PubMed Health⌕ Search

Biomedical subjects

P Maire

Publications and source records attributed to P Maire.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime--a population study in 25 elderly patients.

OBJECTIVE: To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients. METHODS: Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach. RESULTS: Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data. CONCLUSION: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

Aged↗
PubMed2004

Aminoglycoside nephrotoxicity.

The main constraints to the administration of aminoglycosides (AG) are risks of nephrotoxicity and ototoxicity, which can lead to renal and vestibular failure. AG accumulation in the kidney may be related to the dosing schedule. As a result, administration of larger doses on a less frequent basis may reduce the drug accumulation in the renal cortex. Many methods have been proposed to reduce AG nephrotoxicity. (1) Molecular modeling and analog synthesis could lead to intrinsically less toxic AG but this approach is time consuming and expensive. Protective approaches such as the co-administration of polyaspartic acid or defferoxamine appear to be very promising in clinical practice. (2) Population pharmacokinetic computer programs, used to control AG serum concentrations, are correct predictors of efficacy but the estimated concentrations in the second compartment are not reliable predictors of nephrotoxicity because they do not take into account non-linear processes such as the AG uptake in the renal cortex or the tubuloglomerular feedback. (3) Finally, modelling the AG nephrotoxicity with probabilistic approaches and/or with deterministic approaches seems to be very promising. These two approaches appear to be not competitive but very complementary in clinical practice. The probabilistic model can be used to predict nephrotoxicity at the beginning the treatment. The deterministic model can be used to simulate and control nephrotoxicity when it is already unfolding and the treatment must be given for a long period of time.

Aminoglycosides↗
PubMed2003

[PK/PD modeling of aminoglycoside nephrotoxicity].

Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

Amikacin↗
PubMed2002

[Efficacy and toxicity of aminoglycoside therapy in the elderly: combined effect of both once-daily regimen and therapeutic drug monitoring].

UNLABELLED: This study was aimed to compare with previous results (Grillot et al., 1994), the efficacy of amikacin adaptive optimal control in a geriatric hospital. PATIENTS: During six months, 32 patients (aged of 82 +/- 8 years) were included versus 51 during two years (aged of 80 +/- 5). The mean age was not different between the two populations (NS, Student test). They received amikacin initial dosage of 17.7 +/- 5.1 mg/kg/d (vs 13.3 +/- 3.5 for the reference study) and maintenance dosage of 15.1 +/- 4.8 mg/kg/d (vs 11.8 +/- 5.1 for the reference study). METHOD: Two efficacy outcomes (E1 and E2) and 1 toxicity outcome (T) were taken into account: E1 estimated the effect of adaptive control on maximal drug level, E2: overall recovery. Toxicity outcome was used: T the nephrotoxicity (increasing creatininémia over 44 mumol/l). RESULTS: All the results are given versus the reference study. 57.6% versus 29.4% of adaptive strategy were once-a-day. E1: Chi square test show that initial dosage and maintenance dosage are greater our study than the previous one (p < 0.05: 78.8% versus 5.9% for initial dosage, 84.4% versus 13.8% for maintenance dosage). E2: 73.6% overall of recovery versus 77% (NS, Chi square test). T: 94% versus 85% (p < 0.05, Chi square test) of creatininemia variation are lower than 44 mumol/l. Duration of treatment is 9.8 +/- 4.8 versus 15 +/- 9 days (p < 0.5, Student test). CONCLUSIONS: Once-a-day strategy in amikacin therapeutic regimen is no more efficient but decreases toxicity and duration treatment.

Aged↗
PubMed2001

Comparison of nonlinear mixed-effect and non-parametric expectation maximisation modelling for Bayesian estimation of carboplatin clearance in children.

OBJECTIVE: The pharmacodynamic-pharmacokinetic relationships for carboplatin involve the area under the curve of ultrafiltrable plasma concentrations versus time (AUC). The objective of the study was to compare two specific population pharmacokinetic methodologies, nonlinear mixed-effect model (NONMEM) and non-parametric expectation maximisation (NPEM), when they are applied to sparse carboplatin pharmacokinetic data in order to obtain an individual value for carboplatin clearance by Bayesian estimation. METHODS: The data from 117 patients (from 1 month to 18 years old) were available. For 20 patients randomly selected, the carboplatin clearance obtained by Bayesian estimation using two plasma ultrafiltrable concentrations was compared with that obtained by individual analysis using all concentrations. RESULTS: Both methodologies were unbiased with mean relative percentage errors (95%CI) of -1.9% ( 7.8; +4.1%) and +6.4% (-2.1; +14.9%) for NONMEM and NPEM, respectively. A comparison of precision between the two methods showed that they were not significantly different (12.5% for NONMEM, and 18.9% for NPEM), but the percentage error ranged between -21% and + 19% for NONMEM, and -35% and + 42% for NPEM. A NONMEM analysis was also performed with all the data available (117 children) in order to update an equation describing the relationship between carboplatin clearance and the patients' covariates. The best relationship corresponded to the equation: clearance (ml/min) = [4.47 x body weight x (1 -0.22 x Np)/(l + 0.0156 x Scr)] +6.4, with body weight in kilograms and where Scr is serum creatinine in micromoles per litre and Np= 1 or 0 for unilateral nephrectomy or not, respectively. CONCLUSION: These methodologies may be useful for dose individualisation and drug monitoring of carboplatin in paediatric patients. Since the mode of administration of carboplatin in paediatric practice in some protocols is daily 1-h i.v. infusion repeated up to five times, dose individualisation may be performed from the clearance observed after the first administration, given an overall target AUC.

Adolescent↗
PubMed2001

Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation.

OBJECTIVE: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates. This study evaluated the evolution of this variability with gestational age (GA) at birth in relation to renal maturation. METHODS: Population PK values of amikacin were studied in 131 newborns (postnatal age 1 day, GA 24-41 weeks) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per group). PK variables were Kel/Vol, Ks/Vs, Cl/Vol. Cls/ where: Kel = Kslope x GA + Kintercept, Cl = Clslope x GA + Clintercept, and Vol = Vs x body weight. Ki and Cli were held as constants. The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group. RESULTS: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination. Amikacin volume of distribution increased with body weight up to a GA of about 38 weeks and then decreased for highest GA values. However, the PDF for the individual GA groups showed a multimodal PK distribution. Kel, Vol, Vs, Cl, and Cl, standard deviations increased linearly with GA, showing differential renal maturation. The higher the GA, the more interindividual PK variability increased. CONCLUSIONS: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability with high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.

Age Factors↗
PubMed2001

Mixed pharmacokinetic population study and diffusion model to describe ciprofloxacin lung concentrations.

The pharmacokinetics of ciprofloxacin in plasma and lung tissue at steady-state (500 mg b.i.d.) were studied in 38 patients subjected to lung surgery for bronchial epithelioma. The mean characteristics of the patient population were: age = 60 years (range: 48-70), weight=70kg (47-95), height=165cm (range 160-170) and serum creatinine=85microM (range 62-168). Plasma samples, two for each patient and lung samples, one for each patient, were obtained and analyzed. Seven groups were made according to the time of sampling after ingestion of the 5th dose. A three-compartment model was used to describe ciprofloxacin kinetics in plasma and lung. The non-linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean +/- SD of the estimates (coefficient of variation of interindividual variability as a percentage) were central volume of distribution, 39.45+/-52.47l(133%); steady-state volume of distribution, 145.86+/-97.51l(60%), clearance of influx into lung tissue, 35.83+/-22.57l/h(63%), extrapolated elimination rate constant, 0.173+/-0.25/h and extrapolated elimination half-life, 4.02+/-0.89h. The mean +/- SD ciprofloxacin concentration versus time curve in plasma and lung at steady state was simulated using pharmacokinetic parameters and lung physiological parameters, another approach was studied to model the transport of ciprofloxacin into the lung tissue by diffusion. Ciprofloxacin concentration-time history was obtained both by experiments or simulations. The ciprofloxacin level in the lung tissue followed the ciprofloxacin plasma level with a lag time resulting from the time necessary for ciprofloxacin to diffuse through the lung.

Aged↗
PubMed2001

Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens.

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.

Adolescent↗
PubMed2001

Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models.

Amikacin is widely used in the treatment of suspected or confirmed neonatal infections. However, dosage regimens are not well defined in this group of patients because of a wide inter-individual pharmacokinetic variability. An individualized goal-oriented amikacin dosage design was applied using population pharmacokinetic data. A dosing chart was developed for neonates during the first 2 days of life, by using population pharmacokinetic parameter values and USCPACK software. This dosing chart based on gestational age (GA) and body weight gives a once-a-day amikacin dosage regimen involving an injection every 24 h. Validation was performed in 57 neonates less than 2 days old, divided into three GA groups and prospectively treated using the dosing chart. Target peak serum levels of amikacin were obtained in 62-80% of patients after the first dose and in 80-100% after the second dose, and trough concentrations were obtained in 100%. This study has confirmed the need for individualization of amikacin dosage regimens in neonates.

Amikacin↗
PubMed2001

Renal elimination of amikacin and the aging process.

OBJECTIVE: Although amikacin is primarily eliminated via glomerular filtration, drug concentrations are not consistently predicted in all patients. To better describe the relationship between amikacin clearance and both age and renal function, we used a new heuristic approach involving statistical analysis of dependence. DESIGN AND SETTING: Retrospective pharmacokinetic study using data from seven centres in France. PARTICIPANTS: 634 patients with sepsis aged between 18 and 98 years of age who received intravenous amikacin. METHODS: Clearance of amikacin was modelled using the NonParametric EM algorithm for a two-compartment model (NPEM2) with intravenous infusion. RESULTS: A total of 2499 serum amikacin determinations was available for analysis. The relationship between the clearance of amikacin and age was weak. Interestingly, the Z method, which filters data based on dependence criteria, selected data that were best fitted by a polynomial function (r = 0.90; p < 0.001). This representation of the polynomial function was similar to a previously proposed theoretical model describing covariations between the clearance of amikacin and age. However, the polynomial function applied to only 33% of the patients that were selected by the Z method. The correlation between the clearance of amikacin and renal function was also relatively low (r = 0.39). The Z method exhibited a continuous and strong dependence pattern between the clearance of amikacin and age for 49% of the patients. CONCLUSIONS: The Z methodology, which filters data using dependence criteria, confirms that age, renal function and amikacin clearance are strongly related, but only in less than half of a large sample of patients with sepsis without renal pathology. These results suggest that other variables should be taken into account in order to improve the description of the behaviour of amikacin. The Z methodology improved the classical description of relationships between variables, and should be applied to better select pertinent variables in pharmacokinetic studies.

Adult↗
PubMed2000

The alpha subunits of Gz and Gi interact with the eyes absent transcription cofactor Eya2, preventing its interaction with the six class of homeodomain-containing proteins.

Yeast two-hybrid techniques were used to identify possible effectors for the heterotrimeric G protein G(z) in human bone marrow cells. Eya2, a human homologue of the Drosophila Eya transcription co-activator, was identified. Eya2 interacts with activated Galpha(z) and at least one other member of the Galpha(i) family, Galpha(i2). Interactions were confirmed in mammalian two-hybrid and glutathione S-transferase fusion protein pull-down assays. Regions of Eya2-mediating interaction were mapped to the C-terminal Eya consensus domain. Eya2 is an intrinsically cytosolic protein that is translocated to the nucleus by members of the Six homeodomain-containing family of proteins. Activated Galpha(z) and Galpha(i2) prevent Eya2 translocation and inhibit Six/Eya2-mediated activation of a reporter gene controlled through the MEF3/TATA promoter. Although G proteins are known to regulate the activity of numerous transcription factors, this regulation is normally achieved indirectly via one or more intermediates. We show here a novel functional regulation of a co-activator directly by G protein subunits.

Animals↗
PubMed2000

Diurnal changes in the pharmacokinetic behavior of amikacin.

This retrospective study evaluated possible differences in the pharmacokinetic behavior of amikacin between the morning (AM) and evening (PM). Of 634 patients receiving amikacin therapy, 17 received a dose every 12 hours (an i.v. infusion at 8:00 AM and 8:00 PM) with amikacin serum levels obtained after both the AM and PM infusions. Pharmacokinetic parameter values were estimated by the nonparametric EM algorithm (USC*PACK clinical software) for a one-compartment model. All patient data were analyzed in three ways. The parameter values were estimated by fitting the model first only to the serum levels drawn following the AM dose; second, only to the data following the PM dose; and third, to all serum levels (AM + PM). Parameter values found were (mean, median, SD respectively): AM: Kel = 0.181114 h(-1), 0.224460 h(-1), 0.058820 h(-1); Vol = 23.657507 L; 23.376231 L; 1.353253 L; Cl = 4.326720 L x h(-1), 5.303726 L x h(-1), 1.447731 L x h(-1); PM: Kel = 0.110151 h(-1); 0.121295 h(-1); 0.016860 h(-1); Vol = 28.948043 L; 24.091703 L; 9.266628 L; Cl = 3.081761 L x h(-1), 2.810615 L x h(-1); 0.705874 L x h(-1); AM + PM: Kel = 0.165321 h(-1); 0.131796 h(-1); 0.075425 h(-1); Vol = 25.479043 L; 26.187970 L; 5.367054 L. These findings are in agreement with the known diurnal rhythm of glomerular filtration rate. Because pharmacokinetic parameter values are most often estimated using AM data, this may lead to an overevaluation of these values compared with PM or to values for the entire day. The resulting drug regimens may therefore be overestimated regarding the elimination rate constant and underestimated regarding the volume of distribution.

Adult↗
PubMed1999

Developmental regulation of the aldolase A muscle-specific promoter during in vivo muscle maturation is controlled by a nuclear receptor binding element.

During the post-natal period, skeletal muscles undergo important modifications leading to the appearance of different types of myofibers which exhibit distinct contractile and metabolic properties. This maturation process results from the activation of the expression of different sets of contractile proteins and metabolic enzymes, which are specific to the different types of myofibers. The muscle-specific promoter of the aldolase A gene (pM) is expressed mainly in fast-twitch glycolytic fibers in adult body muscles. We investigate here how pM is regulated during the post-natal development of different types of skeletal muscles (slow or fast-twitch muscles, head or body muscles). We show that pM is expressed preferentially in prospective fast-twitch muscles soon after birth; pM is up-regulated specifically in body muscles only later in development. This activation pattern is mimicked by a transgene which comprises only the 355 most proximal sequences of pM. Within this region, we identify a DNA element which is required for the up-regulation of the transgene during post-natal development in body muscles. Comparison of nuclear M1-binding proteins from young or adult body muscles show no qualitative differences. Distinct M1-binding proteins are present in both young and adult tongue nuclear extracts, compared to that present in gastrocnemius extracts.

Alitretinoin↗
PubMed1999

Assessment of acyclovir intraindividual pharmacokinetic variability during continuous hemofiltration, continuous hemodiafiltration, and continuous hemodialysis.

The use of intravenous acyclovir can be particularly complicated in pediatric patients with evolving renal impairment, because of intraindividual pharmacokinetic variability linked to the patient's clinical condition. The objective of this study was to use therapeutic drug monitoring data to assess acyclovir intraindividual pharmacokinetic variability during several types of renal replacement therapy. Bayesian adaptive control of acyclovir dosage regimen was performed in a pediatric patient with bone marrow transplant who developed severe renal impairment. Acyclovir pharmacokinetic parameter values corresponding to the different techniques and periods of renal replacement therapy were estimated using USCPACK PC Clinical Programs and therapeutic drug monitoring data. Results showed a wide intraindividual pharmacokinetic variability during CAVH, CAVHDF, and CVVHD, reflecting not only the performance of each dialysis technique but also the difficulty in making use of each one. The acyclovir elimination rate constant was higher during CVVHD compared to CAVH or CAVHDF. Bayesian method appears to be valuable in assessing intraindividual pharmacokinetic variability, as it allows the clinician to deal with sparse routine patient data.

Acyclovir↗
PubMed1998

Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site.

Myogenin, one of the MyoD family of proteins, is expressed early during somitogenesis and is required for myoblast fusion in vivo. Previous studies in transgenic mice have shown that a 184-bp myogenin promoter fragment is sufficient to correctly drive expression of a beta-galactosidase transgene during embryogenesis. We show here that mutation of one of the DNA motifs present in this region, the MEF3 motif, abolished correct expression of this beta-galactosidase transgene. We have found that the proteins that bind to the MEF3 site are homeoproteins of the Six/sine oculis family. Antibodies directed specifically against Six1 or Six4 proteins reveal that each of these proteins is present in the embryo when myogenin is activated and constitutes a muscle-specific MEF3-binding activity in adult muscle nuclear extracts. Both of these proteins accumulate in the nucleus of C2C12 myogenic cells, and transient transfection experiments confirm that Six1 and Six4 are able to transactivate a reporter gene containing MEF3 sites. Altogether these results establish Six homeoproteins as a family of transcription factors controlling muscle formation through activation of one of its key regulators, myogenin.

Amino Acid Sequence↗
PubMed1998

Proximal sequences of the aldolase A fast muscle-specific promoter direct nerve- and activity-dependent expression in transgenic mice.

Muscle activity is known to modulate the muscle fiber phenotype. Changes in muscle activity (normal or experimentally induced) lead to modifications of the expression status of several muscle-specific genes. However, the transcription regulatory elements involved in the adaptative response are mainly unknown. The aldolase A muscle-specific promoter, pM, is expressed in adult fast twitch muscle with a preferential expression in fast glycolytic-2B fibers. Its activity is induced during postnatal muscle maturation, suggesting a role of nerve and/or muscle activity. Indeed, denervation of gastrocnemius in newborn mice prevented the activation of the promoter in this muscle, despite the nerve-independent formation of 2B fibers. Although the nerve was necessary for pM onset during development, denervating the gastrocnemius in adults had only mild effects on pM activity. By contrast, a transgene including the pM proximal regulatory sequences that are sufficient to reproduce the 2B fiber-specific expression of the endogenous promoter was shown to be highly sensitive to both neonatal and adult denervation. Transgenes containing muscle-specific pM proximal promoter elements were used to delineate the regulatory elements involved in this response to innervation and changes in the contractile activity pattern. Nerve- and activity-dependent elements could be localized in the 130-base pair-long proximal promoter region of the human aldolase A gene.

Animals↗
PubMed1998

A binding site for nuclear receptors is required for the differential expression of the aldolase A fast-twitch muscle promoter in body and head muscles.

In hind limb muscles, the aldolase A muscle-specific promoter is specifically expressed in glycolytic fast-twitch fibers. Here, we show that in addition, it is expressed at higher levels in trunk and limb muscles than in neck and head muscles independent of their fiber-type content. We have identified by analysis of transgenic mice a DNA element that is required for this differential expression and, to a lesser extent, for fiber-type specificity. We show that members of the nuclear receptor superfamily bind this element in skeletal muscle nuclear extracts. Interestingly, in gel mobility shift assays, different complexes were formed with this sequence in tongue nuclear extracts compared with limb or trunk muscle nuclear extracts. Therefore, binding of distinct nuclear receptors to a single regulatory sequence appears to be associated with the location-dependent expression of the aldolase A muscle-specific promoter.

Animals↗