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Selected AbstractsSynthesis, characterization and impedance spectroscopy of the new material [(CH3) (C6H5) 3P] 2CoBr4: a member of the A2BX4 familyCRYSTAL RESEARCH AND TECHNOLOGY, Issue 5 2008M. F. Mostafa Abstract The crystal structure of bis-(methyltriphenylphosphonium) tetrabromocobaltate (II), [(C19H18P)2 CoBr4] is determined: Mr = 933.203, monoclinic, P21, a = 9. 6977 (3) Å, b = 12.5547 (4)Å, c = 16.4503 (6)Å, , = 105.603 (2)°, V = 1929.04 (11)Å3, Z = 2, Dx = 1.607 Mg m -3, T = 298 K. Differential thermal analysis at high temperatures shows three endothermic peaks characterizing four phases, with onset temperatures at T1= 313±2 K, T2 = 320±4 K and T3= 360±1 K. The structural instability detected via the temperature dependence of permittivity at T1 is ascribed to order-disorder transition associated with cation dipole reorientation. Permittivity and ac conductivity studies as a function of temperature (295 K-375 K) and frequency (0.11 kHz < f <100 kHz) are presented. The results indicate the importance of the cation size and shape on the phase transitions in the system. Bulk conductivity behavior is thermally activated. The associated activation energies are in the range 2.9 to 1.0 eV depending on the temperature regime. Two contributions to the ac conductivity, one dominating at low temperatures and high frequencies which are characterized by superlinear frequency exponent and the second dominates at high temperatures characterized by a sublinear frequency exponent. The behavior is interpreted in terms of the jump relaxation model. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] The effect of soil compaction on germination and early growth of Eucalyptus albens and an exotic annual grassAUSTRAL ECOLOGY, Issue 6 2009ALISON K. SKINNER Abstract Most agricultural land has been compacted to some degree by heavy machinery or livestock trampling. This legacy is expected to influence the success of tree seedling recruits in farmland areas where natural regeneration is being encouraged. We investigated the impact of soil compaction on seedlings of a woodland eucalypt (Eucalyptus albens) and an annual grass competitor (Vulpia myuros) in a laboratory experiment. Replicate soil cores were created at five bulk density levels; 1.0, 1.1, 1.2, 1.3 or 1.4 Mg m,3 with a soil water content of 20%. The depth of root penetration declined linearly with increasing bulk density, resulting in a decrease in root depth of around 75% in the most compacted soil compared with the least compacted soil for both species. Shoot length and primary root length did not vary between soil bulk density levels for either species, but seedlings responded to increasing levels of compaction with oblique (non-vertical) root growth. Results suggest that young seedlings of both E. albens and V. myuros will be more susceptible to surface drying in compacted than uncompacted soils and therefore face a greater risk of desiccation during the critical months following germination. Any competitive advantage that V. myuros may have over E. albens is not evident in differential response to soil compaction. [source] Separating host-tree and environmental determinants of honeydew production by Ultracoelostoma scale insects in a Nothofagus forestECOLOGICAL ENTOMOLOGY, Issue 4 2007ROGER J. DUNGAN Abstract 1.,Sugar-rich honeydew excreted (,produced') by insects feeding on phloem sap is a key energy flow in a range of temperate and tropical ecosystems. The present study measured honeydew produced by Ultracoelostoma sp. (Homoptera: Coelostomidiidae) scale insects feeding on Nothofagus solandri var. solandri (Hook f.) Oerst. trees in a temperate evergreen forest in New Zealand. Simultaneous measurements of environmental variables and canopy photosynthesis were conducted to allow separation of host-tree and environmental determinants of honeydew production. These relationships were further examined in experiments where canopy photosynthesis was manipulated by shading or plant nitrogen levels increased by foliar spray. 2.,Rates of honeydew production varied nine-fold from a maximum (± 1 SE) of 64.4 ± 15.2 mg dry mass m,2 bark h,1 in early summer (December) to a minimum of 7.4 ± 4.2 mg m,2 h,1 in winter (August). Rates of production measured 1.4 m from the base of the trees' stems varied significantly with stem diameter, and were higher on medium-sized (18 cm diameter) than small or large stems. 3.,Rates of production were significantly related to environmental conditions over the hours preceding measurement (air temperature and air saturation deficit averaged over the preceding 24 and 12 h respectively). There was no evidence that rates of production were directly related to short-term changes in the supply of carbohydrates from the canopy (either when compared with measurements of unmanipulated photosynthetic rate, or after sugar levels were manipulated by shading 80% of host-trees' leaf area), or to changes in phloem nitrogen content. 4.,The results show that there is no clear effect of host-tree carbon supply on honeydew production; if production is related to photosynthesis, the effect of this is much less important that the large and significant direct effect of environmental conditions on honeydew production. [source] Treatment of intermediate- and high-grade non-Hodgkin's lymphoma using CEOP versus CNOPEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2002A Hellenic Co-operative Oncology Group Study Abstract:Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m,2, vincristine 2 mg, E 70 mg m,2 on day 1 and prednisone 60 mg on days 1,7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m,2. Randomization was stratified according to stages I,IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P = 0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P = 0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate- and high-grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients. [source] A simple model of the eco-hydrodynamics of the epilimnion of Lake TanganyikaFRESHWATER BIOLOGY, Issue 11 2007JAYA NAITHANI Summary 1. The ecosystem response of Lake Tanganyika was studied using a four-component, nutrient,phytoplankton,zooplankton,detritus, phosphorus-based ecosystem model coupled to a nonlinear, reduced-gravity, circulation model. The ecosystem model, an improved version of the earlier eco-hydrodynamics model developed for Lake Tanganyika, was used to estimate the annual primary production of Lake Tanganyika and its spatial and temporal variability. The simulations were driven with the National Centres for Environmental Protection (NCEP) records for winds and solar radiation forcing. 2. The simulated annual cycles of the four ecosystem variables and the daily net primary production were compared with the observations. The comparison showed that simulations reproduced realistically the general features of the annual cycles of epilimnial phosphate, net primary production and plankton dynamics. 3. The climatic simulations for the years 1970,2006 yielded a daily averaged integrated upper layer net production ranging from 0.11 to 1.78 g C m,2 day,1 and daily averaged chlorophyll- a (chl- a) from 0.16 to 4.3 mg m,3. Although the nutrient concentrations in the epilimnion during the strong wind years were high, the net production was low, which is partly because of the greater vertical mixing, produced by strong winds, exposing the phytoplankton to low light conditions in deeper waters. The simulated annual net production and chl- a agreed quite well with observed production available in the literature. 4. We envisage using this model to predict the future scenarios of primary productivity in the lake. [source] Regional-scale measurements of CH4 exchange from a tall tower over a mixed temperate/boreal lowland and wetland forestGLOBAL CHANGE BIOLOGY, Issue 9 2003Cindy Werner The biosphere,atmosphere exchange of methane (CH4) was estimated for a temperate/boreal lowland and wetland forest ecosystem in northern Wisconsin for 1997,1999 using the modified Bowen ratio (MBR) method. Gradients of CH4 and CO2 and CO2 flux were measured on the 447-m WLEF-TV tower as part of the Chequamegon Ecosystem,Atmosphere Study (ChEAS). No systematic diurnal variability was observed in regional CH4 fluxes measured using the MBR method. In all 3 years, regional CH4 emissions reached maximum values during June,August (24±14.4 mg m,2 day,1), coinciding with periods of maximum soil temperatures. In 1997 and 1998, the onset in CH4 emission was coincident with increases in ground temperatures following the melting of the snow cover. The onset of emission in 1999 lagged 100 days behind the 1997 and 1998 onsets, and was likely related to postdrought recovery of the regional water table to typical levels. The net regional emissions were 3.0, 3.1, and 2.1 g CH4 m,2 for 1997, 1998, and 1999, respectively. Annual emissions for wetland regions within the source area (28% of the land area) were 13.2, 13.8, and 10.3 g CH4 m,2 assuming moderate rates of oxidation of CH4 in upland regions in 1997, 1998, and 1999, respectively. Scaling these measurements to the Chequamegon Ecosystem (CNNF) and comparing with average wetland emissions between 40°N and 50°N suggests that wetlands in the CNNF emit approximately 40% less than average wetlands at this latitude. Differences in mean monthly air temperatures did not affect the magnitude of CH4 emissions; however, reduced precipitation and water table levels suppressed CH4 emission during 1999, suggesting that long-term climatic changes that reduce the water table will likely transform this landscape to a reduced source or possibly a sink for atmospheric CH4. [source] Rituximab for congenital haemophiliacs with inhibitors: a Canadian experienceHAEMOPHILIA, Issue 1 2006M. CARCAO Summary., When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti-CD20 monoclonal antibody, which has shown promise in the treatment of B-cell-mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m,2 of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half-life). Patients are concurrently placed on recombinant FVIII (100 U kg,1 day,1). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non-responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management. [source] Micro-organisms and dust exposure in an Italian grain millJOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2005C. Dacarro Abstract Aims:, In order to assess possible occupational risk for workers in a grain mill, we evaluated aerial microbiological contamination in different areas of the mill and at different points of the production line. We also measured the concentration of aerodispersed dust particles. Methods and Results:, An assessment of microbiological contamination levels based on a Global Index of Microbial Contamination per cubic metre (GIMC per m3), an Index of Mesophilic Bacterial Contamination, and an Amplification Index is proposed. The indices were obtained from total and fungal counts. The cleaning sector is the most contaminated area of the mill: the mean GIMC per m3 was 17 213·6. In this area, the average microbial contamination was 11·41 times higher than that in the external environment. The highest concentrations of aerodispersed dust (inhalable 2·763 mg m,3; respirable 1·400 mg m,3) were found in the cleaning area. Conclusions:, The proposed microbiological indices and the concentrations of aerodispersed dust particles show that the most hazardous section of the mill is the cleaning area. The large variation in the data does not depend on seasonal factors, but rather on not easily identifiable conditions of the internal environment which facilitate diffusion and/or proliferation of the micro-organisms. Significance and Impact of the Study:, The proposed microbiological contamination indices and the evaluation of the concentration of dust particles allow the identification of critical positions during the production cycle so that suitable measures to prevent the aerial contamination can be taken. [source] Acute effects of exposure to vapours of standard and dearomatized white spirits in humans.JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2009Abstract A move from ,standard' white spirit (stdWS, 15,20% aromatics) to low-aromatic or dearomatized white spirit (deWS) has been seen, as the latter are considered to carry a smaller risk of health effects. However, data on health risks of deWS on humans are sparse. The aim of this dose-finding study was to identify thresholds of irritation and central nervous system (CNS) effects of the two types of white spirit, as a basis for more detailed studies. Four female and four male healthy volunteers rated symptoms related to irritation, smell and CNS effects on a 0,100 mm visual analogue scale while exposed to increasing levels of deWS or stdWS in eight 10 min steps from 0.5 to 600 mg m,3. Combined ratings of questions related to irritation revealed statistically significant increases compared with pre-exposure ratings at 50 mg m,3 and higher exposures. The ratings increased in a dose-dependent fashion, the medians reaching ,somewhat' for stdWS and ,hardly at all' for deWS. Higher ratings of irritation were found during exposure to stdWS compared with deWS, reaching significance only at 500 mg m,3. The combined ratings of CNS effects reached ,hardly at all', and were significantly increased only for stdWS at 500 and 600 mg m,3. Copyright © 2008 John Wiley & Sons, Ltd. [source] Pulmonary responses and recovery following single and repeated inhalation exposure of rats to polymeric methylene diphenyl diisocyanate aerosolsJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2002Joanne D. Kilgour Abstract Acute and repeated inhalation exposures (for 28 days) to polymeric methylene diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at the end of exposures and after 3, 10 and 30 days of recovery following single acute exposures and after 30 days of recovery following 28 days of exposure. Acute exposures to 10, 30 or 100 mg m,3 PMDI produced clinical signs in all animals that were consistent with exposure to irritant aerosols. An exposure concentration-related body weight loss and increase in lung weight were seen post-exposure, with complete recovery by day 8. The time course of changes in the lung over the initial days following exposure consisted of a pattern of initial toxicity, rapid and heavy influx of inflammatory cells and soluble markers of inflammation and cell damage, increased lung surfactant, a subsequent recovery and epithelial proliferative phase and, finally, a return to the normal status quo of the lung. During these stages there was evidence for perturbation of lung surfactant homeostasis, demonstrated by increased amounts of crystalline surfactant and increased number and size of lamellar bodies within type II alveolar cells. Repeated exposure over 28 days to the less toxic concentrations of 1, 4 or 10 mg m,3 PMDI produced no clinical signs or body weight changes, but an increase in lung weight was seen in animals exposed to 10 mg m,3, which resolved following the 30-day recovery period. Other effects seen were again consistent with exposure to irritant aerosols, but were less severe than those seen in the acute study. Analysis of bronchoalveolar lavage fluid revealed similar changes to those seen in the acute study. At both 10 and 4 mg m,3 PMDI increased numbers of ,foamy' macrophages in lung lavage cell pellet correlated with the increased phospholipid content of the pellet. Changes in lung lavage parameters and electron microscopic evidence again suggested perturbations in surfactant homeostasis. Histologically, bronchiolitis and thickening of the central acinar regions was seen at 10 and 4 mg m,3, reflecting changes in cell proliferation in the terminal bronchioles and centro-acinar regions. Almost all effects seen had recovered by day 30 post-exposure. Both acute and subacute studies demonstrate rapid recovery of effects in the lung following exposure to PMDI, with no progression of these effects even at concentrations higher than those shown to produce tumours in a chronic study. These findings add weight to the hypothesis that pulmonary tumours seen following chronic exposure to PMDI are most likely due to a combination of the chronic irritant effects of repeated exposure, coupled with the presence of insoluble polyureas formed by polymerization of PMDI (found in studies reported here and previous chronic studies), and therefore acute or short-term exposures to PMDI are likely to be of little concern for long-term pulmonary health. Copyright © 2002 John Wiley & Sons, Ltd. [source] Respiratory hypersensitivity to trimellitic anhydride in Brown Norway Rats: a comparison of endpointsJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2002Jürgen Pauluhn Abstract A rat bioassay has been developed to provide an objective approach for the identification and classification of respiratory allergy using trimellitic anhydride (TMA), which is a known respiratory tract irritant and asthmagen. Particular emphasis was placed on the study of route-of-induction-dependent effects and their progression upon inhalation challenge with TMA (,23 mg m,3 for a duration of 30 min), which included analysis of specific and non-specific airway hyperreactivity and pulmonary inflammation initiated and sustained by immunological processes. Refinement of the bioassay focused on procedures to probe changes occurring upon challenge with TMA or methacholine aerosols using physiological, biochemical and immunological procedures. Following challenge with TMA, the rats sensitized to TMA showed marked changes in peak inspiratory and expiratory air flows and respiratory minute volume. In these animals, a sustained pulmonary inflammation occurred, characterized by specific endpoints determined in bronchoalveolar lavage (lactate dehydrogenase, protein, nitrite, eosinophil peroxidase, myeloperoxidase). When compared with the naive controls, lung weights were increased significantly, as were the weights of lung-associated lymph nodes following inhalation induction and auricular lymph nodes following topical induction. The extent of changes observed was equal or more pronounced in animals sensitized epicutaneously (day 0 : 150 µl vehicle/50% TMA on each flank, day 7; booster administration to the skin of the dorsum of both ears using half the concentration and volume used on day 0) when compared with rats sensitized by 5 × 3 h day,1 inhalation exposures (low dose: 25 mg TMA m,3, high dose: 120 mg TMA m,3). In summary, the findings support the conclusion that the Brown Norway rat model is suitable for identifying TMA as an agent that causes both an immediate-type change of breathing patterns and a delayed-type sustained pulmonary inflammatory response. However, it remains unresolved whether the marked effects observed in the topically sensitized rats are more related to a route-of-induction or dose-dependent phenomenon. Copyright © 2002 John Wiley & Sons, Ltd. [source] DISTRIBUTION OF SEDIMENT PHOSPHORUS POOLS AND FLUXES IN RELATION TO ALUM TREATMENT,JOURNAL OF THE AMERICAN WATER RESOURCES ASSOCIATION, Issue 3 2000William F James ABSTRACT: The distribution of sediment physical characteristics, sediment phosphorus (P) pools, and laboratory-based rates of P release from the sediments were used to identify regions and dosage for alum treatment in Wind Lake, Wisconsin. Using variations in sediment moisture content, we identified an erosional zone at depths < 1.4 m and an accumulation zone at depths > 2.6 m. Mean concentrations of porewater P, loosely-bound P, iron- and aluminum-bound P, and mean rates of P release from sediments under anoxic conditions were high in the accumulation zone compared to sediment P characteristics in the erosional zone, indicating focusing of readily mobilized sediment P pools from shallow regions and accumulation to deep regions. We determined that a future alum treatment for control of internal P loading would be most effective at depths > 2.6 in the accumulation zone. The mean rate of anoxic P release from sediments encountered in the accumulation zone (8.3 mg m -2 d -1) was used in conjunction with a summer anoxic period of 122 d, and a treatment area of 1.6 km2 to estimate an internal P load of 1,600 kg to be controlled. Our results suggest that an understanding of the distribution of sediment P pools and P fluxes in lakes provides a strategy for estimating alum dosage and application areas. [source] Retrieval of microphysical and morphological properties of volcanic ash plumes from satellite data: Application to Mt Ruapehu, New ZealandTHE QUARTERLY JOURNAL OF THE ROYAL METEOROLOGICAL SOCIETY, Issue 576 2001A. J. Prata Abstract A quantitative analysis of the properties of several Mt Ruapehu, New Zealand, ash plumes has been performed using multispectral satellite data from the AVHRR-2 and ATSR-2 instruments. The analysis includes: identification of the plume from background clouds using the ,reverse' absorption effect in the thermal channels: modelling and retrieval of particle sizes; determination of the plume height from cloud shadows, stereoscopy and meteorological data; and estimates of the mass of fine particles (radii less than 10 ,m). A new spectral technique for identifying opaque, silica-rich ash clouds is demonstrated by utilizing the near-infrared (1.6 ,m) and visible (0.67 ,m) channels of the ATSR-2, and the optical properties of a simple volcanic cloud are presented for use in radiative transfer studies. It is found that the Ruapehu eruption cloud contained silica-rich ash particles with radii generally less than a few micrometres. The distribution of fine particles is monomodal with a dominant mode peak of about 3 ,m radius. Mass loadings of fine particles are found to be in the range ,1 to ,7 mg m,3, and are consistent with estimates of mass loadings of volcanic clouds from eruptions of other volcanoes. The height of the plume top, derived from radiosonde data and plume-top temperatures in the opaque regions, was found to be between 7.5 and 8.5 km, while the plume thickness was estimated to be between 1.5 and 3 km. Cloud height derived from ATSR-2 stereoscopy on a different plume gave heights in the range 5 to 8 km. The results of this study provide important information on the optical properties of nascent volcanic eruption plumes. This information may prove useful in determining the potential effects of volcanic clouds on local climate, and in assessing any hazard to aviation. [source] Performance evaluation of concurrent rice,fish,prawn culture with and without cull harvestingAQUACULTURE RESEARCH, Issue 9 2010Rajeeb K Mohanty Abstract This study was carried out in farmers' fields for three experimental culture cycles to evaluate the performance of rice,fish,prawn culture. The treatments carried out were deepwater rice mono-cropping (R), and rice,fish,prawn culture with cull harvesting (R,FC) and without cull harvesting (R,F). Water pH and total alkalinity were significantly higher (P<0.05) in R,FC than in R,F, while the concentrations of total suspended solids, plankton and chlorophyll a were higher in R,F. Cull harvesting in R,FC had no marked influence on the concentrations of dissolved oxygen, NH4+, nitrite, nitrate and phosphate compared with the R,F treatment. The significantly higher fish and prawn yields (P<0.05) and species-wise faster individual growth performance in R,FC than in R,F were probably due to periodic cull harvesting, which minimized the competition for food and space as well as physiological stress at reduced density. The paddy yield and percentage increase in paddy yield over rice mono-crop was significantly higher (P<0.05) in R,FC (25%), followed by R,F (16.9%), probably due to lower chlorophyll a (36.7 mg m,3) and plankton density (1.4 × 104 L,1), which minimized the competition for nutrients with rice plants. The highest rice equivalent yield (38.5), output value,cultivation cost ratio (1.56) and enhanced net return (28%) in deepwater rice,fish culture were recorded when cull harvesting was practiced. [source] Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Stijn L. W. Koolen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [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] Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patientsBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2007M.S.Y. Goh Summary Background, Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus. Objectives, Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV). Methods, Patients with PV were treated with intravenous rituximab (375 mg m,2) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued. Results, Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2,8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection). Conclusions, Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications. [source] Pegylated liposomal doxorubicin in stage IVB mycosis fungoidesBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005G. Di Lorenzo Summary Background, Previous studies have shown that pegylated liposomal doxorubicin (LD) is effective in the treatment of relapsing or recalcitrant cutaneous T-cell lymphoma. Objectives, To evaluate the activity and toxicity of LD in patients with stage IVB mycosis fungoides (MF). Methods, In this retrospective study, we evaluated outcomes and recorded adverse effects in 10 patients with MF (seven men and three women) with extracutaneous involvement. Patients were treated with LD 20 mg m,2 administered intravenously every 4 weeks. Results, All patients received at least two cycles of LD, three patients received four cycles and one patient received six cycles. Three patients (30%) had a partial response and two patients had stable disease. Grade 1,2 leucopenia occurred in three of the 10 patients, and grade 4 leucopenia in one. Three patients had grade 2 palmoplantar erythrodysaesthesia. Conclusions, This study demonstrates that LD is beneficial in terms of activity and toxicity in stage IVB MF. These observations should be verified in larger studies. [source] Treatment of advanced mycosis fungoides/Sézary syndrome with fludarabine and potential adjunctive benefit to subsequent extracorporeal photochemotherapyBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2004P. Quaglino Summary Background Purine analogues [fludarabine monophosphate (FAMP); deoxycoformycin and 2-chlorodeoxyadenosine) and extracorporeal photochemotherapy (ECP) have been suggested to be active agents in advanced cutaneous T-cell lymphoma (CTCL) patients. Objectives To explore further the clinical efficacy and safety of FAMP monochemotherapy in advanced CTCL and to evaluate if the sequential association of ECP to FAMP in selected patients may improve the response rate (RR) and/or lengthen the remission duration. Patients and methods Forty-four CTCL patients [17 Sézary syndrome (SS); 26 mycosis fungoides (MF), stage IIB,IV or with peripheral blood involvement; one MF associated with lymphomatoid papulosis (LyP)] were enrolled in this pilot cohort study. All the patients received FAMP 25 mg m,2 5 days monthly; 19 patients (43·2%) underwent ECP after FAMP was discontinued. The majority of patients with erythrodermic CTCL or peripheral blood involvement underwent the combined FAMP,ECP schedule. Results After a median follow-up of 4·2 years, the overall FAMP RR was 29·5% (13/44); a higher RR was obtained in SS (35·3%) than in MF patients (25·9%). According to the treatment group, the RR of the FAMP,ECP group (63·2%) was significantly higher than that of the FAMP monotherapy group (24%; P = 0·021). No statistically significant difference was found in time-to-progression (TTP) or survival by therapy group, even if the TTP of the patients treated with the FAMP,ECP combination therapy was higher (median 13 vs. 7 months). A decrease or a normalization in the CD4+CD26, circulating subset was observed in responding patients, paralleling the reduction in the circulating Sézary cells. Conclusions FAMP confirms its clinical activity as a single agent in SS; conversely, FAMP results do not compare favourably with other therapeutic approaches for advanced stage MF patients. The sequential association of ECP after FAMP seems to increase the RR, even if future randomized studies are needed to confirm these results. [source] | ||||||||||||||||