Morphine is one of the most potent analgesic drugs. However, the utility of morphine in the management of chronic pain is limited by its rapid development of tolerance. Morphine exerts all of its ...pharmacological effects via the μ-opioid receptor. In many systems, tolerance is associated with phosphorylation and desensitization of G-protein-coupled receptors (GPCRs). In case of the μ-opioid receptor, phosphorylation occurs in an agonist-selective manner. High-efficacy agonists such as d-Ala(2)-MePhe(4)-Gly-olenkephalin (DAMGO), fentanyl, or etonitazene stimulate the phosphorylation of both C-terminal threonine 370 (T370) and serine 375 (S375). In contrast, morphine promotes the phosphorylation of S375 but fails to stimulate T370 phosphorylation. Here, we have assessed the contribution of S375 phosphorylation to the development of antinociceptive tolerance to high- and low-efficacy μ agonists in vivo. We show that S375 phosphorylation of the μ-opioid receptor occurs in intact mouse brain in a dose-dependent manner after administration of morphine, fentanyl, or etonitazene. In knock-in mice expressing the phosphorylation-deficient S375A mutant of the μ-opioid receptor, morphine and fentanyl exhibited greater dose-dependent antinociceptive responses than in wild-type mice. However, acute and chronic tolerance to morphine was retained in S375A mutant mice. In contrast, antinociceptive tolerance after repeated subcutaneous application of etonitazene or repeated intracerebroventricular application of DAMGO was diminished. Thus, tolerance to μ agonists with different efficacies develops through distinct pathways. Whereas tolerance induced by DAMGO or etonitazene requires agonist-driven phosphorylation of S375, the development and maintenance of antinociceptive tolerance to morphine occurs independent of S375 phosphorylation.
To evaluate the cost-effectiveness of posaconazole versus standard azoles in the prevention of invasive fungal infection (IFI) in high-risk patients, using a pharmacoeconomic model that was adapted ...to a Swiss setting.
Decision tree models based on the results of two registration trials and subsequent Markov models over patient lifetimes were developed for patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) with neutropenia and for hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD).
By reducing IFIs in AML/MDS patients with posaconazole prophylaxis, the contained IFI-related treatment costs more than compensated for the incremental cost of posaconazole, resulting in savings of CHF 1,118 per patient. Lifetime posaconazole prophylaxis resulted in a benefit of 0.16 life years saved per patient compared with fluconazole/itraconazole. In patients with GVHD, posaconazole prophylaxis prevented 0.04 IFIs, resulting in incremental costs of CHF 7,040 per patient. Lifetime posaconazole prophylaxis resulted in a benefit of 0.15 life years saved per patient, with an incremental cost-effectiveness rate of CHF 48,324 per life year saved.
Given the conditions of the Swiss setting, posaconazole can be considered a cost-effective early treatment strategy that increases survival in patients at risk for IFI and may have a substantial benefit for the economic burden of IFI.
To define the appearance of degenerative changes of the triangular fibrocartilage (TFC) of the wrist on magnetic resonance (MR) images, the TFCs in one wrist of each of 30 healthy subjects in three ...age groups (20-35, 36-50, and greater than 50 years) and six TFCs from fresh cadavers were examined by means of coronal T1-weighted spin-echo sequences. Histologic findings were compared with findings on MR images in the cadaveric TFCs. It was proved that patches or lines of signal hyperintensity within the cadaveric TFCs were caused by degenerative changes and tears. Similar changes of the TFCs on MR images of the healthy subjects may have been caused by degeneration. In the healthy subjects, degenerative changes of the TFC, usually well defined on MR images, occurred at a very early age. The TFC appears to undergo stages of degeneration comparable to those of the menisci of the knee, but differentiation between traumatic and degenerative tears may be difficult.
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