine patients with chronic renal failure and undergoing continuous ambulatory peritoneal dialysis was intermediate between values obtained in healthy volunteers and in patients with renal insufficiency studied between dialyses: half-life, 2.4 h; total clearance, 100 mL/min; urinary or peritoneal clearance, 3 mL/min. The intraperitoneal administration of piperacillin in dialysis fluid (400 mg or 1 g to five patients) increased the half-life (6 to 7 h) and decreased the volume of distribution of about two thirds. In both instances, the area under the curve was well correlated with dosage. The absorption of piperacillin by an inflamed peritoneum in eight patients suffering from peritonitis and treated with 400 mg, 1 g, or 2 g, was increased and returned to normal concurrently with care. Consequently, the recommended dosage is intravenous administration of 2 g of piperacillin every 8 h or intraperitoneal administration of 1 g every 6 h in the dialysate. With such conditions, serum concentrations greater than minimal inhibitory concentrations and sufficient to avoid dissemination of piperacillin-susceptible organisms without risk of accumulation are obtained.

Twenty patients in a stable condition suffering from congestive heart failure were treated with digoxin for at least three weeks and then with nicardipine concomitantly for five days. No statistically significant variation in serum digoxin concentrations determined at seven control times during a 24-hour period or in its mean concentration was found in the two groups of values examined before and after the concurrent nicardipine treatment. The mean increase of 6.8% in the AUC0----24h was not significant either. Since the maximum increase in serum digoxin concentrations at the steady state never exceeded 0.5 ng/ml, a toxic effect is not likely to occur in patients whose digoxin levels are normally monitored.

The symptoms of acute poisoning after accidental administration of ten times the usually prescribed dosage of caffeine in a premature infant included the following neurological signs: incessant tremors, hypertonia, continuous opisthotonos posture, whining and crying and digestive disturbances. The very high serum caffeine levels, 160 mg/l, determined 66 hours after the first administration was confirmed by the very high cerebrospinal fluid caffeine concentration 115 mg/l. Two exchange transfusions performed at an interval of 16 hours produced a large decrease in serum caffeine levels of approximately 40 mg/l each time, and a similar decrease in the cerebrospinal fluid concentration. The clinical status of the infant improved very rapidly and the child's psychomotor development was normal at 3 months of age.

The combined use of high-pressure liquid chromatography (HPLC) and high-resolution gas-liquid chromatography (GLC) afforded a means of isolating three substances in samples of cannabis, of determining their retention times in HPLC and in GLC with and without derivation, and of identifying them, by comparison with the data in the literature, with the three major constituents of cannabis: cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN), without using either control substances or a mass spectrometer. Furthermore, calculation of the peak area ratios (formula: see text); for the different sample varieties can serve as a criterion for the differentiation of resinous cannabis and textile cannabis.

Prilocaine pharmacokinetics were determined in 60 patients receiving the drug by two different routes of administration (intra-articular and subcutaneous) during arthroscopy under local anesthesia with controlled pressure irrigation. Resorption of prilocaine by subcutaneous tissues was slow and did not lead to high serum levels. On the contrary, prilocaine resorption by the synovium was fast and induced a sharp serum peak (265.8 +/- 163.5 ng/ml) in the hour after the end of the examination. The drug was completely eliminated from the blood after 24 hours, as the prilocaine t1/2 is about 5 hours. The first procedure was perfected to reduce the risk of methemoglobinemia, which occurred in four of 105 patients. Applied pressure was lowered to 100 mm Hg to prevent the escape of anesthetic solution into the soft tissue of the leg, the prilocaine concentration was reduced to 1 gm/L, and the arthroscope was only set up after a delay to allow the intra-articular anesthetic effect of prilocaine to become established. So far, 200 arthroscopies have been performed with this improved protocol without any problem.

It has been established that the use of beta-2 sympathomimetic aerosols is a safe and efficacious treatment of asthma. Unexpected cases of sudden death amongst insufficiently-treated patients or patients who stopped their treatment are not linked with the use of these drugs. To assess the risk of possible "receptor desensitization" it is necessary to notify these accidents to the Committee on Safety of Drugs and to take into consideration the opposite results of further administration and termination of treatment.

We studied the kinetics of piperacillin in patients under continuous ambulatory peritoneal dialysis. Piperacillin 2 g was injected intravenously in 6 patients whereas 1 g was given intraperitoneally either a single dose in 3 patients without infection or the same dose every six-hours in 4 patients with peritonitis. Piperacillin was assayed by HPLC. After intravenous administration, the mean plasma piperacillin concentration was 3.1 +/- 5.6 mg/l at 12 h, the mean plasma t1/2 at 2.43 +/- 0.84 h, the volume of distribution at 20.4 +/- 6.3 l and the peritoneal clearance at 0.19 +/- 0.04 ml/min. After iterative intraperitoneal administration, serum and dialysate concentrations of piperacillin were above the minimum inhibitory concentration for susceptible pathogens without antibiotic accumulation. Peritoneal absorption was higher during peritonitis (83.4 +/- 4.8%) than without peritonitis (67.8 +/- 8.5%). Piperacillin 2 g IV every 8 hours or 1 g IP every 6 hours seemed to be the appropriate regimen in patients with chronic renal failure on CAPD.

The pharmacokinetics of intravenous ketoprofen were evaluated in 37 patients suffering from acute ureteral colic. Four studies were established to obtain a rapid and persistent analgesic effect: group I: 100 mg of ketoprofen as bolus; group II: short infusion of 100 mg of ketoprofen (1.5 or 2 hours); group III: loading dose of 35 mg ketoprofen plus an infusion of 25 mg/h and 33 mg/h. Serum concentrations of ketoprofen were measured by high pressure liquid chromatography. The mean (+/- SD) values of pharmacokinetic parameters measured with a 2 open compartment model were as follows: distribution half-life: 0.34 +/- 0.19 h; elimination half-life: 2.05 +/- 0.58 h; kel: 0.96 +/- 0.28 h-1; k21: 0.94 +/- 0.42 h-1; k12: 1.00 +/- 0.70 h-1; volume of central compartment: 5.58 +/- 1.67 l; volume of tissue compartment: 5.14 +/- 2.12 l; plasma clearance: 5.10 +/- 1.14 l. h-1. These results concur with previously published data obtained after oral, rectal or intramuscular administration. Ketoprofen due to its peripheric anti-inflammatory, antiprostaglandins and central actions gives the best results with the intravenous administration. Administration of a ketoprofen bolus suppressed pain within ten minutes in 71% of patients.

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.

Fifteen asthmatic patients receiving a sustained-release theophylline preparation were also treated with spiramycin for at least 5 days. The macrolide antibiotic had no significant effect on the steady-state theophylline concentration, unlike erythromycin and troleandomycin, which belong to the same class of antibiotics. The latter two drugs have different chemical structures and decrease theophylline clearance. Accordingly, spiramycin comedication does not require special serum level drug monitoring or adjustment of the dose of theophylline.

The aim of this study was to observe if a method useful for measuring attentional effects could be applied in testing the differential effects of caffeine, the beta-stimulant salbutamol, and the beta-blocker propranolol. Caffeine (300 mg) was administered to a sample of 19 normal subjects compared to two samples of 40 controls. Caffeine was found to increase attention and vigilance by augmenting the number of repetitions of responses to a verbal stimulus in a free word association test. This pattern was also seen with salbutamol and propranolol, but to a lesser degree.

This enquiry, the limits of which are easy to determine, permits one to note that in patients with chronic hemorrhagic colonic disease samples of digestive juice, carried, out at the level of the colonic mucosa, permit isolation of a large number of pseudomonadaceae, these bacteria are extremely various. A single patient may harbour 10 to 12 species. These bacteria, usually harmless, belong to the natural microbiocenoses, but they may under certain circumstances, increase in number and, according to Fabiani, induce severe symptoms or even be fatal. The mass of bacteria isolated and identified did not permit a study of bacterial sensitivity. The most seriously affected subjects clinically, usually had various bacteria which excludes the accusation of one species and eliminates any idea of bacterial specificity in the constitution of the syndromes observed. The disturbance seems to be a consequence of these chronic diseases and not the cause. In fact, no pathogenic germ was isolated, which one might consider to be responsible for the disease. Finally, it is wise to conclude that patients with irritable colon syndromes who formed part of this investigation, simply presented some imbalance in the bacterial flora which was sometimes very marked with a predominance of proteolytic Pseudomonas.

Five clinical cases of interaction between benzodiazepines on one hand and erythromycin, troleandomycin, josamycin and cimetidine on the other hand have been analyzed. These interactions resulted in severe disorders of behaviour, amnesia (including amnesia-automatism syndrome in one case), disturbances of consciousness and withdrawal syndrome. These disorders were consecutive to inhibition of the hepatic cytochrome P-450 system. Practical means of avoiding this risk consists in limiting such drug combinations, reducing benzodiazepine dosage and, if a combined treatment is necessary, using by preference either benzodiazepines degraded by conjugation instead of oxidation, or macrolides, or anti-H2 compounds with reduced inhibitory effect on microsomes.

Fluconazole concentrations in biological fluids were determined by high-performance gas chromatography. A simple extraction procedure with chloroform, under basic conditions and after the addition of UK-47,265 as the internal standard and with no evaporation stage, was carried out prior to analysis. A solid injector and a 15-m capillary column, coated with a nonpolar phase and connected to a nitrogen-selective detector that afforded an excellent selectivity and sensitivity, constituted the gas chromatographic system. The duration of each analysis was less than 4 min and the minimum detectable serum concentration was 50 ng/mL. In five patients undergoing chronic peritoneal dialysis, the mean serum concentrations +/- SD at 1, 6, and 48 h after the intraperitoneal administration of a single dose of fluconazole were, respectively, 325 +/- 75, 928 +/- 159, and 607 +/- 80 ng/mL.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).