Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines

In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 microM. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.     

Increased levels of plasma cholesteryl ester hydroperoxides in patients with subarachnoid hemorrhage

The pathophysiology of subarachnoid hemorrhage (SAH) may involve free radical production and lipid peroxidation. We examined plasma levels of cholesteryl ester hydroperoxides (CEOOH) and antioxidants in 25 patients with SAH, and 10 neurologic controls with lacunar stroke. Patients with SAH had significantly increased plasma levels of CEOOH, which peaked on day 5 after the ictus. Concentrations of CEOOH were significantly increased, and ascorbic acid concentrations were significantly decreased in patients who developed vasospasm compared with patients without vasospasm. Increased levels of CEOOH were associated with increased mortality and correlated with clinical outcome scales. These results implicate oxidative stress in the pathogenesis of SAH and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.     

Colorectal intussusception: an unusual gastrointestinal complication of hereditary angioedema

One case of prenatally diagnosed congenital diaphragmatic hernia was reviewed in terms of the anesthetic managements. Concentrations of diazepam, pancuronium and fentanyl were measured in maternal, fetal and umbilical serum. As expectedly, the transition of diazepam through the placenta was large and the concentration of diazepam in the fetal serum was equal to that of maternal serum, but only a small amount of pancuronium was transferred.     

Diffuse Reflectance Spectroscopy; Applications,Standards, and Calibration (With Special Reference to Chromatography)

The multitude of areas in which diffuse reflectance spectroscopy can be applied has been described in several books and reviews and ranges from color measurements of textiles, pharmaceuticals, building materials, paper and pulp materials etc., to adsorption studies and other basic investigations in physical, inorganic and organic chemistry.The major area of application is still the measurement of color which has become indispensible in the quality control of colored products, dyes and pigments. Color matching practices and techniques with sophisticated instrumentation which can be fully computerized as well as the use of simpler filter instruments for quality control are mentioned.Transferability of reflectance data i.e., color coordinates, depends on the quality of standards particularly when absolute measurements are desired. The difficulty of finding suitable “white standards” with good reflection properties at low UV and with a good long term stability is discussed. Similar arguments hold for sphere coating materials. For the measurement of fluorescing surfaces suitable standards are lacking which renders transfer of such data almost impossible.The usefulness of diffuse reflectance techniques to study adsorption phenomena on small particle adsorbents is demonstrated with a malachite green-o-carboxylic acid lactone system studied by Kortüm. This or similar systems could be adopted to the measurement of relative surface areas on certain chromatographic adsorbents yielding more realistic values than the BET-method.The most recent area of application has been in the field of chromatography for the in situ evaluation of chromatographic zones in flat-bed chromatography, electrophoresis and isoelectric focusing.In chromatography, standardization is less problematic since usually relative measurements are sufficient. On the other hand one has to find suitable calibration procedures. The use of the Kubelka-Munk function is often questionable since we are usually not dealing with layers of infinite thickness and below 300 nm the conventional adsorbents such as silica gel, alumina or cellulose are strongly absorbing. Experiences with a new function combining the laws of Kubelka-Munk and Lambert-Beer are therefore presented.The problem is also to find calibration techniques which account for chromatographic parameters. Until recently it was believed that a quantitative evaluation of chromatograms required a number of reference zones to be developed on the same chromatogram. In our experience this is no longer true. A novel calibration technique which utilizes the concept of transferable calibration factors is discussed. With this approach a quantitative evaluation of a chromatogram with only one reference spot is possible. Here again scanning and data acquisition can be fully automated. The application of proper calibration procedures to differential reflectance techniques and the measurement of multi-component systems is briefly mentioned.Finally it is demonstrated that it is possible to carry out in situ quantitative measurements on low UV absorbing compounds (down to 190 nm) separated on silica gel surfaces, provided suitable techniques and instrumentation are used.     

Thermo-neutral production of metals and hydrogen or methanol by the combined reduction of the oxides of zinc or iron with partial oxidation of hydrocarbons

Stoichiometry and temperature requirements are determined for combining the endothermic reduction of metal oxides (ZnO, Fe₂O₃, and MgO) with the exothermic partial oxidation of hydrocarbons (CH₄, n-butane, n-octane, and n-dodecane) in order to co-produce simultaneously metals and syngas in thermo-neutral reactions. Thermogravimetric and GC measurements on the combined reduction of ZnO and Fe₂O₃ with the partial oxidation of CH₄ were conducted at 1400 K to experimentally verify the products predicted by equilibrium computations, and resulted in the complete reduction to Zn and Fe, respectively, while producing high quality syngas. A preliminary economic assessment that assumes a natural gas price of 11.9 US$/MWh and credit for zinc sale at 750 US$/metric ton, indicates a competitive cost of hydrogen production at 6.0 US$/MWh, based on its high heating value. The proposed combined process offers the possibility of co-producing metals and syngas in autothermal non-catalytic reactors, with significant avoidance of CO₂ emission.     

Qualification test procedure for solar absorber surface durability

A general test procedure for the qualification of solar absorber surface durability has been developed based on the results of a comprehensive case study performed within the framework of the IEA Solar Heating and Cooling Programme Task X. It was assumed, in the development of the qualification procedure, that the intended use of the absorber surface to be qualified, was in single-glazed flat plate solar collectors for domestic hot water production. The absorber surface should be considered qualified if it met the requirement of a design service life of 25 years with maximum loss in the optical performance of the absorber surface corresponding to a 5% relative reduction in the performance of a solar domestic hot water system. The testing procedure, consisting of three kinds of constant load-accelerated life-time tests, was limited to simulation of the following three kinds of absorber surface degradation processes: (a) high-temperature degradation, e.g. oxidation, (b) degradation by the action of moisture or condensed water on the absorber surface, e.g. hydration or hydrolysis, and (c) degradation caused by high humidity air containing a small concentration of sulphur dioxide as an airborne pollutant, e.g. atmospheric corrosion. To quantify expected environmental stress on the absorber surface related to the environmental factors of interest, microclimate data, representing typical service conditions for absorbers in single-glazed flat plate collectors for domestic hot water production were used.     

Round robin on accelerated life testing of solar absorber surface durability

As degradation by ageing of solar absorber surfaces was identified to be an important quality factor, the Working Group MSTC (‘Materials in Solar Thermal Collectors') of the IEA-SHCP (International Energy Agency-Solar Heating and Cooling Programme) worked out a general test procedure for accelerated lifetime testing (ALT) of these materials, based on methods established by the former Task X of the IEA SHCP. The qualification test procedure was adopted by ISO and is presently dealt within ISO/TC 180 ‘Solar Energy'. The standard proposal in detail describes a procedure how to test the long-term stability of an absorber surface for the use in flat plate collectors for domestic hot water systems. The collectors service lifetime is assumed to be 25 years, at least. Degradation caused by thermal loads, high humidity and condensation and sulphur dioxide are regarded. In order to examine the feasibility and reproducibility of the test method the Working Group MSTC initiated a round robin test in accelerated life testing of solar absorber surfaces. The test was performed according to the ISO standard proposal dated January 1997. In total, five different industrially manufactured absorber coatings were available to the three participating laboratories. Tests concerning the thermal stability as well as the resistance to high humidity and condensation were performed by all three laboratories. The test for determining absorber surface corrosion resistance to air of high humidity containing sulphur dioxide was carried out by one lab only. The outcome of the round robin test shows very good agreement of the results of the different coatings tested for all of the laboratories. The feasibility and reproducibility of the method was fully confirmed.     

Coffee and health: a review of recent human research

Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterol-raising effects of coffee. The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson's disease and liver disease (cirrhosis and hepatocellular carcinoma). Most prospective cohort studies have not found coffee consumption to be associated with significantly increased cardiovascular disease risk. However, coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure and plasma homocysteine. At present, there is little evidence that coffee consumption increases the risk of cancer. For adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. However, some groups, including people with hypertension, children, adolescents, and the elderly, may be more vulnerable to the adverse effects of caffeine. In addition, currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.