Search PubMed⌕ Search

Biomedical subjects

J Debord

Publications and source records attributed to J Debord.

At least 19 recordsLinked to original sources
PubMed2001

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↗
PubMed2000

Adaptive control methods for the dose individualisation of anticancer agents.

Numerous studies have found a clear relationship between systemic exposure and the toxicity or (more rarely) the efficacy of anticancer agents. Moreover, the clearance of most of these drugs differs widely between patients. These findings, combined with the narrow therapeutic index of anticancer drugs, suggest that patient outcome would be improved if doses were individualised to achieve a target systemic exposure. Bayesian maximum a posteriori probability (MAP) forecasting is an efficient and robust method for the optimisation of drug therapy, but its use for anticancer drugs is not yet extensive. The aim of this paper is to review the application of population pharmacokinetics and MAP to anticancer drugs and to evaluate whether and when MAP Bayesian estimation improves the clinical benefit of anticancer chemotherapy. For each drug, the relationships between pharmacokinetic variables [e.g. plasma concentration or the area under the concentration-time curve] and pharmacodynamic effects are described. Secondly, the methodologies employed are considered and, finally, the results are analysed in terms of predictive performance as well as, where possible, the impact on clinical end-points. Some studies were retrospective and intended only to evaluate individual pharmacokinetic parameter values using very few blood samples. Among the prospective trials, a few studied the pharmacokinetic/pharmacodynamic relationships which provided the basis for routine pharmacokinetic monitoring. Others were performed in clinical context where MAP Bayesian estimation was used to determine maximum tolerated systemic exposure (e.g. for carboplatin, topotecan, teniposide) or for pharmacokinetic monitoring (e.g. for methotrexate or platinum compounds). Indeed, its flexibility in blood sampling times makes this technique much more applicable than other limited sampling strategies. These examples demonstrate that individual dose adjustment helps manage toxicity. The performance of pharmacokinetic monitoring is linked to the methodology used at each step of its design and application. Moreover, a limitation to the use of pharmacokinetic monitoring for certain anticancer drugs has been the difficulty in obtaining pharmacokinetic or pharmacodynamic data. Recent progress in analytical methods, as well as the development of noninvasive methods (such as positron emission tomography) for evaluating the effects of chemotherapy, will help to define pharmacokinetic-pharmacodynamic relationships. Bayesian estimation is the strategy of choice for performing pharmacokinetic studies, as well as ensuring that a given patient benefits from the desired systemic exposure. Together, these methods could contribute to improving cancer chemotherapy in terms of patient outcome and survival.

Animals↗
PubMed1998

Inhibition of arylesterase by aliphatic alcohols.

The inhibition of arylesterase (EC 3.1.8.1) by 11 aliphatic alcohols (one to seven carbon atoms) was studied in blood serum from healthy donors. Inhibition curves were described by the Hill equation, with a Hill coefficient (n) close to unity, except for some alcohols, mainly the lowest. The inhibiting activity of the alcohols was highly dependent on their structure, since the C50 values covered about three orders of magnitude. The least active compound was methanol (C50 approximately 1 M) and the most active was heptanol (C50 approximately 7.4 x 10(-4) M). The A and B isozymes (differing by the amino acid at position 191) had similar inhibition parameters with the alcohols tested. Quantitative structure-activity relationships were computed with either the experimental solvation parameters of Abraham [6] or the theoretical parameters of Wilson and Famini [11]. Both methods gave similar results, with a slight advantage to the empirical parameters in terms of simplicity and statistical significance. The two main determinants of inhibition were identified as molecular volume and lack of polarity. The effect of volume was non-linear, tending to a maximum when the length of the alcohol increased. For a given number of carbon atoms, the best inhibitor was the least polar compound. These results point to a binding site consisting mainly of nonpolar aliphatic amino acids, and located in the depth of the protein molecule.

Carboxylic Ester Hydrolases↗
PubMed1998

Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients.

OBJECTIVE: To develop a population pharmacokinetics of vinorelbine in a population of non-small-cell lung cancer (NSCLC) patients using a Bayesian estimation in order to calculate for any further patient, individual pharmacokinetic parameters from few blood samples. METHODS: Vinorelbine was given by a 15-min infusion (30 mg x m(-2)) to eight patients with NSCLC. Its serum concentration was determined by HPLC and its pharmacokinetics was described by a three-compartment open model with elimination from the central compartment. Volume of the central compartment (V1) and rate constants (k10, k12, k21, k13, k31) were selected as population pharmacokinetic parameters and computed by non-linear regression (two-step approach) from 14 to 18 concentration measurements per course. Subsequently, these parameters were used by the Bayesian estimator to calculate individual pharmacokinetics from only 2 or 3 measured concentrations. RESULTS: The population mean values (CV%) of V1, k10, k12, k21, k13, k31, CL, t1/2gamma were respectively 21 l (55%), 3.2 h(-1) (29%), 7.7 h(-1) (74%), 1.3 h(-1) (67%), 4.7 h(-1) (53%), 0.04 h(-1) (20%), 57 l x h(-1) (31%) and 43 h (36%). The comparison of results obtained from the Bayesian estimator and from the three-compartment model showed that CL and t1/2gamma were well predicted (relative deviation: +/- 12 to 22%) by the Bayesian method using only two blood samples. CONCLUSION: We demonstrated that Bayesian estimation allows, at minimal cost and minimal disturbance for the patient, the determination of several vinorelbine pharmacokinetic parameters and therefore dose adaptation from as few as two drug concentrations, measured at 6 h and 24 h after infusion.

Aged↗
PubMed1998

Decrease of serum paraoxonase activity in chronic renal failure.

Paraoxonase is an esterase that hydrolyzes organophosphate compounds. The enzyme is associated with HDL and could protect LDL against peroxidation, which suggests a possible involvement of paraoxonase in the antiatherogenic properties of HDL. Paraoxonase activity has been shown to be low in patients with myocardial infarction, diabetes mellitus, or familial hypercholesterolemia. Because cardiovascular disease is the main cause of death in chronic renal failure, serum paraoxonase activity was measured by spectrophotometry using three synthetic substrates (phenyl acetate, paraoxon, and 4-nitrophenyl acetate) in 305 patients with kidney disease, including 47 patients with non-end-stage chronic renal failure, 104 patients treated with hemodialysis, 22 patients treated with peritoneal dialysis, and 132 renal transplant patients. Patients were compared with two groups of aged-matched control subjects (total number = 195). Especially with 4-nitrophenyl acetate, paraoxonase activity was lower in patients with some degree of renal insufficiency (chronic renal failure [P < 0.05], chronic hemodialysis [P < 10(-4)], chronic peritoneal dialysis [P < 10(-4)]) than in control subjects. In transplant patients, paraoxonase activity was not found to be different from that in control subjects. The decrease of paraoxonase activity and thus the reduction of its antiatherogenic properties in renal failure could be an essential factor of premature vascular aging, especially when dialysis is used. Renal transplantation seems to restore paraoxonase activity.

Adolescent↗
PubMed1998

Influence of biological variables upon pharmacokinetic parameters of intramuscular methotrexate in rheumatoid arthritis.

The pharmacokinetics of methotrexate were studied in 22 patients receiving 5-15 mg per week in a single i.m. administration for rheumatoid arthritis. The data consisted of 3 plasma levels per patient, taken at 2, 6, and 12 hours after the administration. The concentration of methotrexate was determined by fluorescence polarization immunoassay. The pharmacokinetic parameters of a 2-compartment model were determined by Bayesian estimation using the population values of Bressolle et al. [1996]. The fitted parameters were: total plasma clearance of methotrexate (CL), first-order absorption constant (ka), volume of central compartment (V1), and transfer constants between the 2 compartments (k12 and k21). Additional parameters were derived from the fitted ones: maximal concentration (Cmax), time to maximum (tmax), volume of distribution at steady-state (Vss), and terminal half-life (t1/2). Twenty-one biological covariates were considered to explain the interpatient variability. The relationships between these covariates and the pharmacokinetic parameters were investigated by principal component analysis and multiple regression analysis. About 90% of the variability of CL were explained by 4 variables (sex, age, height and serum creatinine). About 50%-70% of the variability of the other pharmacokinetic parameters were explained by a set of covariates including age, height, creatinine, creatinine clearance, and dose. The effect of dose was noticed mainly on k12, Vss, and t1/2, thus suggesting that the transfer of the drug from plasma to tissues may be nonlinear. The possibility of predicting CL with a good precision would facilitate the computation of dosage regimens in these patients.

Adult↗
PubMed1998

Is there an optimal time to administer methotrexate in the treatment of rheumatoid arthritis?

OBJECTIVE: To determine the optimal time to administer methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: In a crossover study 23 patients were administered MTX intramuscularly at either 10 AM or 6 PM. A 2 week interval separated the 2 injections. MTX concentrations were measured using a fluorescence polarization immunoassay. Pharmacokinetic variables were estimated using a Bayesian approach. The morning and evening schedules were compared using analysis of variance to determine the optimal time of injection. RESULTS: No statistical difference was found in the pharmacokinetics of MTX according to hour of injection. A difference in the creatinine clearance, however, was observed in the samples obtained at noon and 8 PM, but clearance of MTX was unchanged. CONCLUSION: Pharmacokinetic variables suggest that MTX can be administered either in the morning (10 AM) or evening (6 PM) in the treatment of RA.

Adult↗
PubMed1997

Simultaneous determination of lidocaine and bupivacaine in human plasma: application to pharmacokinetics.

High-performance liquid chromatography has been applied to the simultaneous determination of lidocaine and bupivacaine levels in human plasma, using etidocaine as internal standard. The method was found to be linear in the range 10-2,000 micrograms/l for lidocaine and 20-1,000 micrograms/l for bupivacaine. Within-day and day-to-day coefficients of variation were generally lower than 12%. The method was applied to a pharmacokinetic study of lidocaine and bupivacaine during peribulbar anesthesia in ocular surgery. Both compounds displayed a slow apparent elimination rate. The method described here permitted the determination of the complete pharmacokinetic profiles of the two anesthetics, although they were administered at quite different doses.

Aged↗
PubMed1997

Cholinesterase inhibition by derivatives of 2-amino-4,6-dimethylpyridine.

Derivatives of 2-amino-4,6-dimethylpyridine, aryl(alkyl)carboxamides, thiocarbamides and amidrazones, already known for their anti-inflammatory properties, were found to be moderately active inhibitors of acetyl and butyrylcholinesterase. Quantitative structure-activity relationships showed that the binding affinity was enhanced by the following structural modifications: (1) increase in molecular volume, (2) decrease in the energy of the lowest unoccupied molecular orbital, (3) insertion of a methylene group between the amide carbonyl and the aromatic ring, (4) replacement of the amide oxygen by sulfur. The affinity remained, however, weaker than that of the specific inhibitor 9-amino-1,2,3,4-tetrahydroacridine (tacrine). The association of anti-inflammatory and cholinesterase inhibiting activities within the same compound may prove useful for the treatment of Alzheimer's disease.

Acetylcholinesterase↗
PubMed1997

Population pharmacokinetics of amikacin in geriatric patients studied with the NPEM-2 algorithm.

The population pharmacokinetics of amikacin were studied in 40 geriatric medicine patients (aged 59-95 years, average 78 years) by the NPEM-2 algorithm, using a 2-compartment model. The fitted parameters were: renal clearance of amikacin, expressed as a fraction of creatinine clearance (CLS) and volume of the central compartment, expressed as a fraction of body weight (VS). The nonrenal clearance of amikacin (CLi) and the transfer constants between the 2 compartments (k12 and k21) were held constant. The distribution of each pharmacokinetic parameter was characterized by the median and the 50% dispersion factor (DF50) which is the interval between the 25th and 75th percentiles, divided by 1.32. The parameters were thus estimated by the following values: CLs = 0.91 +/- 0.45 and Vs = 0.29 +/- 0.10 l x kg-1. The volume of distribution was increased with respect to the usual value of 0.20 l x kg-1. The interindividual variability was high, particularly for clearance. Although the median value of CLs was close to unity, indicating that for most patients the elimination kinetics of amikacin followed that of creatinine, there was a slight probability to observe much higher values of CLs (up to 5), indicating that for some aged patients the elimination of amikacin was less altered than that of creatinine. These parameters were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 20 patients by the Bayesian method, with 2 blood samples per patient. For each patient the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 hours with no significant bias and a precision of 3.5 mg x 1(-1). This study confirms the ability of the NPEM-2 algorithm to provide reference population values for use in Bayesian monitoring of aminoglycoside therapy.

Aged↗
PubMed1997

Tungsten determination in biological fluids, hair and nails by plasma emission spectrometry in a case of severe acute intoxication in man.

A healthy 19-year-old recruit in a French artillery regiment drank 250 mL of a mixture of beer and wine that had rinsed in a hot 155-mm gun-barrel. Fifteen minutes later, he complained of nausea followed by seizures. He was comatose for 24 h, presenting signs of encephalopathy. A moderate renal failure was noted initially and worsened to an extensive tubular necrosis with anuria on the day after the incident. The first toxicological investigations only showed a 0.31 g/L blood ethanol. Then inductively-coupled plasma (ICP) emission-spectrometry revealed very high concentrations of tungsten in the "beverage" as well as in gastric content, blood and urine (1540 mg/L, 8 mg/L, 5 mg/L, and 101 mg/L, respectively). The nature of the metal was confirmed by ICP coupled to mass spectrometry. A simple and reliable ICP quantitative assay of tungsten in biological fluids, hair and nails was then developed. It showed high blood levels (> 0.005 mg/L) until day 13 in spite of six hemodialyses, and in urine until D33. Tungsten was also incorporated in hair and nails. To the best of our knowledge, such an intoxication has never been reported before though this drinking seems to be traditional in the French Artillery. It has probably been favored by the unusually high volume of beverage absorbed and by the new alloy of the gun, containing tungsten. The clinical evolution was satisfactory over weeks and the patient was declared totally cured after five months.

Adult↗
PubMed1996

The role of hyaluronidase on lidocaine and bupivacaine pharmacokinetics after peribulbar blockade.

Orbital regional anesthesia is the only circumstance where hyaluronidase is routinely added to local anesthetics to accelerate the onset of the block. The aim of this study was to compare the pharmacokinetics of lidocaine and bupivacaine with or without hyaluronidase for peribulbar blockade. Twenty-one patients scheduled for cataract surgery with lens implantation were included in this prospective randomized study. Peribulbar blocks were achieved with plain bupivacaine 0.5% (5.5 mL), lidocaine 2% (5.5 mL), and hyaluronidase (100 IU = 2 mL) (n = 10) ir sterile water (2 mL) (n = 11). Plasma bupivacaine and lidocaine concentrations were measured by high-performance liquid chromatography at regular intervals from the end of the local anesthetic injection until the 360th minute. Maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) were obtained for all the patients except one who needed a supplementary injection and was excluded from the study. The time to onset and duration of the analgesia and akinesia were monitored at the times of sampling. Motor blockade was incomplete in two patients in each group without affecting surgery. The Tmax and absorption half-life (t1/2a) of lidocaine and bupivacaine were not different within each group (P > 0.05). The Tmax of lidocaine was shorter in the presence of hyaluronidase (17.1 +/- 2.6 min vs 32.7 +/- 6.0 min) as well as the Tmax of bupivacaine (16.8 +/- 3.0 min vs 26.5 +/- 4.4 min). The Cmax of lidocaine and bupivacaine were not modified by the addition of hyaluronidase. The clearance, terminal half-life, and volume of distribution were not different between groups. The absorption of lidocaine and bupivacaine from the peribulbar space are hastened by the addition of hyaluronidase. The Tmax of lidocaine is not different from that of bupivacaine within each group suggesting that the absorption of local anesthetics is minimally influenced by the liposolubility of the drugs. Moreover, hyaluronidase influences the absorption kinetics of both lidocaine and bupivacaine in the same manner.

Absorption↗
PubMed1995

Population pharmacokinetics of amikacin in intensive care unit patients studied by NPEM algorithm.

The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one-compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (Cs = 0.96 +/- 0.33), and either the total volume of distribution (Vd = 23.9 +/- 7.0 l) or the volume of distribution relative to body weight (Vs = 0.36 +/- 0.10 l.kg-1. The volume of distribution was increased with respect to the usual value of 0.25 l.kg-1. The statistical distribution of these pharmacokinetic parameters was approximately gaussian, with no significant correlation between volume of distribution and clearance. The medians and standard deviations of Cs and Vs were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg.l-1 for peaks and 0.5 mg.l-1 for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.

Adolescent↗
PubMed1995

[Pharmacokinetics of lidocaine and bupivacaine after peribulbar block with additional hyaluronidase].

OBJECTIVE: To assess the time course of plasma concentrations of lidocaine and bupivacaine associated with hyaluronidase for peribulbar block. STUDY DESIGN: Prospective study. PATIENTS: Ten patients (mean age = 71 +/- 11 yrs, mean weight 63 +/- 10 kg) scheduled for cataract surgery with lens implantation. METHOD: Lidocaine 2% (5.5 mL = 110 mg) and bupivacaine 0.5% (5.5 mL = 27.5 mg) associated with hyaluronidase (80 IU) were injected supra and infra-orbitally, in patients premedicated with midazolam. Blood samples wer0 collected at constant time intervals from the end of infiltration until the 6th hour. The plasma concentrations of local anesthetics were measured with the HPLC technique. RESULTS: The median plasma peak concentration was 1.74 mg.L-1 after 10 min for lidocaine, and 0.52 mg.L-1 after 7.5 min for bupivacaine respectively. CONCLUSIONS: The similar delays of occurrence of peak concentrations confirm that liposolubility is not the only factor of diffusion of local anaesthetics from the periocular fat into the blood stream. The peak concentrations are far below the alleged toxic concentrations. When associated with hyaluronidase, the peak concentrations occur as rapidly as after endotracheal or paracervical administration.

Aged↗
PubMed1995

Comparison of 2- and 3-compartment models for the Bayesian estimation of methotrexate pharmacokinetics.

Moderate and high-dose methotrexate was given by a 4-h infusion to 10 patients. The pharmacokinetics of methotrexate, determined by fluorescence polarization immuno-assay, was successively described by a 2- and a 3-compartment open model with elimination from the central compartment. Population pharmacokinetic parameters were obtained by non-linear regression from 8 data points for each course and were subsequently used to fit the same data by the Bayesian estimation method. According to Akaike's information criterion, the 3-compartment model was found statistically superior in 7 patients out of 10. Using this model clearance was well predicted (+/- 5%) by the Bayesian method with only 2 points taken at the end of the infusion and 24 h after. The prediction was less good for the steady-state volume of distribution (+/- 18%) and the half-lives (+/- 20-30%). This procedure enables a good estimation of individual pharmacokinetic parameters for methotrexate, specially with clearance, at minimal cost and minimal disturbance for the patient.

Adolescent↗
PubMed1994

Pharmacokinetics and dosage regimens of amikacin in intensive care unit patients.

The pharmacokinetics of amikacin have been studied in 40 intensive care unit (ICU) patients using a two-compartment model and the Bayesian estimation method implemented in the USC PC-PACK program of Jelliffe et al. The volume of the central compartment was significantly higher in these patients (0.36 l.kg-1) than in the reference population (0.20 l.kg-1). A method has been designed to compute dosage regimens in order to maintain a constant steady-state average plasma concentration of 8 mg.l-1 for repeated i.v. infusions. The regimen calculated for the 'average' ICU patient varies between 11 mg.kg-1 three times per day for the patient with normal renal function and 6 mg.kg-1 every 2 days for the anuric patient. This regimen is intended to begin amikacin therapy in an ICU patient, while the population pharmacokinetic parameters would allow the individualization of the regimen by means of the Bayesian method.

Amikacin↗