SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 M. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.Hepatitis C virus (HCV) is a member of the Flaviviridae family, which comprises three distinct genera, including the flaviviruses (such as yellow fever virus, dengue virus, West Nile virus, and Japanese encephalitis virus), the pestiviruses (bovine viral diarrhea virus and classical swine fever virus), and the hepaciviruses (of which HCV is the only member) (16). HCV is highly polymorphic, and current taxonomic schemes recognize six major genotypes and several subtypes. Although no strict relationship exists between the genotype and the severity of HCV disease or the clinical outcome, numerous clinical studies indicate that patients who are infected with genotype 1 viruses are less responsive to antiviral therapy than individuals who are infected with genotypes 2 through 6 (10, 11). Chronic infection with HCV now represents a major global health problem, with approximately 170 million people worldwide being infected (26). The current standard of care for chronic hepatitis C virus infection involves treatment for up to 1 year with combination chemotherapy of pegylated alpha interferon coadministered with ribavirin. At this time, there are no approved drugs specifically indicated for the treatment of patients who do not respond to first-line therapy. Complete clearance of the virus is achieved in approximately 50% of all HCV-infected patients who initiate therapy (10, 11), and the response rates are related to viral factors (the genotype and the viral load), as well as multiple host factors (the presence of liver fibrosis, cirrhosis, ethnicity, coinfection with HIV type 1 [HIV-1], alcohol consumption, and metabolic disorders).At this time, the combined action of interferon and ribavirin against HCV infection is poorly understood. The e...
Three fast search routines to be used in the encoding phase of vector quantization (VQ) image compression systems are presented. These routines, which are based on geometric considerations, provide the same results as an exhaustive (or full) search. Examples show that the proposed algorithms need only 3-20% of the number of mathematical operations required by a full search and fewer than 50% of the operations required by recently proposed alternatives.
The aim of this investigation was to develop, digitally record, evaluate, and equate Mandarin trisyllabic words, which could then be used to measure the SRT. A selection of 90 frequently utilized trisyllabic words were digitally recorded by male and female talkers of Standard Mandarin and presented to 20 normally hearing subjects at 13 intensity levels (-10 to 14dB HL) in 2dB increments. Using logistic regression, psychometric functions were then calculated for all words. Twenty-four trisyllabic words with steep psychometric function slopes were selected, and their intensities were digitally adjusted to match the mean subject PTA (3.0 dB HL). The mean slopes for the 24 selected male and female trisyllabic Mandarin Chinese words were 11.3%/dB and 12.1%/dB, respectively. Thus we developed a list of words which were homogeneous with respect to audibility and slope. Digital recordings of the psychometrically equivalent trisyllabic words are available on compact disc.
Alternative models of responsiveness are evaluated for goodness of fit to moves made by negotiators in six international negotiations: five arms-control talks and one base-rights negotiation. Three models, developed originally by Stoll and McAndrew (1986), are referred to as directional (tit-for-tat), trend, and comparative reciprocity. Seven models are variants on trend and comparative reciprocity including various lags and weightings for earlier and recent moves, as well as a combined trend and comparative model. The results indicate clear support for the comparative model in all of the negotiations analyzed: Negotiators responded to the difference between moves made by themselves and others in the previous round, adjusting their next move in the direction of the other's previous move. They did not respond to a monitored trend in the other's moves. Nor did the combined trend and comparative model improve predictions over the comparative model alone. Implications are discussed for the importance of fairness in the process of negotiating, for theories of information processing in bargaining, and for the “threshold-adjustment” hypothesis.
The purpose of this study was to develop, digitally record, evaluate, and psychometrically equate a set of Mandarin bisyllabic word lists for use in measurement of speech discrimination. Familiar bisyllabic words were digitally recorded by male and female talkers of Standard Mandarin. Percentage of correct word recognition was measured for each word at ten intensity levels ( -5 to 40 dB HL) in 5 dB increments using 20 normally hearing subjects. Using logistic regression, 200 words with the steepest logistic regression slopes were included in four psychometrically equivalent word lists of 50 words each, and eight half-lists of 25 words each. To increase auditory homogeneity of the lists, the intensity of words in each list was digitally adjusted so that the threshold of each list was equal to the midpoint between the mean thresholds of the male and female half-lists. Digital recordings of the psychometrically equivalent word recognition lists are available on compact disc.
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