The style dimension of language variation has not been adequately explained in sociolinguistic theory. Stylistic or intraspeaker variation derives from and mirrors interspeaker variation. Style is essentially speakers' response to their audience. In audience design, speakers accommodate primarily to their addressee. Third persons – auditors and overhearers – affect style to a lesser but regular degree. Audience design also accounts for bilingual or bidialectal code choices. Nonaudience factors like topic and setting derive their effect by association with addressee types. These style shifts are mainly responsive – caused by a situational change. Speakers can also use style as initiative, to redefine the existing situation. Initiative style is primarily referee design: divergence from the addressee and towards an absent reference group. Referee design is especially prevalent in mass communication. (Sociolinguistic variation, code-switching. bilingualism, accommodation theory, ethnography of communication, mass communication)
AimsThe primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon a-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone.Methods In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. Results The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout halflives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase halflives was 5-7 h. IFN demonstrated an increase in bioavailability (~2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2∞,5∞-oligoadenylate synthetase (2∞5∞-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2∞5∞-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN-reductions in white cells, neutrophils and platelets; ribavirin-reduced haemoglobin) and characteristic adverse event profiles (IFN-headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin-headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. Conclusions There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.
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