High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.     

Spiroergometric evaluation of the effectiveness of treatment of cardiac insufficiency with cardiac glycosides

There were 29 patients with rheumatic heart disease and early stages of cardiac insufficiency under observation. Spiroergometry with the "Ergotest" device was conducted in dynamics to check whether the proper dose of the cardiac glycoside had been chosen. The results attest to the considerable improvement in the spiroergometric indices in patients with early stages of cardiac insufficiency who had been treated with digitalis. Spiroergometry yielded important additional criteria of the effectiveness of digitalization, particularly in individuals with normal or diminished rate of cardiac contractions.     

Transient gain control in EDFA's by dual-cavity optical automaticgain control

We report a novel method for automatic gain control of optical amplifiers: dual-cavity optical automatic gain control. The method exploits inhomogeneous broadening in erbium-doped fibers to clamp the erbium gain spectrum with two oscillating lasers. The technique significantly reduces surviving channel steady-state and transient power excursions by automatic reduction of relaxation oscillations and spectral hole burning     

Mechanisms of dimer and trimer formation from ultraviolet-irradiated α-tocopherol

α-Tocopherol (α-TH) undergoes ultraviolet (UV)-induced photooxidation on the surface of mouse skin to produce a dihydroxydimer, a spirodimer, and trimers as the major products. To study the photochemistry involved, we UV-irradiated α-TH in a thin film on a glass petri dish. Photooxidation yielded a mixture of dihydroxydimer, spirodimer, and trimers. In the time-course studies, the dihydroxydimer accumulated and then was further oxidized, whereas the spirodimer and trimers accumulated more gradually. Reaction of two tocopheroxyl radicals forms the dihydroxydimer, whereas the spirodimer may be formed either by photooxidation of α-TH to an orthoquinone methide (o-QM) followed by a Diels-Alder reaction or by photooxidation of α-TH to the dihydroxydimer, followed by two-electron oxidation. Irradiation of a mixture of d ₁₀-labeled and unlabeled (d ₀) dihydroxydimer produced a mixture of labeled and unlabeled spirodimers as detected by positive atmospheric pressure chemical ionization-mass spectrometry. The absence of mixed label spirodimers among products indicated that direct oxidation of the dihydroxydimer is a facile route to the spirodimer and is probably the major spirodimer-forming reaction in α-TH photooxidations. Trimer formation from the dihydroxydimer and the spirodimer was observed, however, and requires an o-QM intermediate. Photooxidation of d ₁₀-labeled and unlabeled (d ₀) dihydroxydimers yielded mixed isotopomers of the trimer products, thus demonstrating that the dihydroxydimer and spirodimers underwent conversion to o-QM intermediates. Photochemical conversion of α-TH to UV-absorbing dimer and trimer products may contribute to photoprotection by topically applied α-TH.     

Sustainability of Small Reservoirs and Large Scale Water Availability Under Current Conditions and Climate Change

Semi-arid river basins often rely on reservoirs for water supply. Small reservoirs may impact on large-scale water availability both by enhancing availability in a distributed sense and by subtracting water for large downstream user communities, e.g. served by large reservoirs. Both of these impacts of small reservoirs are subject to climate change. Using a case-study on North-East Brazil, this paper shows that climate change impacts on water availability may be severe, and impacts on distributed water availability from small reservoirs may exceed impacts on centralised water availability from large reservoirs. Next, the paper shows that the effect of small reservoirs on water availability from large reservoirs may be significant, and increase both in relative and absolute sense under unfavourable climate change.     

Laboratory and Field Investigations of Polymer and Crumb Rubber Modified Bitumen

In this paper, properties of new kind of modified bitumen are presented. Bituminous binder was modified with mix modification using polymer and additive of crumb rubber. Terminal blend process at the refinery was applied to produce the mixed modified binder. Laboratory tests were focused on the characterization of the properties of 45/80-55 CR binder with comparison to reference 50/70 and conventional polymer modified 45/80-55 bitumen. Based on conventional binder tests such as penetration, softening point and Fraass breaking point as well as BBR （bending beam rheometer） and DSR （dynamic shear rheometer） tests, rheological properties were investigated. For determination of stability of the polymer and crumb rubber, modified bitumen tube testing method was used. Based on the results analysis, improvement of the viscoelastic properties of polymer and crumb rubber modified bitumen was observed. Conventional properties and stability tests showed that it is possible to pass standard requirements for polymer modified bitumen. Mixed modification and terminal blend allow to use crumb rubber as a modifier with elimination of the separation of crumb rubber during transportation and storage at high temperature. In this paper, experience from filed sections with use of the asphalt mixture with new kind of modified bitumen is presented.     

Ciprofloxacin pharmacokinetics in burn patients

Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50 microM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats. These results, which agree with previous findings, suggest that for these sex steroids extrapolation to humans of results obtained in rats might be questionable.