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Biomedical subjects

C Le Guellec

Publications and source records attributed to C Le Guellec.

At least 19 recordsLinked to original sources

[Prescriptions and children].

Because of a lack in drug evaluation in children, they receive many off license drugs prescription, which means drugs prescribed in an indication, dosage, formulation or age different from the license terms. However, drug evaluation is crucial in paediatrics population because of pharmacokinetics and pharmacodynamics modifications throughout organism development, which make usually wrong any extrapolation to children of data obtained in adults. Drug safety is generally better in infants except in newborns who are at a particularly high drug-related risk because of high frequency of off license drug use, many drugs association and drugs metabolism immaturity. The lack of evaluation in children, the fact that children are the unique target population of some drugs or the maturation phenomena explain some adverse effects more specific in children. The more the children are young, the more they are exposed to medication or drug utilization errors. Physician must take what the SPC, as found in the Vidal dictionary, mentions about children into account while prescribing. Drugs with a paediatric license must be preferred overall, however it should be kept in mind that a paediatric license means only that the drug is active in the indication of the license but it doesn't position it regarding other therapeutic alternatives. Off labeling prescription should be based on a supposed benefit, which had to be justified if a severe side effect occurred.

Child↗

Relationship between calcineurin inhibition and plasma endothelin concentrations in cyclosporine-A-treated kidney transplant patients.

OBJECTIVE: The inter-individual variability of cyclosporine (CsA) pharmacokinetics is well known. However, there is obviously also an inter-individual pharmacodynamic variability, which might be explored by the measurement of biomarkers of CsA effects. METHODS: In 11 renal transplant patients, blood CsA concentrations, calcineurin inhibition in peripheral blood mononuclear cells and endothelin plasma concentrations were measured over a 4-h period after CsA intake. RESULTS: Mean plasma endothelin concentrations were higher than those of healthy subjects (3.66+/-0.46 pg ml(-1) versus 3.15+/-0.40 pg ml(-1), P<0.01) but were not related to CsA dose or blood concentrations. There was a linear relationship between calcineurin inhibition at t (0) and mean endothelin concentrations (r (2)=0.51, P<0.05). Patients with gingival hypertrophy had higher mean endothelin concentrations than patients without this complication (4.0 pg ml(-1) versus 3.4 pg ml(-1), P<0.01), although CsA doses and concentrations were not different between these two groups. CONCLUSION: We observed a correlation between calcineurin inhibition and endothelin concentrations. Endothelin plasma concentrations is a biomarker of CsA effect, which may provide more information than CsA blood concentrations.

Adult↗

Population pharmacokinetics of cisapride in neonates.

OBJECTIVES: We conducted a population pharmacokinetic analysis of cisapride in neonates to study whether metabolic immaturity in this population may lead to increased concentrations. METHODS: Cisapride was administered orally in 91 neonates at the dose of 0.2 mg/kg four times a day. Plasma concentrations were measured using a validated HPLC method. A one-compartment model with first-order absorption was fitted to the data using NONMEM software. RESULTS: One to seven plasma samples were obtained from neonates aged 7-123 days. Cisapride concentrations ranged from 5.5 ng/mL to 172 ng/mL and were not higher than those reported in adults. The absorption constant rate was fixed to 2.5 h-1. Clearance (CL/F) and volume of distribution (V/F) both significantly correlated to weight (WT), but addition of this covariate in V/F did not improve the objective function after it was added in the CL/F covariate model. Prematurity, postnatal age, or coadministered drugs did not affect cisapride clearance. Final population pharmacokinetic parameters (interindividual variability) were: V/F=17,200 mL (90.4%) and CL/F=3.91 x WT(3/4) mL/h (36.3%). CONCLUSIONS: Our finding that cisapride clearance is primarily influenced by weight is in agreement with current recommendations of weight-adjusted doses. This study indicates that no clinically relevant maturational changes in cisapride clearance have to be considered during the first quadrimester of life.

Cisapride↗

Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection.

Published data suggest that therapeutic drug monitoring of human immunodeficiency virus protease inhibitors would improve the management of antiretroviral therapy. The authors have developed a high-pressure liquid chromatographic assay allowing simultaneous determination of six protease inhibitors (ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, and lopinavir), using carbamazepine as internal standard. Detection was based on a dual wavelength ultraviolet spectrophotometer and can be improved by the use of a photodiode array detector. Monitoring was performed 1 month after initiation of therapy or in instances of therapeutic failure, side effects, suspicion of noncompliance, drug interactions, or malabsorption. Trough concentrations were 0.15 to 13.6 mg/L for ritonavir, 0.06 to 9.7 mg/L for indinavir, 0.03 to 5.5 mg/L for saquinavir, and 0.15 to 4.15 mg/L for nelfinavir. Concentrations below the limit of quantification were observed in 63/438 (14%) of the patients. Target concentrations are not well established, and reported in vitro inhibitory concentrations may be of limited value. The authors therefore chose to compare observed concentrations with mean plasma concentrations reported in clinical trials. Observed saquinavir and indinavir concentrations were often below or close to these target concentrations, particularly when used as a single protease inhibitor. Concentration-controlled studies should now be used to select proper target concentrations for each protease inhibitor, either prescribed alone or in combination.

Area Under Curve↗

Application of a gamma model of absorption to oral cyclosporin.

BACKGROUND: Some drugs, such as cyclosporin, exhibit flat and delayed absorption profiles, with a correlation between the delay and the peak width. Such profiles can be described by an absorption model in which the absorption rate is derived from a gamma distribution (of which the classical first-order absorption model is a special case). OBJECTIVE: To develop a model for the pharmacokinetics of extravascular administration of cyclosporin and apply it to a study of the pharmacokinetics of cyclosporin microemulsion in stable renal transplant recipients. PATIENTS AND PARTICIPANTS: 21 renal transplant patients receiving oral cyclosporin microemulsion 75 to 175 mg twice daily. METHODS: The equation of the plasma concentration-time curve after oral administration was expressed as a convolution product between the absorption rate and a multi-exponential impulse response. The convolution integral was computed analytically and expressed in terms of the incomplete gamma function. Cyclosporin was assayed by liquid chromatography/mass spectrophotometry. The model was fitted by nonlinear regression, using a specially developed program. RESULTS: The gamma model yielded a good fit in all of the 21 patients studied. Attempts to fit the same data by a classical exponential with lag-time model failed in most patients. CONCLUSIONS: This model could simplify the Bayesian monitoring of cyclosporin therapy.

Area Under Curve↗

[Comparative diffusion of fusidic acid, oxacillin, and pristinamycin in dermal interstitial fluid after repeated oral administration].

OBJECTIVE: The aim of this study was to use the suction bullae technique to compare skin diffusion of 3 antibiotics commonly used for skin infections (fusidic acid, oxacillin, pristinamycin) and to estimate their potential activity at the site of skin infections. SUBJECTS AND METHODS: This comparative open study was conducted in 12 healthy volunteers using a repeated latin square experimental scheme. Antibiotic concentrations in serum and suction bullae fluid were measured by high performance liquid chromatography after 5.5 days of repeated oral administration of fusidic acid (1 g/d), oxacillin (2 g/d), and pristinamycin (2 g/d). RESULTS: Mean antibiotic concentrations in serum and interstitial fluid (suction bullae fluid) were highest for fusidic acid with a Cmax at 91.3 +/- 23.0 mg/l and 45.5 +/- 18.0 mg/l respectively (interstitial fluid/serum ratio=49 +/- 10 p. 100). For oxacillin, Cmax was 8.3 +/- 3.6 mg/l and 0.98 +/- 0.49 mg/l (ratio 13 +/- 5 p. 100). Pristinamycin concentrations were low with a Cmax at 0.51 +/- 0.40 and 0.26 +/- 0.15 mg/l (ratio 73 +/- 57 p. 100). Comparing the area under the interstitial fluid and the serum concentration-time curves showed that the best diffusion was obtained with pristinamycin (114 +/- 61 p. 100), followed by fusidic acid (57 +/- 13 p. 100) and oxacillin (48 +/- 25 p. 100). DISCUSSION: These data were used to calculate indicators of potential efficacy in the interstitial dermal fluid: inhibitor quotient (Cmax/MIC) and AUIC (ASC/MIC), indicator of the time antibiotic concentrations are maintained above the minimal inhibitor concentration (MIC). This showed that fusidic acid was potentially more active against all staphylococci. For streptococci, the observed interstitial concentrations of pristinamycin and of fusidic acid should theoretically inhibit streptococci A growth, but oxacillin was the most adapted antibiotic.

Administration, Oral↗

Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach.

High-dose methotrexate (HD-MTX) with leucovorin rescue is a component of therapy in children with acute lymphoblastic leukaemia. Since MTX toxicity is related to drug exposure, a monitoring of serum MTX concentrations at H24, H48, H72 and until the concentration is less than 0.2 micromol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 micromol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MTX concentration reaches 0.2 micromol/L in order to decrease the number of samples drawn and to allow for a more rapid patient discharge. Methotrexate population parameters were estimated from a retrospective analysis of 60 infusions in 23 children and MTX concentrations were predicted from an independent set of 20 courses in 14 children with a Bayesian approach using either one (H48) or two (H24 and H48) samples. The following population parameters were obtained using a two-compartment model: CL = 3.51 L/h (inter-individual variability: 66%), Vd = 8.67 L (58%), k12 = 0.0044 h(-1)(105%), k21 = 0.039 h(-1)(25%). Clearance and Vd were found to increase with weight and age respectively. Both sampling schedules tested for the Bayesian estimation enabled accurate prediction of concentrations and provided satisfactory precision despite a small bias. When considering the ability to predict the time at which the threshold was reached, the one-sample (H48) schedule gave the best results. We conclude that a sampling schedule involving only one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 micromol/L in each individual.

Adolescent↗

Inhaled fenoterol-ipratropium bromide in mechanically ventilated patients with chronic obstructive pulmonary disease.

In 18 patients with chronic obstructive pulmonary disease intubated and mechanically ventilated, we prospectively randomized 200 micrograms fenoterol-80 micrograms ipratropium bromide (four puffs) from a metered-dose inhaler (MDI) versus 1.25 mg fenoterol-500 micrograms ipratropium bromide in 5 ml saline from a nebulizer (NEB). Respiratory mechanics were assessed before and 30 min after the end of each delivery by the rapid end-inspiratory airway occlusion technique. We did vary on single breaths the inflation flow (V) from 0.2 to 1.2 L. s-1, at constant inflation volume. The total respiratory resistance of the respiratory system (Rrs) was partitioned into airway (Rint,rs) and tissue (DeltaRrs) resistances. We found that Rrs was equivalently reduced, from 16.49 +/- 1.37 to 14.85 +/- 1.88 cm H2O. L-1. s with MDI (p < 0.05) and from 18.04 +/- 1.85 to 15.15 +/- 1.33 cm H2O. L-1. s with NEB (p < 0.01). Whereas the prevailing effect of MDI was to reduce Rint,rs, that of NEB was to decrease DeltaRrs. In addition, the V resistance of the respiratory system over the whole range of V was significantly affected by NEB but not by MDI.

Administration, Inhalation↗

Improved selectivity for high-performance liquid chromatographic determination of clonazepam in plasma of epileptic patients.

We report a high-performance liquid chromatography method for clonazepam determination in plasma. The use of a synthetic silica-based stationary phase markedly improved clonazepam resolution compared to standard reversed-phase columns. A liquid-liquid extraction was used, associated with reversed-phase chromatography, gradient elution and ultraviolet detection. Accuracy and precision were satisfactory at therapeutic concentrations. Selectivity was studied for benzodiazepines or other antiepileptic drugs, with particular attention to newly marketed drugs i.e., gabapentine and vigabatrin. No interfering substance was evidenced. Under the conditions described, it was possible to quantify clonazepam at nanogram level even when carbamazepine was present at therapeutic concentrations.

Anticonvulsants↗

Stability of rifampin in plasma: consequences for therapeutic monitoring and pharmacokinetic studies.

Interest in determining plasma levels of rifampin for adjustment of dosage regimens has increased, but conflicting results exist concerning rifampin stability. The authors developed a high-performance liquid chromatography assay to monitor rifampin plasma concentrations that was used to study the possible degradation of rifampin in plasma samples. This report describes the stability of rifampin in plasma kept at an ambient temperature for 24 hours or stored at -20 degrees C for 2 weeks. The possible protective effect of adding ascorbic acid was also studied. The results indicate that rifampin degrades rapidly in plasma at an ambient temperature, and a 54% loss was observed within 8 hours. This degradation can be effectively prevented by adding ascorbic acid, thus prolonging stability for up to 12 hours. The same results were observed with samples obtained as part of routine drug monitoring. Degradation was found to be greater at low rifampin concentrations. The authors subsequently demonstrated that decomposition of rifampin occurs after storage for 1 week at -20 degrees C. However, in samples supplemented with ascorbic acid before freezing, no degradation was observed within 14 days at the two concentrations tested. Rifampin was more stable in specimens drawn from treated patients, suggesting possible in vivo stabilization of the molecule. Further studies are needed to determine stability of rifampin for longer storage periods. On the basis of these results, plasma samples obtained from patients receiving rifampin should be immediately supplemented with ascorbic acid and analyzed as soon as possible.

Antibiotics, Antitubercular↗

Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs.

This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species. Propofol glucuronidation was studied in microsomal fractions from rat, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes. The propofol-uridine diphosphate-glucuronosyltransferase (UGT) activity measured in liver microsomes was higher in rabbit than in rat. Among the three tested species, human livers exhibited the highest activity, with only small variability in the three samples studied. Animal kidney, but not lung (animal or human), microsomes were able to glucuronidate propofol, meaning that extrahepatic metabolism of propofol exists, at least in the kidney, in the tested species (rat and rabbit). Since metabolic interactions are potential sources of prolonged drug effect or overdose, we screened the effect of 21 compounds (known substrates of various UGT or potentially coadministered drugs) on the glucuronidation of propofol by human liver microsomes. Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation. Inhibition was observed with several drugs potentially coadministered during pre-, per, or postoperative periods (e.g., acetylsalicyclic acid, ketoprofen, oxazepam, fentanyl). Although not directly transposable to the in vivo situation, these results indicate that such interactions are theoretically possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

Monitoring of pefloxacin serum concentrations in intensive care unit patients: comparison of a new immunoassay with high-performance liquid chromatography.

Serum quinolone concentrations are not routinely measured in clinical practice. However, in order to optimize quinolone treatment, monitoring of serum concentrations could sometimes be useful particularly in critically ill patients. A new enzyme-linked immunosorbent assay (ELISA) that permits direct determination of pefloxacin in serum is described. To validate this new assay, pefloxacin concentrations were measured in 314 serum samples from 74 intensive care unit patients treated with pefloxacin (400 mg i.v. twice daily). Reference concentrations were obtained by reverse phase high-performance liquid chromatography (HPLC) with spectrofluorometric detection. Results showed that concentrations measured by ELISA correlated very well with those by HPLC (r = 0.957; y = 1.03 and x -0.15). In this population, the concentrations found by ELISA varied between individuals (Cmin = 0.70-39 micrograms/ml; Cmax = 5.2-40 micrograms/ml). However, 86% of the measured Cmax and Cmin levels were adequate for optimal pefloxacin therapy. Only 11% of Cmin and 14% of Cmax were below the optimal values (i.e., 2 and 8 micrograms/ml, respectively). These results suggest that despite the large therapeutic index of pefloxacin, monitoring of its serum concentrations using a rapid ELISA technique may be useful for optimal antimicrobial treatment of certain intensive care unit patients.

Adolescent↗

Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes.

The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive inhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibition of dextromethorphan-O-demethylation: lomustine (Ki = 7.7 microM), doxorubicin (Ki = 75 microM), vinorelbine (Ki = 22 microM), and vinblastine (Ki = 42 microM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.

Antineoplastic Agents↗

Identification and estrogen induction of two estrogen receptors (ER) messenger ribonucleic acids in the rainbow trout liver: sequence homology with other ERs.

The estrogen-binding region of the cDNA for chicken ER reveals a mRNA of 3.5 kilobases (kb) in rainbow trout liver. The level of this messenger, which is very low in the liver of naive male animals, can be increased by estrogen stimulation. With this chicken probe, we have isolated a clone from a lambda gt10 trout liver cDNA library. The partial cDNA sequence, which encompasses most of the coding region, shows two domains of striking amino acid homology with human, avian, and Xenopus estrogen receptors (ERs) (DNA binding region: 90%, Hormone binding region: 60%). With this specific probe rainbow trout ER, we detected another messenger (4.5 kb) that is less expressed than the 3.5 kb messenger. The kinetics of stimulation of the two messengers is compared with the kinetics of accumulation of vitellogenin mRNA after E2 administration. This report constitutes the first identification of ER mRNA from a fish.

Amino Acid Sequence↗