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Inhibitor Concentration (inhibitor + concentration)
Selected AbstractsSynergistic effect of halide ions and polyethylene glycol on the corrosion inhibition of aluminium in alkaline mediumJOURNAL OF APPLIED POLYMER SCIENCE, Issue 6 2009S.A. Umoren Abstract The corrosion inhibition of aluminium in alkaline medium was studied at 30 and 40°C in the presence of polyethylene glycol (PEG) using gravimetric (weight loss) and thermometric techniques. The effect of halides (KCl, KBr, and KI) on the inhibitory action of PEG was also studied. It was found that PEG acted as inhibitor for aluminium corrosion in the alkaline medium. Inhibition efficiency increased with increasing inhibitor concentration. An increase in temperature led to increase in both the corrosion rate and inhibition efficiency in the absence and presence of inhibitor and halides. Phenomenon of chemical adsorption mechanism is proposed from the values of Ea, Qads, and ,G obtained. The adsorption of PEG on the surface of aluminium was found to obey Flory,Huggins and Temkin adsorption isotherms. The synergism parameter, S1 evaluated was found to be greater than unity indicating that the enhanced inhibition efficiency caused by the addition of halides is synergistic in nature. The inhibition efficiency, surface coverage and synergism parameter increased in the order; I,> Br,> Cl, showing that a joint adsorption of PEG and halide ions on aluminium plays a significant role in the adsorption process. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 [source] Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman PrimateJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2001George B. Stroup Abstract Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis. [source] Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2003A 3D-QSAR-CoMFA method for new antiviral drug design Abstract The predicted inhibition constant (Ki) and the predicted inhibitor concentration (IC90) of the HIV-1 protease (HIV-1 PR) inhibitors: symmetric and nonsymmetric - benzyl, ketone, oxime, pyrazole, imidazole, and triazole cyclic urea derivatives, were obtained by the 3D-CoMFA (Comparative Molecular Field Analysis) method. The CoMFA statistical parameters: cross-validate correlation coefficient (q2), higher than 0.5, and the fitted correlation coefficient (r2), higher than 0.90 validated the predicted biological activities. The best predictions were found for the trifluoromethyl ketoxime derivative (log 1/Ki predict = 8.42), the m-pyridineCH2 pyrazole derivative (log 1/Ki predict = 9.77) and the 1,2,3 triazole derivative (log 1/Ki predict = 7.03). We attempted to design a new potent HIV-1 protease inhibitor by addition of o-benzyl to the (p-HOPhCH2) pyrazole 12f derivative inhibitor. A favorable steric area surrounded the o-benzyl, suggesting a possible new potent HIV-1 protease inhibitor. [source] QSAR study of ,-lactam antibiotic efflux by the bacterial multidrug resistance pump AcrB,JOURNAL OF CHEMOMETRICS, Issue 5 2004Márcia M. C. Ferreira Abstract AcrAB-TolC is the most important efflux pump system of Gram-negative bacteria, responsible for their resistance to lipophilic and amphilic drugs. In this work, HCA,PCA studies were performed to investigate the relationship between efflux activities (negative logarithm of minial inhibitor concentration, pMIC) of three strains of S. thypimurium with respect to ,-lactams, and to analyze the relationship between lipophilicity parameters calculated by different methods. The analyses demonstrate that pMICs strongly depend on properties of both bacterial strains and drug molecules, and that lipophilicity parameters do not necessarily contain the same information about the drugs. QSAR studies have shown that the calculated lipophilicities, in some cases, are non linearly related to the pMICs originated by active AcrAB-TolC bacterial pumps, due to the existence of ,-lactams with nitrogen- and sulfur-rich substituents. Among the most important ,-lactam molecular properties quantitatively related to pMICs are lipophilicity and electronic and hydrogen,bonding properties. Parameters describing these properties were included in the QSAR study to obtain parsimonius regression models for MICs. ,-Lactams were classified as good, moderately good and poor AcrAB-TolC substrates. Their stereoelectronic molecular properties, especially the Y-component of the molecular dipole moment and hydrogen binding properties, reflected this classification. Copyright © 2004 John Wiley & Sons, Ltd. [source] Scavenging effect of melatonin on hydroxyl radicals generated by alloxanJOURNAL OF PINEAL RESEARCH, Issue 4 2000H.J. Brömme Alloxan can act as a generator of reactive oxygen species (ROS) as long as sufficient suitable reducing agents (e.g. reduced glutathione) and oxygen are available. Using electron spin resonance-spectroscopy and the oxygen-centered spin trap DEPMPO, we demonstrate that hydroxyl radicals (OHzrad;) are formed in vitro by alloxan in the presence of glutathione (GSH) and chelated divalent iron. Furthermore, peroxidation of polyunsaturated fatty acids from phosphatidylcholine-containing liposomes with concomitant formation of malondialdehyde (MDA) was used as a further indicator for a preceding OHzrad; formation. Melatonin, the main secretory product of the pineal gland, is an effective scavenger of OHzrad;. The 50%-inhibitor concentration (IC50-value) for melatonin to scavenge OHzrad; generated from the alloxan/GSH-reaction in the presence of ferrous ions was 23 ,mol/L. In contrast to the ability to effectively scavenge OHzrad;, the potential of melatonin to prevent lipid peroxidation is considerably less pronounced. [source] Prediction of herb,drug metabolic interactions: a simulation studyPHYTOTHERAPY RESEARCH, Issue 6 2005Shufeng Zhou Abstract In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb,drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb,drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright © 2005 John Wiley & Sons, Ltd. [source] Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2006José Moltó What is already known about this subject ,,The concentration of protease and non-nucleoside reverse transcriptase inhibtors in plasma has been related to both efficacy and toxicity. ,,Most antiretroviral concentration data come from selected populations of patients undergoing therapeutic drug monitoring programmes, which may overestimate interindividual variability. What this study adds ,,Our study has demonstrated the large interindividual variability in antiretroviral drug concentrations in an unselected population of patients during routine clinical practice. ,,These results may provide interesting information to clinicians for the management of antiretroviral therapy in HIV-infected patients. Aims The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. Methods One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were >,4.0 mg l,1, >,6.0 mg l,1 and >,0.85 mg l,1, respectively. Results Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. Conclusion Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice. [source] Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase-2 (gelatinase A) without inhibiting its activationCANCER, Issue 6 2003Erika H. M. Kerkvliet Ph.D. Abstract BACKGROUND In the current study, the authors investigated the effects of synthetic low molecular weight inhibitors of matrix metalloproteinases (MMPs) on the expression and activation of MMP-2 in a three-dimensional tissue system. METHODS Rabbit periosteal explants were cultured with or without various concentrations of the MMP inhibitors CT1166, CT1399, or CT1746, and conditioned media and tissue extracts were analyzed for the expression and activity of MMP-2. RESULTS The data showed that blocking the activity of all MMPs with relatively high inhibitor concentrations completely prevented the conversion of pro-MMP-2 into its active form and that the level of protein was decreased. Selective inhibition of the activity of gelatinases (MMP-2 and MMP-9) by using low inhibitor concentrations, however, induced a higher level of active MMP-2 and increased its expression significantly. CONCLUSIONS The current observations indicate that selective inhibitors of MMPs affect the expression and activity of MMP-2, thus providing clues regarding the differing effects such inhibitors appear to have when applied in vivo. Cancer 2003;97:1582,88. © 2003 American Cancer Society. DOI 10.1002/cncr.11193 [source] | ||||||||||