Home About us Contact
|
Home About us Contact | ||
|
|
||
Apparent Volume (apparent + volume)
Selected AbstractsEffects of induced hyperthermia on pharmacokinetics of ropivacaine in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010Romain Guilhaumou Abstract Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 °C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median ± inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 ± 0.000800 L/min vs. 0.0134 ± 0.00134 L/min), apparent volume of distribution (Vd) (2.19 ± 0.27 L vs. 1.57 ± 0.73 L) and a significant decrease in exposure (488 ± 50.6 mg.min/L vs. 572 ± 110 mg.min/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 ± 8.42 ,g/g vs. 3.48 ± 3.26 ,g/g) and no significant difference between cardiac concentrations in the two groups (5.38 ± 4.83 ,g/g vs. 3.73 ± 2.44 ,g/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood,brain barrier permeability during hyperthermia. The hyperthermia-induced increase in Vd could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients. [source] Cover Picture: Colloidal Synthesis of Hollow Cobalt Sulfide Nanocrystals (Adv. Funct.ADVANCED FUNCTIONAL MATERIALS, Issue 11 2006Mater. Abstract Hollow nanocrystals have been synthesized through a mechanism analogous to the Kirkendall Effect. When a cobalt nanocrystal reacts with sulfur in solution, the outward diffusion of cobalt atoms is faster than the inward diffusion of sulfur atoms through the sulfide shell. The dominating outward diffusion of cobalt cations produces vacancies that can condense into a single void in the center of the nanocrystal at high temperatures. This process provides a general route to the synthesis of hollow nanostructures of a large number of compounds and is described in the Full Paper by A.,P. Alivisatos and co-workers on p.,1389. Formation of cobalt sulfide hollow nanocrystals through a mechanism similar to the Kirkendall Effect has been investigated in detail. It is found that performing the reaction at >,120,°C leads to fast formation of a single void inside each shell, whereas at room temperature multiple voids are formed within each shell, which can be attributed to strongly temperature-dependent diffusivities for vacancies. The void formation process is dominated by outward diffusion of cobalt cations; still, the occurrence of significant inward transport of sulfur anions can be inferred as the final voids are smaller in diameter than the original cobalt nanocrystals. Comparison of volume distributions for initial and final nanostructures indicates excess apparent volume in shells, implying significant porosity and/or a defective structure. Indirect evidence for fracture of shells during growth at lower temperatures was observed in shell-size statistics and transmission electron microscopy images of as-grown shells. An idealized model of the diffusional process imposes two minimal requirements on material parameters for shell growth to be obtainable within a specific synthetic system. [source] Pharmacokinetics after an intravenous single dose of the opioid ketobemidone in childrenACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010S. LUNDEBERG Background: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in children because these properties have not been reported previously. Methods: Thirty children, newborn to 10 years, scheduled for elective surgery were included in the trial. Ketobemidone hydrochloride was administered as a single intravenous bolus dose and ketobemidone and norketobemidone concentrations were measured by LC-MS over 8 h. Pharmacokinetic parameters were determined using compartmental methods. Results: Six children were excluded from pharmacokinetic analysis because of incomplete blood sampling. The values of ketobemidone clearance (l/h/kg) given as median (range) were 0.84 (0.29,3.0) in Group A (0,90 days), 0.89 (0.55,1.35) in Group B (1,2.5 years) and 0.74 (0.50,0.99) in Group C (7,10 years). The corresponding values for apparent volume of distribution (l/kg) were 4.4 (3.7,6.9) (Group A), 2.6 (2.0,5.6) (Group B) and 3.9 (2.7,5.0 (Group C), and for elimination half-life (h) 3.0 (1.4,8.9) (Group A), 2.0 (1.2,4.7) (Group B) and 3.7 (2.4,6.9) (Group C), respectively. In the two neonates the elimination half-life was almost 9 h. The metabolite norketobemidone did not reach levels above the limit of quantification (0.07 ng/ml) in any of the patients. Conclusion: The pharmacokinetic parameters of ketobemidone in children older than 1 month appear to be similar to those in adults. Because of the large interindividual variability of the pharmacokinetics in neonates, further studies especially in this age group are warranted. [source] Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysisJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2009H. Fukuchi MS Summary Objective:, To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (nonmem) in Japanese patients treated with oral therapy. Method:, Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. Results:, Estimates generated using nonmem indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0·16 · TBW · 0·53AGE , 65 · 0·78BMI , 25 · DD0·51, Vd (L) = 10·2 · TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) ,65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m2) ,25 = 1 for patient was 25 kg/m2 or over and 0 otherwise and Vd is apparent volume of distribution. The clearance of AMD decreased significantly by 22·3% with a BMI higher than 25 kg/m2. The clearance of AMD also decreased significantly by 46·9% when patient age was more than 65 years. Conclusion:, Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD. [source] Pharmacokinetics and tolerability of modafinil tablets in Chinese subjectsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2008P. Xu PhD Summary Objective:, To investigate the pharmacokinetics and tolerability of modafinil in Chinese subjects. Methods:, Twelve healthy volunteers were given an escalating single dose of modafinil (100, 200 and 400 mg) in a three-period study (study 1). Another 12 volunteers received 100 mg twice daily for 7 days in multiple-dose study (study 2). Blood samples were taken from 0 to 60 h for study 1. And samples for study 2 were collected before administration on three consecutive morning and then from 0 to 60 h after the last dose. Pharmacokinetic parameters were calculated and compared with results from published data. Results:, In study 1, Cmax and area under the concentration,time curve of modafinil and modafinil acid were increased proportionally with dose levels; t1/2 was independent on the dose levels. In study 2, the steady state was reached on day 4, and mean trough plasma concentration of modafinil was 1·36 ± 0·34 ,g/mL. Apparent plasma clearance and apparent volume of distribution were lower in 100 mg twice-daily group than those in 100 mg single group. The adverse events were mild and moderate in study 1 and 2. Conclusions:, In this pharmacokinetic study, modafinil was safe and well tolerated by young healthy Chinese subjects. The major pharmacokinetic parameters of modafinil in Chinese subjects are similar to those reported in Caucasians although the half-life seems to be longer in the former than in the latter. This apparent difference requires investigation. [source] Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patientsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2005E. Yukawa PhD Summary Objective:, To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. Method:, A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. Results:, The final pharmacokinetic model was Cl (L/h) = 3·75·TBW0·567·AGE,0·374·Conc,0·719·1·48DOSE , 5, Vd (L/kg) = 4·13 and ka (h,1) = 0·363, where Cl is total body clearance, Vd is apparent volume of distribution, ka is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (,g/mL), and DOSE , 5 = 1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. Conclusion:, Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect. [source] Pharmacokinetics of oxolinic acid in gilthead sea bream, Sparus aurata L.JOURNAL OF FISH DISEASES, Issue 7 2002G Rigos This is the first study on the pharmacokinetic parameters of oxolinic acid (OA) in gilthead sea bream, Sparus aurata L. The kinetic profile of OA was studied after a single intravascular injection (20 mg kg,1) in 100 g fish at 20 °C. The distribution half-life (t1/2,) and the elimination half-life (t1/2,) of the drug were found to be short (0.51 and 12.60 h, respectively). The drug penetration from the plasma to the tissues was adequate as the apparent volume of distribution of the drug at steady-state (Vd(ss)) was found to be 2.11 L kg,1. The mean residence time (MRT) of OA was short (14.25 h) and the total clearance rate (ClT) of the drug was low (0.15 L kg,1 h,1). The bioavailability (F,%) of OA following oral administration (30 mg kg,1) was also low (14%). Maximum values were observed for muscle at 0.5 h after injection, with levels declining as with subsequent sampling. At the first two time points (0.5 and 1 h) plasma levels of OA were higher than muscle, however, the reverse was evident for subsequent samples. Following oral administration, highest muscle levels were found at 16 h and, with the exception of the 24-h sampling, muscle OA concentrations were higher than plasma at all time points. The fast elimination of OA suggests short withdrawal times with reference to human consumption of treated fish. [source] Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2010Dong-Hyun Choi Abstract Objectives, The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases. Methods, The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated. Key findings, Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 µm, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration,time curve of losartan by 31.4,61.1% and peak plasma concentration of losartan by 31.8,50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite,parent area under the plasma concentration,time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174. Conclusions, The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin. [source] Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Sandhya Ramanathan-Girish There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg,1 per week) or as a single dose injection (20 mg kg,1). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameter to correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin. [source] Pharmacokinetics of intravenous ceftiofur sodium and concentration in body fluids of foalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009S. MEYER The objectives of this study were to determine pharmacokinetics of intravenous (i.v.) ceftiofur in foals, to compare ultra-high performance liquid chromatography tandem mass spectometry (UPLC-MS/MS) and microbiologic assay for the measurement of ceftiofur concentrations, and to determine the minimum inhibitory concentration (MIC) of ceftiofur against common equine bacterial pathogens. In a cross-over design, ceftiofur sodium was administered i.v. to six foals (1,2 days-of-age and 4,5 weeks-of-age) at dosages of 5 and 10 mg/kg. Subsequently, five doses of ceftiofur were administered i.v. to six additional foals between 1 and 5 days of age at a dose of 5 mg/kg q 12 h. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur-related metabolites were measured in plasma, synovial fluid, urine, and CSF by use of UPLC-MS/MS. A microbiologic assay was used to measure ceftiofur activity for a subset of plasma samples. Following i.v. administration of ceftiofur at a dose of 5 mg/kg to 1,2 day-old foals, DCA had a t½ of 7.8 ± 0.1 h, a body clearance of 74.4 ± 8.4 mL/h/kg, and an apparent volume of distribution of 0.83 ± 0.09 L/kg. After multiple i.v. doses at 5 mg/kg, DCA concentrations in CSF were significantly lower than concurrent plasma concentrations. Ceftiofur activity using a microbiologic assay significantly underestimated plasma concentrations of DCA. The MIC of ceftiofur required to inhibit growth of 90% of isolates of Escherichia coli, Pasteurella spp, Klebsiella spp, and ,-hemolytic streptococci was <0.5 ,g/mL. Intravenous administration of ceftiofur sodium at the rate of 5 mg/kg every 12 h would provide sufficient coverage for the treatment of susceptible bacterial isolates. [source] Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2004B. KuKanich Dextromethorphan is an N -methyl- d -aspartate (NMDA) noncompetitive antagonist which has been used as an antitussive, analgesic adjunct, probe drug, experimentally to attenuate acute opiate and ethanol withdrawal, and as an anticonvulsant. A metabolite of dextromethorphan, dextrorphan, has been shown to behave pharmacodynamically in a similar manner to dextromethorphan. The pharmacokinetics of dextromethorphan were examined in six healthy dogs following intravenous (2.2 mg/kg) and oral (5 mg/kg) administration in a randomized crossover design. Dextromethorphan behaved in a similar manner to other NMDA antagonists upon injection causing muscle rigidity, ataxia to recumbency, sedation, urination, and ptyalism which resolved within 90 min. One dog repeatedly vomited upon oral administration and was excluded from oral analysis. Mean ± SD values for half-life, apparent volume of distribution, and clearance after i.v. administration were 2.0 ±0.6 h, 5.1 ± 2.6 L/kg, and 33.8 ± 16.5 mL/min/kg. Oral bioavailability was 11% as calculated from naïve pooled data. Free dextrorphan was not detected in any plasma sample, however enzymatic treatment of plasma with glucuronidase released both dextromethorphan and dextrorphan indicating that conjugation is a metabolic route. The short half-life, rapid clearance, and poor bioavailability of dextromethorphan limit its potential use as a chronic orally administered therapeutic. [source] Isoxsuprine hydrochloride in the horse: a reviewJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2002R. S. ERKERT Isoxsuprine hydrochloride has been suggested for use in horses for treatment of navicular syndrome and laminitis. The drug has been shown to be a , -adrenoreceptor antagonist with , -adrenoreceptor agonistic properties, with both characteristics contributing to vasodilation and uterine relaxation. In addition, the drug is capable of decreasing blood viscosity and platelet aggregation. Studies have shown i.v. isoxsuprine to have a plasma half-life of <3 h with a large apparent volume of distribution. Cardiovascular effects resolve rapidly following i.v. administration, but are absent with oral dosing. Oral bioavailability is 2.2% with a high first pass effect. Isoxsuprine has an apparent affinity for melanin that may contribute to extended renal excretion. Clinical trials appear to support the use of isoxsuprine for treatment of navicular disease. However, poor bioavailability, lack of cardiovascular effects following oral administration, superficial support in clinical trials, and new evidence regarding the pathogenesis of navicular syndrome indicate that the use of isoxsuprine for treatment of navicular syndrome or laminitis is questionable at best. [source] Simultaneous measurement of water flow velocity and solute transport in xylem and phloem of adult plants of Ricinus communis over a daily time course by nuclear magnetic resonance spectrometryPLANT CELL & ENVIRONMENT, Issue 5 2001A. D. Peuke ABSTRACT A new method for simultaneously quantifying rates of flow in xylem and phloem using the FLASH imaging capabilities of nuclear magnetic resonance (NMR) spectrometry was applied in this study. The method has a time resolution of up to 4 min (for the xylem) and was used to measure the velocity of flows in phloem and xylem for periods of several hours to days. For the first time, diurnal time course measurements of flow velocities and apparent volume flows in phloem and xylem in the hypocotyl of 40-d-old Ricinus communis L were obtained. Additional data on gas exchange and the chemical composition of leaves, xylem and phloem sap were used to assess the role of leaves as sinks for xylem sap and sources for phloem. The velocity in the phloem (0·250 ± 0·004 mm s,1) was constant over a full day and not notably affected by the light/dark cycle. Sucrose was loaded into the phloem and transported at night, owing to degradation of starch accumulated during the day. Concentrations of solutes in the phloem were generally less during the night than during the day but varied little within either the day or night. In contrast to the phloem, flow velocities in the xylem were about 1·6-fold higher in the light (0·401 ± 0·004 mm s,1) than in the dark (0·255 ± 0·003 mm s,1) and volume flow varied commensurately. Larger delays were observed in changes to xylem flow velocity with variation in light than in gas exchange. The relative rates of solute transport during day and night were estimated on the basis of relative flow and solute concentrations in xylem and phloem. In general, changes in relative flow rates were compensated for by changes in solute concentration during the daily light/dark cycle. However, the major solutes (K+, NO3,) varied appreciably in relative concentrations. Hence the regulation of loading into transport systems seems to be more important to the overall process of solute transport than do changes in mass flow. Due to transport behaviour, the chemical composition of leaves varied during the day only with regard to starch and soluble carbohydrates. [source] Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbitsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2004Yu C. Kim Abstract The pharmacokinetics and pharmacodynamics of torasemide were evaluated after intravenous administration of the same total dose of torasemide at a dose of 1mg/kg to rabbits with different infusion times, 1 min (treatment I), 30 min (treatment II) and 2 h (treatment III). The loss of water and electrolytes in urine induced by torasemide was immediately replaced with infusion of an equal volume of lactated Ringer's solution. All the pharmacokinetic parameters of torasemide, such as total area under the plasma concentration,time curve from time zero to time infinity (AUC), total body clearance (CL), apparent volume of distribution at steady state (Vss), terminal half-life and mean residence time (MRT), were independent of infusion times. However, the 8h urine output (235, 534 and 808 ml) and 8h urinary excretion of sodium (24.2, 80.1 and 89.2 mmol) and chloride (27.1, 89.2 and 94.0 mmol) were significantly greater in treatments II and III than those in treatment I, although the total 8 h urinary excretion of unchanged torasemide (1210, 1210 and 1310 µg) were not significantly different among the three treatments. This could be due to the higher diuretic efficiencies in treatments II and III. Copyright © 2004 John Wiley & Sons, Ltd. [source] Sustained Growth of Explants from Mediterranean Sponge Crambe crambe Cultured In Vitro with Enriched RPMI 1640BIOTECHNOLOGY PROGRESS, Issue 3 2006F. Garcia Camacho Marine sponges are potential sources of many unique metabolites, including cytotoxic and anticancer compounds. Natural sponge populations are insufficient or inaccessible for producing commercial quantities of metabolites of interest. It is commonly accepted that tissue (fragments, explants, and primmorphs) and in vitro cell cultivation show great potential. However, there is little knowledge of the nutritional requirements of marine sponges to carry out efficient and sustained in vitro culture and progress has been slow. In marine invertebrate fila many unsuccessful attempts have been made with in vitro cultures using typical commercial animal cell media based on sources of dissolved organic carbon (DOC) (e.g., DMEM, RPMI, M199, L-15, etc.). One of the reasons for this failure is the use of hardly identifiable growth promoters, based on terrestrial animal sera. An alternative is the use of extracts from marine animals, since they may contain nutrients necessary for growth. In this work we have cultivated in vitro explants of the encrusting marine sponge Crambe crambe. It is one of the most abundant sponges on the Mediterranean coastline and also possesses an array of potentially active metabolites (crambines and crambescidins). Initially a new approach was developed in order to show consumption of DOC by explants. Thus, different initial DOC concentrations (300, 400, 700 and 1200 mg DOC L,1) were assayed. Consumption was evident in all four assays and was more marked in the first 6 h. The DOC assimilation data were adjusted to an empirical model widely used for uptake kinetics of organic dissolved compounds in marine invertebrates. Second, a protocol was established to cultivate explants in vitro. Different medium formulations based on RPMI 1640 commercial medium enriched with amino acids and inorganic salts to emulate seawater salinity were assayed. The enrichment of this medium with an Octopusaqueous extract in the proportions of 10% and 20% (v/v) resulted in an evident sustained long-term growth of C. crambe explants. This growth enhancement produced high metabolic activity in the explants, as is confirmed by the high ammonium and lactate content in the medium a few days after its renewal and by the consumption of glucose. The lactate accumulation increased with the size and age of explants. Prior to these experiments, we successfully developed a robust new alternative method, based on digital image treatment, for accurate determination of the explant apparent volume as growth measure. [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] Pharmacological profile of the new antihistaminesCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 1 2005J.-P. Tillement Summary The second-generation H1 antihistamines are a highly efficacious drug class in the treatment of allergic rhinitis (AR) and dermatitis, and distinct from the first-generation H1 antihistamines, predominantly because of their non-sedating nature at recommended dosages. Despite a marked chemical heterogeneity, the non-sedating H1 antihistamines have many similarities, in particular, high affinity for H1 receptors, high efficacy, anti-inflammatory effects, which may be independent of direct H1 -receptor function, and lack of central nervous system side-effects. Some studies have suggested that differences in the chemical structures of these compounds generally lead to differences in the pharmacokinetic properties, which determine their overall clinical usefulness. In particular, it has been demonstrated that there are differences in selectivity for H1 receptors, the apparent volume of distribution, metabolism and elimination and interaction with other drugs. A comparison of levocetirizine, fexofenadine, desloratadine and mizolastine (some of the most commonly prescribed drugs in the treatment of AR and dermatitis) has demonstrated that, unlike levocetirizine and fexofenadine, desloratadine and mizolastine can bind to muscarinic receptors and cardiac K+ channels, and therefore have both lower selectivity and the potential to induce muscarinic and serious cardiac side-effects. However, this is noted at higher than recommended doses. Similarly, desloratadine and mizolastine undergo extensive metabolism and, together with fexofenadine, have the potential to interact with other drugs, in turn increasing the potential for severe toxic effects. In contrast, levocetirizine is not metabolized, is eliminated rapidly from the body, does not demonstrate any significant drug interactions and has the lowest volume of distribution. These findings suggest that levocetirizine is likely to be a safer drug than fexofenadine, desloratadine and mizolastine. [source] The Effect of Ablation Electrode Length and Catheter Tip to Endocardial Orientation on Radiofrequency Lesion Size in the Canine Right AtriumPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 1 2002RODRIGO C. CHAN CHAN, R.C., et al.: The Effect of Ablation Electrode Length and Catheter Tip to Endocardial Orientation on Radiofrequency Lesion Size in the Canine Right Atrium. Although the determinants of radiofrequency lesion size have been characterized in vitro and in ventricular tissue in situ, the effects of catheter tip length and endocardial surface orientation on lesion generation in atrial tissue have not been studied. Therefore, the dimensions of radiofrequency lesions produced with 4-, 6-, 8-, 10-, and 12-mm distal electrode lengths were characterized in 26 closed-chested dogs. The impact of parallel versus perpendicular catheter tip/endocardial surface orientation, established by biplane fluoroscopy and/or intracardiac echocardiography, on lesion dimensions was also assessed. Radiofrequency voltage was titrated to maintain a steady catheter tip temperature of 75°C for 60 seconds. With a perpendicular catheter tip/tissue orientation, the lesion area increased from 29 ± 7 mm2 with a 4-mm tip to 42 ± 12 mm2 with the 10-mm tip, but decreased to 29 ± 8 mm2 with ablation via a 12-mm tip. With a parallel distal tip/endocardial surface orientation, lesion areas were significantly greater: 54 ± 22 mm2 with a 4-mm tip, 96 ± 28 mm2 with a 10- mm tip and 68 ± 24 mm2 with a 12-mm tip (all P < 0.001 vs perpendicular orientation). Lesion lengths and apparent volumes were larger with parallel, compared to perpendicular tip/tissue orientations, although lesion depth was independent of catheter tip length with both catheter tip/tissue orientations. Electrode edge effects were not observed with any tip length. Direct visualization using intracardiac ultrasound guidance was subjectively helpful in insuring an appropriate catheter tip/tissue interface needed to maximize lesion size. Although atrial lesion size is critically dependent on catheter tip length, it is more influenced by the catheter orientation to the endocardial surface. This information may also be helpful in designing electrode arrays for the creation of continuous linear lesions for the elimination of complex atrial tachyarrhythmias. [source] The pharmacokinetics of ethosuximide enantiomers in the ratBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001J. Mifsud Abstract A chiral gas chromatographic assay previously developed for quantitative analysis of ethosuximide and its major metabolites in rat urine has been adapted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious rats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacokinetic parameters were estimated using standard non-compartmental methods. Comparison of the pharmacokinetic parameters of (S)-ethosuximide and (R)-ethosuximide showed that total body clearance of (R)-ethosuximide was significantly larger than that of (S)-ethosuximide and that elimination half-life was significantly shorter following administration of both 40 mg i.v. and i.p. doses, indicating that there is stereoselective elimination of ethosuximide. However, no significant differences were found between apparent volumes of distribution. In addition, no significant differences were found for either enantiomer between the estimates of the pharmacokinetic parameters obtained following administration as the individual enantiomer and as a constituent of the racemic mixture. This indicates that, at the doses studied, the preferential faster elimination of (R)-ethosuximide is not dependent upon the presence of the (S)-enantiomer. Also, for each enantiomer, the lack of any significant difference between estimates of clearance when administered as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other. Copyright © 2001 John Wiley & Sons, Ltd. [source] | |||||||||||||