Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds and neutralizes IL-6R, resulting in the inhibition of various IL-6-mediated biological activities, including inflammation-related, immunomodulatory and tissue/matrix remodelling effects. Randomized, double-blind, controlled phase III studies and a number of early clinical observational studies have shown that treatment with TCZ results in rapid and sustained improvement in the signs and symptoms of RA among different patient populations. These studies have established the efficacy and safety of TCZ. Here, we review the pleiotropic functions of IL-6 and how it impinges on many aspects of RA pathogenesis, and highlight the clinical experience to date with TCZ as an emerging new treatment option for RA.
This paper reports the densities, viscosities, and electrical conductivities of the two pyrrolidinium ionic liquids, N-methoxymethyl-N-methylpyrrolidinium bis(fluorosulfonyl)amide ([Pyr1,1O1][FSA]) and N-butyl-N-methylpyrrolidinium bis(fluorosulfonyl)amide ([Pyr1,4][FSA]), over the temperature range T = (273.15 to 363.15) K at atmospheric pressure. The densities were fitted to polynominals, and the viscosities and electrical conductivities were analyzed with the Vogel–Fulcher–Tammann and Litovitz equations. The densities and electrical conductivities of [Pyr1,1O1][FSA] are higher than those of [Pyr1,4][FSA], while the viscosities of the former salt are smaller than those of the latter. The Walden plots (double logarithm graph of molar conductivity vs fluidity (reciprocal viscosity)) give the straight lines with the slopes being 0.91 to 0.94. The present results for [Pyr1,1O1][FSA] and [Pyr1,4][FSA] are compared with those for the bis(trifluoromethanesulfonyl)amide ([NTf2]−) analogues, [Pyr1,1O1][NTf2] and [Pyr1,4][NTf2].
Microdosing studies are effective in enabling the early identification of the pharmacokinetic properties of compounds administered to humans. However, the nonlinearity of the pharmacokinetics between microdose and therapeutic dose, attributable to the saturation of metabolic enzymes and transporters, is a major concern. Verapamil and quinidine are good substrates of both the multidrug resistance 1 transporter (MDR1) and the cytochrome P450 (CYP) 3A4 enzyme (CYP3A4). We investigated their dose-dependent pharmacokinetics in healthy subjects. Four different doses of verapamil or quinidine were administered orally to each subject, and the plasma concentrations of the parent drugs and their major metabolites were measured. The dose-normalized area under the plasma concentration-time curve (AUC) values of quinidine and verapamil increased in a dose-dependent manner and were 2.6- and 2.3-fold higher, respectively, at the therapeutic dose than at microdose. These results suggest that the nonlinear pharmacokinetics of these drugs is caused mainly by the saturation of MDR1 and/or CYP3A4 in the small intestine.
Realization of an ultraclean Si wafer surface is essential for achieving the advanced process in the ultralarge scale integrated production such as low-temperature process and high selectivity. An ultraclean wafer surface is defined as a surface completely free from particles, organic impurities, metallic impurities, native oxide, surface microroughness, and adsorbed impurities. Since metallic impurities, one of the above contaminants, cause fatal damage to device characteristics, metallic impurities on the wafer surface need to be suppressed at least below 10 l~ atom/cm 2 which is the level of the detection limit of total reflection x-ray fluorescence. The current dry processes such as ion implantation and reactive ion etching cause metallic contamination of 1012 to 1013 atom/cm 2. In order to remove the metallic contamination, the wet cleaning process plays an increasingly important role. When organic impurities remain on the wafer surface, native oxide and metallic impurities on the wafer cannot be completely removed. In order to establish an ultraclean wafer surface, therefore, it is crucial to remove organic impurities first of all. The wet cleaning process is the only possible method at present to remove trace organic contaminants on the wafer surface. We have studied the segregation and removal of metallic impurities on the solid/liquid interface between chemicals and various Si wafer surfaces (p, n, p+, n+). We tested several chemicals employed in the process to remove oxide on the Si surface. Metals featuring high electronegativity (such as Cu) are directly adsorbed on the bare Si surface while taking electrons away from the Si surface. It has been found that these metals are hard to remove. We used Cu as being representative of metals to be directly adsorbed on the bare Si surface and studied its segregation and removal on the solid/liquid interface between Si wafer and chemicals to keep the Si surface bare such as DHF, DHF-H~O2, and BHF. It has been found that Cu ion in DHF adheres on every Si wafer surface that we used in our study (p, n, p § n § especially on the n+-Si surface. The DHF-H202 solution is found to be effective in removing metals featuring high electronegativity such as Cu from the p-St and n-St wafers. Even when the DHF-H202 solution has Cu ions at the concentration of 1 ppm, this solution is found effective in cleaning the wafer. In the case of the n*-Si and p+-Si wafers, however, their surfaces get contaminated with Cu when Cu ion of 10 ppb remains in the DHF-H203 solution. When BHF is used, Cu in BHF is more likely to contaminate the p-St, n-St, and p+-Si wafers but is less likely to contaminate the n*-Si wafer. It is also revealed that the surfactant added to BHF to improve its wettability onto the Si wafer is effective in preventing Cu precipitation onto the p-St, n-St, and p*-Si wafers. This effect of the surfactant, however, is not observed on the n+-Si wafer. It is found also that the surface microroughness on the n § wafer is increased when it is immersed in the DHF-H202 soluti...
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