COMPARATIVE PHARMACOKINETICS OF ORAL AND INTRAVENOUS IFOSFAMIDE/MESNA/METHYLENE BLUE THERAPY

This paper is available online at http://www.dmd.org ABSTRACT: Oral treatment with ifosfamide results in dose-limiting encephalopathy. Methylene blue is effective in reversal and prophylaxis of this side effect. In the present study, the pharmacokinetics of ifosfamide after iv and po therapy in combination with prophylactic administration of methylene blue were investigated. Nine patients with metastatic non-small cell lung cancer were treated by a combination of ifosfamide (3 days), sodium 2-mercaptoethane sulfonate (4 days), and etoposide (8 days). Cycles were repeated every 28 days. Ifosfamide was administered orally, with the exception of one of the first two cycles, when it was administered as a short infusion (randomly assigned). The patients received methylene blue in doses of 50 mg po 3 times daily; an initial dose of 50 mg was given the evening before chemotherapy. Urine samples were collected over the entire treatment period, and concentrations of ifosfamide and its major metabolite, 2-chloroethylamine, were measured by gas liquid chromatography. By the same technique, 2-and 3-dechloroethylifosfamide were determined in plasma and urine. Overall alkylating activity in urine was assayed by reaction of the alkylating metabolites with 4-(4-nitrobenzyl)-pyridine. The chemotherapeutic regimen was well-tolerated by all of the patients studied. There was no evidence of a shift in the metabolic pattern dependent on the route of administration. From the data, we conclude that methylene blue has a neuroprotective effect and that the pharmacokinetics of ifosfamide are not influenced by its comedication

Exponential Decay of Correlations in a Model for Strongly Disordered 2D Nematic Elastomers

Lattice Monte-Carlo simulations were performed to study the equilibrium ordering in a two-dimensional nematic system with quenched random disorder. When the disordering field, which competes against the aligning effect of the Frank elasticity, is sufficiently strong, the long-range correlation of the director orientation is found to decay as a simple exponential, Exp[-r/x]. The correlation length {x} itself also decays exponentially with increasing strength of the disordering field. This result represents a new type of behavior, distinct from the Gaussian and power-law decays predicted by some theories.Comment: Latex file (4 pages) + 2 EPS figure

Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna ± GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. Patients and methods: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. Results: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosup-pression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studie

Slow stress relaxation in randomly disordered nematic elastomers and gels

Randomly disordered (polydomain) liquid crystalline elastomers align under stress. We study the dynamics of stress relaxation before, during and after the Polydomain-Monodomain transition. The results for different materials show the universal ultra-slow logarithmic behaviour, especially pronounced in the region of the transition. The data is approximated very well by an equation Sigma(t) ~ Sigma_{eq} + A/(1+ Alpha Log[t]). We propose a theoretical model based on the concept of cooperative mechanical resistance for the re-orientation of each domain, attempting to follow the soft-deformation pathway. The exact model solution can be approximated by compact analytical expressions valid at short and at long times of relaxation, with two model parameters determined from the data.Comment: 4 pages (two-column), 5 EPS figures (included via epsfig

Plasticity and memory effects in the vortex solid phase of twinned YBa2Cu3O7 single crystals

We report on marked memory effects in the vortex system of twinned YBa2Cu3O7 single crystals observed in ac susceptibility measurements. We show that the vortex system can be trapped in different metastable states with variable degree of order arising in response to different system histories. The pressure exerted by the oscillating ac field assists the vortex system in ordering, locally reducing the critical current density in the penetrated outer zone of the sample. The robustness of the ordered and disordered states together with the spatial profile of the critical current density lead to the observed memory effects

Peak effect, vortex-lattice melting-line and order - disorder transition in conventional and high-T superconductors

We investigate the order - disorder transition line from a Bragg glass to an amorphous vortex glass in the H-T phase diagram of three-dimensional type-II superconductors with account of both pinning-caused and thermal fluctuations of the vortex lattice. Our approach is based on the Lindemann criterion and on results of the collective pinning theory and generalizes previous work of other authors. It is shown that the shapes of the order - disorder transition line and the vortex lattice melting curve are determined only by the Ginzburg number, which characterizes thermal fluctuations, and by a parameter which describes the strength of the quenched disorder in the flux-line lattice. In the framework of this unified approach we obtain the H-T phase diagrams for both conventional and high-Tc superconductors. Several well-known experimental results concerning the fishtail effect and the phase diagram of high-Tc superconductors are naturally explained by assuming that a peak effect in the critical current density versus H signalizes the order - disorder transition line in superconductors with point defects.Comment: 15 pages including 11 figure

Evolution of the fishtail-effect in pure and Ag-doped MG-YBCO

We report on magnetic measurements carried out in a textured YBa$_2$Cu$_3$O$_{7-\delta}$ and YBa$_2$(Cu$_{1-x}$Ag$_x$)$_3$O$_{7-\delta}$ (at $x \approx$ 0.02) crystals. The so-called fishtail-effect (FE) or second magnetization peak has been observed in a wide temperature range 0.4~$<T/T_c<$~0.8 for $\textbf{H}\parallel c$. The origin of the FE arises for the competition between surface barrier and bulk pinning. This is confirmed in a non-monotonically behavior of the relaxation rate $R$. The value $H_{max}$ for Ag-doped crystals is larger than for the pure one due to the presence of additional pinning centers, above all on silver atoms.Comment: 6 pages, 6 figure

Elastic-to-plastic crossover below the peak effect in the vortex solid of YBa2Cu3O7 single crystals

We report on transport and ac susceptibility studies below the peak effect in twinned YBa2Cu3O7 single crystals. We find that disorder generated at the peak effect can be partially inhibited by forcing vortices to move with an ac driving current. The vortex system can be additionally ordered below a well-defined temperature where elastic interactions between vortices overcome pinning-generated stress and a plastic to elastic crossover seems to occur. The combined effect of these two processes results in vortex structures with different mobilities that give place to history effects.Comment: 4 pages, 4 figures. Published in PRB Rapid Comm., February 1, 200

Metastability and Transient Effects in Vortex Matter Near a Decoupling Transition

We examine metastable and transient effects both above and below the first-order decoupling line in a 3D simulation of magnetically interacting pancake vortices. We observe pronounced transient and history effects as well as supercooling and superheating between the 3D coupled, ordered and 2D decoupled, disordered phases. In the disordered supercooled state as a function of DC driving, reordering occurs through the formation of growing moving channels of the ordered phase. No channels form in the superheated region; instead the ordered state is homogeneously destroyed. When a sequence of current pulses is applied we observe memory effects. We find a ramp rate dependence of the V(I) curves on both sides of the decoupling transition. The critical current that we obtain depends on how the system is prepared.Comment: 10 pages, 15 postscript figures, version to appear in PR