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L H (l + h)
Selected AbstractsEffect of oxygen transfer rates on alcohols production by Candida guilliermondii cultivated on soybean hull hydrolysateJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 2 2009Ângela Cristina Schirmer-Michel Abstract BACKGROUND: In this research the use of soybean hull hydrolysate (SHH) as substrate for xylitol and ethanol production using an osmotolerant strain of Candida guilliermondii was studied. The production of alcohols was investigated in batch cultivations in which the variable parameter was the volumetric oxygen mass transfer coefficient (kLa) obtained from three different conditions of air supply: anaerobic (150 rpm, no aeration); microaerobic (300 rpm, 1 vvm), and aerobic (600 rpm, 2 vvm), corresponding to kLa values of 0; 8; and 46 h,1, respectively. RESULTS: SHH, although presenting a very high osmotic pressure (1413 mOsm kg,1), was completely metabolized under aerobic conditions with high biomass productivities of 0.49 g cells (L h),1, with little formation of ethanol. Xylitol was produced under microaeration, with product yield of 0.22 g g,1 xylose, with the formation of glycerol as a by-product. No xylose was metabolized under anaerobic conditions, but ethanol was produced from hexoses with high product yields of 0.5 g g,1. CONCLUSION: These results suggest that the hydrolysis of soybean hull and its conversion to ethanol and other alcohols could be an important use of this agro-industrial waste, which could be used for biofuel, xylitol or biomass production, depending on the aeration conditions of the cultures. Copyright © 2008 Society of Chemical Industry [source] Effect of temperature on pharmacokinetics of enrofloxacin in mud crab, Scylla serrata (Forsskål), following oral administrationJOURNAL OF FISH DISEASES, Issue 3 2008W H Fang Abstract The study was conducted to evaluate the pharmacokinetics of enrofloxacin following a single oral gavage (10 mg kg,1) in mud crab, Scylla serrata, at water temperatures of 19 and 26 °C. Enrofloxacin concentration in haemolymph was determined using high-performance liquid chromatography (HPLC). A multiple and repeated haemolymph sampling from the articular cavity of crab periopods was developed. The haemolymph of an individual crab was successfully sampled up to 11 times from the articular cavity. The profile of haemolymph enrofloxacin concentration of an individual crab versus time was thus achieved. The mean haemolymph enrofloxacin concentration versus time was described by a two-compartment model with first-order absorption at two water temperatures. The peak concentrations of haemolymph enrofloxacin at 19 and 26 °C were 7.26 and 11.03 ,g mL,1, at 6 and 2 h, respectively. The absorption and distribution half-life time ( and t1/2,) at 19 °C were 3.7 and 4.5 h, respectively, which were markedly larger than the corresponding values (1.1 and 1.5 h) at 26 °C; the elimination half-life time (t1/2,) was 79.1 and 56.5 h at 19 and 26 °C, respectively. The area under curve (AUC), total body clearance (Cl) and mean residence time (MRT0,,) at 19 °C were 636.0 mg L,1 h, 0.016 L h,1 kg,1 and 102.5 h, respectively; the corresponding values at 26 °C were 583.4 mg L,1 h, 0.018 L h,1 kg,1and 63.7 h. These results indicate that enrofloxacin is absorbed and eliminated more rapidly in mud crab at 26 °C than at 19 °C. [source] A descriptive force-balance model for droplet formation at microfluidic Y-junctionsAICHE JOURNAL, Issue 10 2010Maartje L. J. Steegmans Abstract In a previous article, we studied the basics of emulsification in microfluidic Y-junctions, however, without considering the effect of viscosity of the disperse phase. As it is known from investigations on many different microstructures that viscosity and viscosity ratio are governing parameters for droplet size, we here investigate whether this is also the case for microfluidic Y-junctions and do so for a wide range of process conditions. The investigated Y-junctions have a width of 19.9 or 12.8 ,m and a depth of 5.0 ,m, and the formed monodisperse droplets (CV < 1%) are between 3 and 20 ,m. We varied the disperse-phase viscosity using different oils (1,105 mPa s), and continuous-phase viscosity using glycerol,water and ethanol,water mixtures (1.0,6.2 mPa s), which corresponds to disperse-to-continuous-phase viscosity ratios from 0.4 to 105.0. Through the variation of the liquids, also a range in interfacial tensions (12,55 mN m,1) is assessed. The disperse-phase flow rate is varied from 0.039 to 18.0 ,L h,1, the continuous-phase flow rate from 1.39 ,L h,1 to 0.41 mL h,1, and this corresponds to flow rate ratios from 1.1 × 10,3 to 0.14, which is once again based on wide range of conditions. For all these conditions, in which droplets are formed in the dripping and jetting regime, the droplet size could be described with a model based on the existing force-balance model, but now extended to incorporate the cross-sectional area of the droplet and the resistance with the wall. Surprisingly enough, it was found that the droplet size is not influenced by the disperse-phase viscosity, or the viscosity ratio, but it is dominated by the resistance with the wall and the continuous-phase properties. Because of this, emulsification with Y-junctions is intrinsically simpler than any other shear-based method as droplet size is only determined by the continuous phase. © 2010 American Institute of Chemical Engineers AIChE J, 2010 [source] Continuous pilot plant,scale immobilization of yeast in ,-carrageenan gel beadsAICHE JOURNAL, Issue 7 2004C. Decamps Abstract A novel continuous two-phase dispersion process was developed to produce ,-carrageenan gel microspheres, using static mixers. It was shown that yeast-loaded carrageenan beads, with controlled diameter and tight size distribution, can be produced on a continuous basis, in a scalable mixer, at production rates appropriate to both pilot plant,scale and, potentially, industrial-scale operations. Immobilized yeast are intended to be used in continuous brewing operations. The effects of the static mixer diameter (D), the number of mixing elements (Ne), the fluid linear velocity (V), and the volumetric fraction (,) of ,-carrageenan, on the mean diameter and size distribution of the resulting gel microspheres, were studied. Image analysis showed that mean diameter was strongly influenced by the average linear fluid velocity through the mixer, and by the mixer diameter. The number of mixer elements and the mixer diameter governed bead size dispersion. A productivity of 10 L h,1 of beads was attained using a 1.27-cm-diameter static mixer. Because the productivity is proportional to the mixer diameter squared, this process, although suited for the production of small-size beads (down to 50 ,m), would be technically and economically feasible for a large industrial immobilization process. However, because the coefficient of variability increased with mixer diameter, and thus with scale-up, operational improvements are suggested, such as the use of smaller-diameter mixers operating in parallel, to reduce the size dispersion. © 2004 American Institute of Chemical Engineers AIChE J, 50: 1599,1605, 2004 [source] Comparison of the performances of different fermentation strategies on cell growth and bacteriocin production by Lactobacillus curvatus CWBI-B28JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 3 2007Hakim Ghalfi Abstract The dynamics of cell growth and bacteriocin production by Lactobacillus curvatus CWBI-B28 in modified De Man/Rogosa/Sharp (mMRS) broth with various concentrations of glucose and complex nitrogen source (CNS; peptone, yeast extract and meat extract) was investigated in flask fermentations and in a laboratory fermentor using batch and fed-batch cultivations. In fed-batch fermentation the rate of feeding of the reactor with the substrates was either maintained constant (0.12 L h,1) or varied exponentially as a function of time. The results showed that both cell growth and bacteriocin activity were influenced by changes in the concentrations of glucose and CNS. Optimal growth and bacteriocin activity were obtained in mMRS broth containing 40 g L,1 glucose and 40 g L,1 CNS (mMRS40/40). A bacteriocin titre of 4266 AU mL,1 and a cell count of 8.7 log colony-forming units (cfu) mL,1 were recorded when this medium was used for cultivation. In batch fermentation using the same medium, a higher cell count (9.5 log cfu mL,1) and twice as much bacteriocin as in flask fermentation were produced. The highest bacteriocin titre (8533 AU mL,1) was obtained with fed-batch fermentation at an exponentially varying rate of feeding. Bacteriocin activity and cell dry mass did not always correlate. Copyright © 2007 Society of Chemical Industry [source] The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trialsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009C. VEYRAT-FOLLET Summary.,Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min,1). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h,1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux , rapid onset of action and long-acting anticoagulant effect , offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux. [source] Effects of Arg-Gly-Asp Sequence Peptide and Hyperosmolarity on the Permeability of Interstitial Matrix and Fenestrated Endothelium in JointsMICROCIRCULATION, Issue 6 2004A. POLI ABSTRACT Objectives: The aims were to assess the contribution of arg-gly-asp (RGD) mediated cell integrin,matrix bonds to interstitial hydraulic resistance and to fenestrated endothelial permeability in joints. Joint fluid is generated by filtration from fenestrated capillaries and drains through a fibronectin-rich synovial intercellular matrix. The role of parenchymal cell,matrix bonding in determining tissue hydraulic resistance is unknown. Methods: The knee cavity of anesthetized rabbits was infused with saline or the competitive hexapeptide blocker GRGDTP, with or without added osmotic stress (600 mosm saline). Intra-articular pressure Pj, net trans-synovial drainage rate s, and the permeation of Evans blue-labeled albumin (EVA) from plasma into the joint cavity were measured. Results: GRGDTP increased the hydraulic conductance of the synovial drainage pathway, ds/dPj, by 71% (p = .02, paired t test, n = 6 animals). Synovial plasma EVA clearance (control 7.1 ± 0.8 ,L h,1, mean ± SEM, n = 15) was unaffected by GRGDTP (7.0 ± 2.3 ,L h,1, n = 6) or hyperosmolarity (4.9 ± 1.5 ,L h,1, n = 8) but was increased by GRGDTP and hyperosmolarity together (15.9 ± 4.8 ,L h,1, n = 5) (p = .01, ANOVA). Changes in dPj/dt evoked by GRGDTP plus hyperosmolarity, but neither alone, demonstrated increased microvascular filtration into the joint cavity (p < .001, ANOVA), as did changes in fluid absorption from the infusion system at fixed Pj. Conclusions: RGD-mediated bonds between the parenchymal cells and interstitial polymers reduce the interstitial hydraulic conductance by 42%. This helps to retain the lubricating fluid inside a joint cavity. RGD-mediated bonds also support the macromolecular barrier function of fenestrated endothelium, but in vivo this is evident only in stressed endothelium (cf. in vitro). [source] Variation in clearance and ingestion rates by larvae of the black-lip pearl oyster (Pinctada margaritifera, L.) feeding on various microalgaeAQUACULTURE NUTRITION, Issue 1 2003M.S. Doroudi Abstract Clearance rate (CR) and ingestion rate (IR) of different sizes (89, 125 and 188 ,m shell length) of Pinctada margaritifera larvae were determined when feeding on various microalgae. The microalgae tested were the diatoms, Chaetoceros muelleri and C. simplex, and flagellates, Tahitian Isochrysis aff. galbana, Pavlova lutheri and P. salina at 5 or 10 cells ,L,1. Both CR and IR of microalgae tested in this study increased with increasing larval size; but at all larval sizes, diatoms resulted in lower CR and IR. Of the microalgae tested, P. margaritifera larvae showed greatest CR and IR with the two Pavlova spp. Maximum CR for P. salina was 10.5, 21.2 and 29.7 ,L h,1 for larvae with shell lengths of 89, 125 and 188 ,m, respectively. The highest IR values for P. margaritifera larvae with shell lengths of 89, 125 and 188 ,m were 8.7, 81.0 and 165.7 cells·larva,1 h,1, respectively. CR and IR of P. salina were approximately five times higher than those recorded for C. muelleri and C. simplex. [source] A preliminary evaluation of physiological filtration variables for Crassostrea corteziensis (Hertlein, 1951) and Anadara tuberculosa (Sowerby, 1833) in shrimp aquaculture effluentsAQUACULTURE RESEARCH, Issue 15 2009Emilio Peña-Messina Abstract This study examined the main filtration variables [filtration rate (FR), clearance rate (CR) and assimilation efficiency (AE)] of the Cortez oyster, Crassostrea corteziensis (Hertlein, 1951), and the mud cockle, Anadara tuberculosa (Sowerby, 1833), in shrimp aquaculture effluents at three different flux velocities (1.5, 3 and 4.5 L h,1) using a 36-respirometer system, each with a 0.5 L capacity. Under inverted photoperiod conditions, free variations in the environmental parameters were allowed to mimic effluent conditions during a pair of 12-h trials. The FRs for both species (0.124, 0.328 and 0.402 L h,1 for the Cortez oyster; 0.093, 0.189 and 0.345 L h,1 for the mud cockle) were relatively low as compared with those reported for similar or related species. The CRs were higher for the Cortez oyster (20.04, 52.92 and 64.70 L h,1) than for the mud cockle (10.96, 22.95 and 42.12 L h,1); in both cases, the values were in the range reported previously for the last species. The AE for both mollusks (over 92% for the Cortez oyster and over 95% for the mud cockle) was very high and greater than that found by other authors for the same or related species. The three filtration variables were better at higher effluent flux velocities. These preliminary results strongly suggest that both species are good candidates to be considered for bioremediation of aquaculture effluents. [source] Pharmacokinetics and tissue residues of marbofloxacin in crucian carp (Carassius auratus) after oral administrationAQUACULTURE RESEARCH, Issue 6 2009Yanlei Zhu Abstract Pharmacokinetics and residue elimination of marbofloxacin (MBF) were studied in crucian carp (Carassius auratus, 250±30 g) kept at two water temperatures of 15 and 25 °C. Marbofloxacin concentrations in plasma and tissues were analysed by means of high-performance liquid chromatography using an ultraviolet detector. The limits of detection were 0.02 ,g mL,1, 0.02 ,g g,1, 0.025 ,g g,1, 0.02 ,g g,1 and 0.025 ,g g,1 in plasma and muscle, skin, liver and kidney respectively. Fish were administered orally at a single dosage of 10 mg kg,1 body weight in the PK group. The data were fitted to two-compartment open models at both temperatures. At 15 °C, the absorption half-life () and distribution half-life (t1/2,) of the drug were 0.36 and 4.48 h respectively. The corresponding values at 25 °C were 0.23 and 0.87 h respectively. The elimination half-life (t1/2,) was 50.75 h at 15 °C and 25.05 h at 25 °C. The maximum MBF concentration (Cmax) differed little between 15 (6.43 ,g mL,1) and 25 °C (8.36 ,g mL,1). The time to peak concentration was 1.74 h at 15 °C and 0.78 h at 25 °C. The apparent volume of distribution (Vd/F) of MBF was estimated to be 1.36 and 0.87 L kg,1 at 15 and 25 °C respectively. The area under the concentration,time curve (AUC) was 301.80 ,g mL,1 h at 15 °C and 182.80 ,g mL,1 h at 25 °C. The total clearance of MBF was computed as 0.03 and 0.05 L h,1 kg,1 at 15 and 25 °C respectively. After repeated oral administration at a dosage of 10 mg kg,1 body weight per day for 3 days, the results showed that the elimination half-lives () of MBF from all tissues at 15 °C were longer than that at 25 °C. Therefore, water temperature is an important factor to be considered when deciding a reasonable withdrawal time. [source] Algal diets for broodstock maintenance of the doughboy scallop Mimachlamys asperrima (Lamarck)AQUACULTURE RESEARCH, Issue 8-9 2000W A O'connor The effect of monospecific algal diets on filtration rate (algal cells h,1) and fecundity of Mimachlamys asperrima was investigated. Filtration rates of seven algal species were monitored to indicate species preferences and to estimate maximum daily filtration rates. Cells of Chaetoceros calcitrans and Pavlova lutheri were filtered most rapidly; however, on a cell weight (mg h,1) and cell volume (,L h,1) basis, scallops filtered more Rhodomonas salina and Tetraselmis chui from the water column. Filtration rates when fed the diatom Chaetoceros muelleri were the lowest of the tested species, with a relatively low weight and volume of the algae filtered. Maximum filtration rates of the tested species were estimated to vary between 2.25 × 109 and 7.68 × 109 cells scallop,1 day,1. Filtration of algal species by M. asperrima varied in accordance with both scallop size and water temperature. Five of the seven algal species previously tested were then selected for use as monoalgal diets for female M. asperrima and fed for 4 weeks. Fecundity of scallops after this treatment did not necessarily reflect filtration rates, being greatest for scallops fed C. muelleri, which was significantly greater than that of the scallops fed C. calcitrans. Percentage development of eggs to D-veliger larvae did not differ in accordance with the maternal diet. A combined diet of C. muelleri, P. lutheri and Tahitian Isochrysis aff. galbana averaging ,,2.5 × 109 cells scallop,1 day,1 was found to be suitable for the maintenance and conditioning of M. asperrima broodstock in recirculating systems. [source] Uptake and biotransformation of 2,4,6-trinitrotoluene (TNT) by microplantlet suspension culture of the marine red macroalga Portieria hornemanniiBIOTECHNOLOGY & BIOENGINEERING, Issue 3 2006Octavio Cruz-Uribe Abstract Microplantlets of the marine red macroalga Portieria hornemannii efficiently removed the explosive compound 2,4,6-trinitrotoluene (TNT) from seawater. Photosynthetic, axenic microplantlets (1.2 g FW/L) were challenged with enriched seawater medium containing dissolved TNT at concentrations of 1.0, 10, and 50 mg/L. At 22°C and initial TNT concentrations of 10 mg/L or less, TNT removal from seawater was 100% within 72 h, and the first-order rate constant for TNT removal ranged from 0.025 to 0.037 L/gFW h under both illuminated conditions (153 µE/m2s, 14:10 LD photoperiod) and dark conditions. Two immediate products of TNT biotransformation, 2-amino-4,6-dinitrotoluene and 4-amino-2,6-dintrotoluene, were identified in the liquid culture medium, with a maximum material balance recovery of 29 mole%. Only trace levels of these products and residual TNT were found within the fresh cell biomass. Removal of TNT by P. hornemannii microplantlets at initial concentrations of 1.0 or 10 mg/L did not affect the respiration rate. At an initial TNT concentration of 10 mg/L, net photosynthesis decreased towards zero, commensurate with the removal of dissolved TNT from seawater, whereas at an initial TNT concentration of 1.0 mg/L, the net photosynthesis rate was not affected. © 2005 Wiley Periodicals, Inc. [source] Experimental Study and Design of a Submerged Membrane Distillation BioreactorCHEMICAL ENGINEERING & TECHNOLOGY (CET), Issue 1 2009J. Phattaranawik Abstract A hybrid process incorporating membrane distillation in a submerged membrane bioreactor operated at elevated temperature is developed and experimentally demonstrated in this article. Since organic particles are rejected by an ,evaporation' mechanism, the retention time of non-volatile soluble and small organics in the submerged membrane distillation bioreactor (MDBR) is independent of the hydraulic retention time (mainly water and volatiles). A high permeate quality can be obtained in the one-step compact process. The submerged MD modules were designed for both flat-sheet membranes and tubular membrane configurations. The process performance was preliminarily evaluated by the permeate flux stabilities. The module configuration design and air sparging used in the MDBR process were tested. Flux declines were observed for the thin flat-sheet hydrophobic membranes. Tubular membrane modules provided more stable permeate fluxes probably due to the turbulent condition generated from air sparging injected inside the tubular membrane bundles. The experiments with the submerged tubular MD module gave stable fluxes of approximately 5,L/m2 h over 2,weeks at a bioreactor temperature of 56,°C. The total organic carbon in the permeate was consistently lower than 0.7,mg/L for all experiments. [source] Effects of Sulfuric Acid Loading and Residence Time on the Composition of Sugarcane Bagasse Hydrolysate and Its Use as a Source of Xylose for Xylitol BioproductionBIOTECHNOLOGY PROGRESS, Issue 5 2005Silvio S. Silva A 22 full factorial design was employed to evaluate the effects of sulfuric acid loading and residence time on the composition of sugarcane bagasse hydrolysate obtained in a 250-L reactor. The acid loading and the residence time were varied from 70 to 130 mg acid per gram of dry bagasse and from 10 to 30 min, respectively, while the temperature (121 °C) and the bagasse loading (10%) were kept constant. Both the sulfuric acid loading and the residence time influenced the concentrations of xylose and inhibitors in the hydrolysate. The highest xylose concentration (22.71 g/L) was achieved when using an acid loading of 130 mg/g and a residence time of 30 min. These conditions also led to increased concentrations of inhibiting byproducts in the hydrolysate. All of the hydrolysates were vacuum-concentrated to increase the xylose concentration, detoxified by pH alteration and adsorption into activated charcoal, and used for xylitol bioproduction in a stirred tank reactor. Neither the least (70 mg/g, 10 min) nor the most severe (130 mg/g, 30 min) hydrolysis conditions led to the best xylitol production (37.5 g/L), productivity (0.85 g/L h), and yield (0.78 g/g). [source] Effect of Dipotassium Clorazepate on Ainygdaloid-Kiiidling and Comparison Between Amygdaloid- and Hippocampal-Kindled Seizures in RatsEPILEPSIA, Issue 2000Kouichiro Amano Purpose: We reportcd previously that dipotassium clorazcpate (potassium 7-chloro-2, 3-dihydro-2-oxo-S-phcnyI- l H- l, 4-bcnzodiazepinc-3-carboxylate potassium hydroxide: DC), an antianxiety drug, suppressed hippocampel kindled scizures in rats i n a dose-dependent manner (Amano et al. Psychiatry Clin Neuroscienccs 1998; 52: 459,462). Its effect on kindling, howcver, has not been evaluated. Moreover, differcnces in the anticonvulsive effccts of conventional anticonvulsants bctween amygdaloid-and hippocampal-kindlcd seizures have becn reportcd (Kamci et al. Arch. Int. Pharmacodyn I98 1; 249: 164,176). To clarify the anticonvulsive propcrties of DC, we examined its effects on amygdaloid kindling and compared it for 7 succcssive days against amygdaloid- and hippocampal-kindled seizures using thc rat kindling model of epilcpsy. Methods: Adult inale Wistar rata weighing 220,330 g werc used. Electrodes were implanted stereotaxically into thc left basoiatcfiil amygdala or the left dorsal hippocampus under pcntobarhital ancsthesia. Expcriment 1: Anticonvulsive effect on amygdaloid-kindled seizurcs. Rats having >5 consecutive stage-5 seimrcs were htimulated at the generalizcd seizure-triggering threshold (GST) intensity 30 minutes after i.p. administration or DC or saline. Experiment 2: Effect on amygdala kindling. In other groups of Tiits, the amygdala was stimulated once daily following 30 minutes i.p. administration or DC at 5 mg/kg or saline until the first stage-5 seizure was attained. Experimcnt 3: Comparison of anticonvulsive effect bctween amygdaloid- and hippocampal-kindled scizures. In other groups of rats having 5 consecutive stage-5 seizures, the GST was determined. Furthermorc, rats having >I0 stage-5 scizures induced at thc GST intensity were testcd once a day for 7 consecutive days. Thc stimulation was delivercd 30 minutes aftcr i.p. administration of DC or saline. Results: Expcriment I: DC suppresscd amygdaloid-kindled scizures in a dose-depcndent manner. Significant reduction of aftcr-discharge duration compared with the control group was observed at dosagcs of 2 mg/kg or more, hut complete suppression of after-discharges was observed in only I of 7 sessions at the highcst dose. Expcriment 2: Thc number of stimulations rcquired for the first stage-5 seiiurc in the 5 mg/kg dosage group was 14.1+1.4 stimulations, which was significantly greater than the 10.2+1.7 stimulations in the control group (P4.01). The contralateral cortical afterdischarge duration i n the DC treated group was signilicantly shortcr than thc afterdischarge duration in the amygdala at the first 7 stimulations, whereas it was significantly shorter only the first 3 stimulations i n the control group. Experiment 3: DC suppressed amygdaloid-kindled seizures at 2 and 5 mg/kg, whcreas I mg/kg or morc suppresscd hippocampal-kindlcd seizures. Conclusions: Thc result of the present study suggcst that thc principal anticonvulsive cffect of DC is likely to be relatcd mainly to attenuation of propagation of scizure activity rather than to an elevatcd seizure threshold, which may support our previously findings that increased stimulus intensity could not complctcly reverse thc anticonvulsive effects of DC. Thus, differences in effective dosages in both amygdaloid- and hippocampal-kindled seizures may suggcst a difference in the neuronal mechanisms that arc cvolved in this kindling. The present study dcmonstratcd that DC has a modest anticonvulsive effect without serious adverse effccts, which indicates thc clinical uscfulness of DC for treatment intractable epilepsy. [source] Etude comparative de la disponibilité de l'eau en irrigation goutte à goutteIRRIGATION AND DRAINAGE, Issue 3 2001A.V. Ould Mohamed El-Hafedh goutteur; écartement; durée d'irrigation; fréquence d'arrosage Abstract Dans le but de déterminer la meilleure combinaison entre période et durée d'irrigation pour différents écartements inter-goutteurs, nous avons essayé d'analyser la disponibilité de l'eau au sein de la zone racinaire d'une culture de tomate irriguée à l'aide d'une rampe de goutteurs débitant chacun 4 l h,1. Trois écartements ont été étudiés à savoir 30, 50 et 70 cm. Lorsqu'on a pris une durée d'arrosage systématique de 4h30mn, nous avons observé à la fin des irrigations des teneurs en eau volumiques moyennes dépassant la capacité au champ pour les trois écartements. En effet, à l'examen de l'évolution des teneurs en eau au sein du bulbe, il est remarqué que la teneur en eau à la capacité au champ a été atteinte après 25 minutes, 50 minutes et deux heures respectivement pour 30, 50 et 70 cm. Mais l'humidification de toute la ligne de culture n'a été observée qu'après des temps respectifs d'une heure, deux heures et quatre heures (Ould Mohamed El-Hafedh et al., 2000). Les irrigations ont été reprises avec ces durées réduites (une heure, deux heures et quatre heures respectivement pour les écartements 30, 50 et 70 cm) en vue d'évaluer et comparer les consommations en eau de la culture sous les différents traitements. Dans le cas de l'irrigation d'une durée de 4h30mn, la période séparant deux arrosages successifs a été de cinq, quatre et trois jours respectivement pour les écartements 30, 50 et 70 cm. Pour les irrigations des durées réduites, on a constaté qu'il est impératif d'irriguer après trois jours pour les deux écartements 50 et 70 cm et après deux jours pour l'écartement 30 cm. En comparant les consommations en eau pour les durées réduites et la durée systématique de 4h30mn, on a observé une économie d'eau de l'ordre de 20, 15 et 5% respectivement pour 30, 50 et 70 cm d'écartement. D'autre part, la comparaison entre les durées réduites montre que la plus importante économie en eau a été réalisée avec 50 cm d'écartement. Copyright © 2001 John Wiley & Sons, Ltd. In order to determine the best combination between duration and frequency of drip irrigation for various inter-dripper spacing, we analysed the availability of water within the root zone of a tomato culture irrigated using lateral drippers each outputting 4 l h,1 discharge rate. Three spacings were studied, namely 30, 50 and 70 cm. Studying systematic irrigation duration of 4½ hours, we observed at the end of each irrigation average volumetric water contents exceeding the field capacity. Indeed, with the examination of the evolution of the water contents within the bulb, it is noticed that the water content at the field capacity was reached after 25 minutes, 50 minutes and 2 hours respectively for 30, 50 and 70 cm spacing. But the humidification of the whole culture line was observed only after the respective times of 1, 2 and 4 hours (Ould Mohamed El-Hafedh et al., 2000). The irrigations were taken again with these reduced durations (1, 2 and 4 hours for 30, 50 and 70 cm spacing respectively) in order to evaluate and compare water consumption of the culture under the various treatments. In case of systematic irrigation duration, the period separating two successive waterings was five, four and three days for 30, 50 and 70 cm spacing respectively. For the reduced irrigation durations, it is imperative to irrigate after three days for the 50 and 70 cm spacings and after two days for the 30 cm spacing. Comparing water consumption for the reduced durations and those of the systematic duration, we observed water savings of about 20, 15 and 5% respectively for 30, 50 and 70-cm spacing. The comparison between the reduced durations shows that the most significant water saving was obtained with the 50 cm spacing. Copyright © 2001 John Wiley & Sons, Ltd. [source] Clonidine disposition in children: a population analysisPEDIATRIC ANESTHESIA, Issue 6 2007AL Potts Background:, There are few data describing clonidine population pharmacokinetics in children (0,15 years) despite common use. Current paediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods:, Published data from four studies investigating clonidine PK after intravenous, rectal and epidural administration (n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of IV clonidine 1,2 ,g·kg,1 bolus in children after cardiac surgery (n = 30, EC approval granted). A population pharmacokinetic analysis of clonidine time-concentration profiles (380 observations) was undertaken using nonlinear mixed effects modelling. Estimates were standardised to a 70 kg adult using allometric size models. Results:, Children had a mean age of four (SD 3.6 years, range 1 week,14 years) year and weight 17.8 (SD 12.6, range 2.8,60 kg). A two compartment disposition model with first order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14 (CV 28.3%) 1 h,1·70 kg,1, central volume of distribution (V1) 56.7 (67.5%) l·70 kg,1, inter-compartment clearance (Q) 143 (19.1%) l h,1 70 kg,1 and peripheral volume of distribution (V2) 123 (72.8%) l.70kg,1. Clearance at birth was 4.7 l·h,1·70kg,1 and matured with a half-time of 25.5 weeks to reach 85% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 180%, V2 117%). There was a lag time of 2.6 (CV 64%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum 1.04 (CV31%) h vs 0.28 (CV24%) h. The relative bioavailability of epidural and rectal clonidine was unity (F = 1). Conclusions:, Clearance in neonates is approximately one third that described in adults, consistent with immature clearance pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [source] Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Raquel F. Reinoso Abstract The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20,35 h), a low plasma clearance (0.10,0.22 l h,1 kg,1) and a relatively large volume of distribution (2,6 l kg,1). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (,22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg,1 to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times. Copyright © 2001 John Wiley & Sons, Ltd. [source] Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Lihua Zeng WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Kyoung Soo Lim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. , However, as yet few ,validated' or ,qualified' biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS , This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. , LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. AIMS LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects. METHODS A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15-0444 concentration,time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6,20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6,21.9 and 0.40,0.48 l h,1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen. [source] Population pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Zheng Jiao WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection. , Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS? , The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time. , New drug,drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMS This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTS The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h,1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem. CONCLUSIONS These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients. [source] Population pharmacokinetics of oral diclofenac for acute pain in childrenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Joseph F. Standing WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range. , Diclofenac is frequently used ,off-label' in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5,2.5 mg kg,1). There is currently no licensed oral paediatric formulation of diclofenac. WHAT THIS STUDY ADDS , Using a new diclofenac oral suspension, a dose of 1 mg kg,1 in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses. AIMS To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml,1) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children. METHODS Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg,1 dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults. RESULTS A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and VD/F were 53.98 l h,1 70 kg,1 and 4.84 l 70 kg,1 respectively. Allometric size models appeared to predict adequately changes in CL and VD with age. Of the simulated doses investigated, 1 mg kg,1 gave paediatric AUC(0,12 h) to adult 50 mg AUC(0,12 h) ratios of 1.00, 1.08 and 1.18 for ages 1,3, 4,6 and 7,12 years respectively. CONCLUSIONS This study has shown 1 mg kg,1 diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses. [source] Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Shigeru Satoh WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Circadian variations of tacrolimus pharmacokinetics are controversial. , Also, the pharmacokinetics has time-dependent variability, such as a decrease in oral clearance and increase in the dose-adjusted AUC after transplantation. , Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified. WHAT THIS STUDY ADDS , Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated-time administration strategy. , Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics. , The CYP3A5 polymorphism may be associated with the time-dependent changes in tacrolimus oral clearance. AIMS We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation. METHODS Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization. RESULTS Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC0,12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml,1 (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h,1 kg,1 (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics. CONCLUSION Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation. [source] Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008Christa E. Nath WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The pharmacokinetics of oral busulphan given four times daily has been extensively studied. , Large inter- and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring. , However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6-h dosing interval, due to late absorption in some patients. , Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose. WHAT THIS STUDY ADDS , Inter- and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable. , Children with immune deficiencies, in particular, have widely variable exposure. AIM To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. METHODS Busulphan (120 mg m,2, 130 mg m,2 or 3.2 mg kg,1) was administered over median 2.1 h. Blood samples (4,10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration,time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m,2 dose in 13 children who had busulphan pharmacokinetic monitoring. RESULTS Clearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h,1 (% CV 61%), 0.23 ± 0.08 l h,1 kg,1 (% CV 35%) and 5.79 ± 1.59 l h,1 m,2 (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h,1) and CL (l h,1 kg,1), but not with CL (l h,1 m,2). AUC normalized to the 130 mg m,2 dose ranged from 14.1 to 56.3 mg l,1.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h,1 m,2) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. CONCLUSIONS There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h,1 m,2) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required. [source] A population pharmacokinetic meta-analysis of maraviroc in healthy volunteers and asymptomatic HIV-infected subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2008Phylinda L. S. Chan AIMS To develop a population pharmacokinetic model for maraviroc, a noncompetitive CCR5 antagonist, after oral administration of tablets to healthy volunteers and asymptomatic HIV-infected subjects and to quantify the inherent variability and influence of covariates on the parameters of the model. METHODS Rich pharmacokinetic data available from 15 studies in healthy volunteers (n = 365) and two studies in asymptomatic HIV-infected subjects (n = 48) were analysed using NONMEM. Maraviroc was administered as single or multiple oral tablet doses under fasted and fed conditions. Doses ranged from 100 to 1800 mg day,1. RESULTS A two-compartment model parameterized to separate out absorption and clearance components on bioavailability was used. Absorption was described by a lagged first-order process. A sigmoid Emax model described the effect of dose on absorption. A visual predictive check and nonparametric bootstrap evaluation confirmed that the model was a good description of the data. Typical CL, Vc and Vp values for a 30-year-old non-Asian are 51.5 l h,1, 132 l and 277 l, respectively. CONCLUSIONS For the typical non-Asian subject, fasted bioavailability increased asymptotically with dose from 24% at 100 mg to 33% at 600 mg. A high-fat meal taken with maraviroc reduced exposure by 43% for a 100-mg dose to approximately 25% at doses of 600 mg. The typical Asian subject had a 26.5% higher AUC than the typical non-Asian subject irrespective of dose, a difference not considered to be clinically relevant. None of the other covariates tested had any clinically relevant effects on exposure. [source] Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2007Marie Antignac What is already known about this subject , ,In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. , ,Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients. What this study adds , ,Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus. , ,Clearance was modelled and days postoperation and corticosteroids dose were significant covariates. Aims The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics. Methods The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring. Results A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h,1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h,1. Moreover clearance increased by approximately 1.6 fold (range 0.5,1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg,1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F. Conclusions The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance. [source] Desloratadine dose selection in children aged 6 months to 2 years: comparison of population pharmacokinetics between children and adultsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2007Samir K. Gupta What is already known about this subject ,,According to recent literature, the pathophysiologies of allergic rhinitis and chronic idiopathic urticaria are thought to be similar in adults and children. In addition, the response to antihistamine treatment is similar in adults and children, suggesting a similar concentration-response relationship. ,,However, an appropriate dose selection and the pharmacokinetics of desloratadine in children of ,6 months,,2 years old have never been addressed in the literature. What this study adds ,,This study demonstrated that desloratadine syrup offers a safe treatment option for allergic conditions in young children. ,,A suitable dose for children aged ,6 months,<1 year is 1.0 mg, while the corresponding predicted dose for children aged ,1 year,,2 years is 1.25 mg. These paediatric doses yielded similar systemic desloratadine exposures (AUC) to those seen with a typical adult dose of 5.0 mg. Aims The aim of this study was to identify the dose of desloratadine in children aged ,6 months,,2 years that would yield a single-dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup. Methods In a phase 1, single-dose, open-label, pharmacokinetic study in 58 children aged ,6 months,<1 year and ,1 year,,2 years were randomly assigned to desloratadine syrup 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml), respectively. Because the volume of blood that could be collected from individual subjects was limited, a population pharmacokinetic approach was used to estimate the pharmacokinetics of desloratadine. Safety was assessed based on results of screening and postdose physical examinations, laboratory safety tests, vital signs, and adverse events. Results The apparent clearance (CL/F) of desloratadine, population estimate (%CV), in children aged ,6 months,<1 year was 27.8 l h,1 (35) and corresponding values in children ,1 year,,2 years was 35.5 l h,1 (51), compared with 137 l h,1 (58) for adults. The CL/F ratios (children to adults) indicated that doses of 1 mg for ,6 months,<1 year and 1.25 mg for ,1 year,,2 years would result in similar systemic exposure to that observed in adults receiving the recommended 5 mg dose. Desloratadine was well tolerated with no safety issues. Conclusions Doses of 1.0 and 1.25 mg in children aged ,6 months,,2 years should result in an exposure to desloratadine similar to that of adults receiving doses of 5 mg. [source] Age-related differences in the pharmacokinetics of stavudine in 272 children from birth to 16 years: a population analysisBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007V. Jullien Aims To develop a population pharmacokinetic model for stavudine in children and to investigate the consistency of the currently recommended dose based on adult target concentrations. Methods The pharmacokinetics of stavudine were investigated using a population approach. Individual estimates of CL/F were used to calculate the stavudine dose required to achieve the area under the concentration-time curve reported in adults given recommended doses. Results Stavudine pharmacokinetics were well described by a one-compartment model with zero-order absorption. Typical population estimates (% interindividual variability) of the apparent distribution volume (V/F) and plasma clearance (CL/F) were 40.9 l (32%) and 16.5 l h,1 (38%), respectively. Stavudine V/F and CL/F were similarly related to age. Mean calculated doses (0.61 mg kg,1 for children less than 2 weeks, 1.23 mg kg,1 for children more than 2 weeks with bodyweight less than 30 kg, and 31.5 mg for children with a bodyweight between 30 and 60 kg) were in agreement with the current paediatric doses (0.5 mg kg,1, 1 mg kg,1, and 30 mg, respectively). Conclusions Our findings support the current recommended paediatric dosage regimens for stavudine, as they result in the same exposure to the drug as in adults. [source] | |||||||||||||||||||