Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies

PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2'-position of paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m(2)). RESULTS: In vitro, DHA-paclitaxel was found to bind extensively to human plasma (99.6 +/- 0.057%). The binding was concentration independent (P = 0.63), indicating a nonspecific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 +/- 0.0018 to 0.055 +/- 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0-1000 microg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (+/- SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 +/- 0.029 microg.h/ml (at 660 mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was associated with the dose-limiting neutropenia in a maximum-effect model (R(2) = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2)) is similar to that achieved with paclitaxel on clinically relevant dose schedules. CONCLUSIONS: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution ( approximately 4 liters) and slow systemic clearance ( approximately 0.11 liters/h)

Distribution of Dissolved Nitrogen Compounds in the Water Column of a Meromictic Subarctic Lake

In order to better understand the biogeochemical cycle of nitrogen in meromictic lakes, which can serve as a model for past aquatic environments, we measured dissolved concentrations of nitrate, nitrite, ammonium, and organic nitrogen in the deep (39 m maximal depth) subarctic Lake Svetloe (NW Russia). The lake is a rare type of freshwater meromictic water body with high concentrations of methane, ferrous iron, and manganese and low concentrations of sulfates and sulfides in the monimolimnion. In the oligotrophic mixolimnion, the concentration of mineral forms of nitrogen decreased in summer compared to winter, likely due to a phytoplankton bloom. The decomposition of the bulk of the organic matter occurs under microaerophilic/anaerobic conditions of the chemocline and is accompanied by the accumulation of nitrogen in the form of N-NH4 in the monimolimnion. We revealed a strong relationship between methane and nitrogen cycles in the chemocline and monimolimnion horizons. The nitrate concentrations in Lake Svetloe varied from 9 to 13 μM throughout the water column. This fact is rare for meromictic lakes, where nitrate concentrations up to 13 µM are found in the monimolimnion zone down to the bottom layers. We hypothesize, in accord with available data for other stratified lakes that under conditions of high concentrations of manganese and ammonium at the boundary of redox conditions and below, anaerobic nitrification with the formation of nitrate occurs. Overall, most of the organic matter in Lake Svetloe undergoes biodegradation essentially under microaerophilic/anaerobic conditions of the chemocline and the monimolimnion. Consequently, the manifestation of the biogeochemical nitrogen cycle is expressed in these horizons in the most vivid and complex relationship with other cycles of elements

Lichen, moss and peat control of C, nutrient and trace metal regime in lakes of permafrost peatlands

Permafrost thaw in continental lowlands produces large number of thermokarst (thaw) lakes, which act as a major regulator of carbon (C) storage in sediments and C emission in the atmosphere. Here we studied thaw lakes of the NE European permafrost peatlands - shallow water bodies located within frozen peat bogs and receiving the majority of their water input from lateral (surface) runoff. We also conducted mesocosm experiments via interacting lake waters with frozen peat and dominant ground vegetation - lichen and moss. There was a systematic decrease in concentrations of dissolved C, CO2, nutrients and metals with an increase in lake size, corresponding to temporal evolution of the water body and thermokarst development. We hypothesized that ground vegetation and frozen peat provide the majority of C, nutrients and inorganic solutes in the water column of these lakes, and that microbial processing of terrestrial organic matter controls the pattern of CO2 and nutrient concentrations in thermokarst lakes. Substrate mass-normalized C, nutrient (N, P, K), major and trace metal release was maximal in moss mesocosms. After first 16 h of reaction, the pCO2 increased ten-fold in mesocosms with moss and lichen; this increase was much less pronounced in experiments with permafrost peat. Overall, moss and lichen were the dominant factors controlling the enrichment of the lake water in organic C, nutrients, and trace metals and rising the CO2 concentration. The global significance of obtained results is that the changes in ground vegetation, rather than mere frozen peat thawing, may exert the primary control on C, major and trace element balance in aquatic ecosystems of tundra peatlands under climate warming scenario

Carbon emission from thermokarst lakes in NE European tundra

Emission of greenhouse gases (GHGs) from inland waters is recognized as highly important and an understudied part of the terrestrial carbon (C) biogeochemical cycle. These emissions are still poorly quantified in subarctic regions that contain vast amounts of surface C in permafrost peatlands. This is especially true in NE European peatlands, located within sporadic to discontinuous permafrost zones which are highly vulnerable to thaw. Initial measurements of C emissions from lentic waters of the Bolshezemelskaya Tundra (BZT; 200,000 km(2)) demonstrated sizable CO(2)and CH(4)concentrations and fluxes to the atmosphere in 98 depressions, thaw ponds, and thermokarst lakes ranging from 0.5 x 10(6)to 5 x 10(6) m(2)in size. CO(2)fluxes decreased by an order of magnitude as waterbody size increased by > 3 orders of magnitude while CH(4)fluxes showed large variability unrelated to lake size. By using a combination of Landsat-8 and GeoEye-1 images, we determined lakes cover 4% of BZT and thus calculated overall C emissions from lentic waters to be 3.8 +/- 0.65 Tg C yr(-1)(99% C-CO2, 1% C-CH4), which is two times higher than the lateral riverine export. Large lakes dominated GHG emissions whereas small thaw ponds had a minor contribution to overall water surface area and GHG emissions. These data suggest that, if permafrost thaw in NE Europe results in disappearance of large thermokarst lakes and formation of new small thaw ponds and depressions, GHG emissions from lentic waters in this region may decrease

Carbon emission from thermokarst lakes in NE European tundra

Emission of greenhouse gases (GHGs) from inland waters is recognized as highly important and an understudied part of the terrestrial carbon (C) biogeochemical cycle. These emissions are still poorly quantified in subarctic regions that contain vast amounts of surface C in permafrost peatlands. This is especially true in NE European peatlands, located within sporadic to discontinuous permafrost zones which are highly vulnerable to thaw. Initial measurements of C emissions from lentic waters of the Bolshezemelskaya Tundra (BZT; 200,000 km2) demonstrated sizable CO2 and CH4 concentrations and fluxes to the atmosphere in 98 depressions, thaw ponds, and thermokarst lakes ranging from 0.5 × 106 to 5 × 106 m2 in size. CO2 fluxes decreased by an order of magnitude as waterbody size increased by > 3 orders of magnitude while CH4 fluxes showed large variability unrelated to lake size. By using a combination of Landsat‐8 and GeoEye‐1 images, we determined lakes cover 4% of BZT and thus calculated overall C emissions from lentic waters to be 3.8 ± 0.65 Tg C yr−1 (99% C‐CO2, 1% C‐CH4), which is two times higher than the lateral riverine export. Large lakes dominated GHG emissions whereas small thaw ponds had a minor contribution to overall water surface area and GHG emissions. These data suggest that, if permafrost thaw in NE Europe results in disappearance of large thermokarst lakes and formation of new small thaw ponds and depressions, GHG emissions from lentic waters in this region may decrease

Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma

Objective: To investigate post-transplant immunotherapy with escalating donor-lymphocyte infusions (DLI) and novel agents (thalidomide, bortezomib, and lenalidomide) to target complete remission (CR). Materials and Methods: Thirty-two patients with multiple myeloma who achieved only partial remission after allogeneic stem cell transplantation were treated with DLI. If no CR was achieved, one of the novel agents was added to target CR. Results: CR defined either by European Group for Blood and Marrow Transplantation criteria, flow cytometry, or molecular methods as assessed by patient-specific immunoglobulin H-polymerase chain reaction or plasma cell chimerism polymerase chain reaction was accomplished in 59%, 63%, and 50% of patients, respectively. Achievement of CR resulted in improved 5-year progressive-free and overall survival, according to European Group for Blood and Marrow Transplantation criteria (53% vs 35%; p = 0.03 and 90% vs 62%; p = 0.06), flow cytometry (74% vs 15%; p = 0.001 and 100% vs 52%; p = 0.1), or molecular methods (84% vs 38%; p = 0.001 and 100% vs 71%; p = 0.03). Conclusions: Our finding demonstrates the clinical relevance of posttransplantation therapies to upgrade remission, and of remission's depth for long-term survival in myeloma patients