ABSTRACT
BACKGROUND: The effects of dexmedetomidine on the propofol-sparing effect and intraoperative hemodynamics during remifentanil-based propofol-supplemented anesthesia have not been well investigated. METHODS: Twenty patients undergoing breast surgery were randomly allocated to receive dexmedetomidine (group DEX) or placebo (group C). In the DEX group, dexmedetomidine was loaded (1 µg/kg) before anesthesia induction and was infused (0.6 µg/kg/h) during surgery. Anesthesia was induced with a target-controlled infusion (TCI) of propofol (effect site concentration, Ce; 3 µg/ml) and remifentanil (plasma concentration, Cp, 10 ng/ml). The Ce of TCI-propofol was adjusted to a bispectral index of 45-55, and Cp of TCI-remifentanil was fixed at 10 ng/ml in both groups. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded at baseline (T-control), after the loading of study drugs (T-loading), 3 min after anesthesia induction (T-induction), tracheal intubation (T-trachea), incision (T-incision), 30 min after incision (T-incision30), and at tracheal extubation (T-extubation). MAP% and HR% (MAP and HR vs. T-control) were determined and the propofol infusion rate was calculated. RESULTS: The propofol infusion rate was significantly lower in the DEX group than in group C (63.9 ± 16.2 vs. 96.4 ± 10.0 µg/kg/min, respectively; P < 0.001). The changes in MAP% at T-induction, T-trachea and T-incision in group DEX (-10.0 ± 3.9%, -9.4 ± 4.6% and -11.2 ± 6.3%, respectively) were significantly less than those in group C (-27.6 ± 13.9%, -21.7 ± 17.1%, and -25.1 ± 14.1%; P < 0.05, respectively). CONCLUSIONS: Dexmedetomidine reduced the propofol requirement for remifentanil-based anesthesia while producing more stable intraoperative hemodynamics.
ABSTRACT
A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/chemistry , Pyrimidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Thymine/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Dogs , HIV Reverse Transcriptase/metabolism , Humans , Microsomes/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thymine/chemical synthesis , Thymine/chemistry , Thymine/pharmacokineticsABSTRACT
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Pyrimidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Thymine/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Dogs , HIV Reverse Transcriptase/metabolism , Humans , Hydrogen Bonding , Microsomes/metabolism , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thymine/chemical synthesis , Thymine/chemistry , Thymine/pharmacokineticsABSTRACT
OBJECTIVES: To block the different mechanisms of HIV mucosal transmission, it is likely that use of several microbicide molecules will lead to the best protection against HIV transmission. Indeed, the combination of microbicides with complementary mechanisms of action is expected to increase the antiviral potency of the formulation. METHODS: The gp120-interacting plant lectin HHA ('Hippeastrum hybrid agglutinin'), the non-nucleoside reverse transcriptase inhibitor KRV2110 and the fusion inhibitor enfuvirtide (T20) were combined in 12 drug associations by using the Ray combination design method. Their activity against HIV-1(BaL) was assessed by the lymphocyte infectivity reduction assay and by the single-cycle BaL pseudovirus (PV) assay. In addition, their cell tolerance was evaluated for HEC-1 and HeLa epithelial cell lines, both originating from genital tissue. RESULTS: All evaluated combinations showed synergistic activity in both lymphocyte infectivity reduction and single-cycle BaL PV assays. The combination HHA + KRV2110 resulted in the highest cell viability, whereas the combinations including T20 exhibited a dose-dependent decrease in cell viability, demonstrating the differential tolerance of epithelial cell lines to the combinations. CONCLUSIONS: These observations provide a rational basis for in vitro testing of microbicide candidate molecule combinations, including anti-HIV-1 and cytotoxic cellular assays.
