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- Labotka, R. J., et al.
(författare)
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Ammonia permeability of erythrocyte membrane studied by 14N and 15N saturation transfer NMR spectroscopy
- 1995
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Ingår i: American Journal of Physiology - Cell Physiology. - 0363-6143 .- 1522-1563. ; 268:3, s. C686-699
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Tidskriftsartikel (refereegranskat)abstract
- The permeability of biological membranes to the rapidly penetrating compound ammonia is extremely difficult to study due to the lack of readily available radionuclides. 14N and 15N saturation transfer nuclear magnetic resonance (NMR) experiments were used to measure the erythrocyte membrane permeability of ammonia under equilibrium exchange conditions. When 14N spectra from erythrocytes suspended in NH4Cl solution were obtained in the presence of the extracellular shift reagent dysprosium tripolyphosphate, intracellular and extracellular ammonia signals were readily resolved. Comparison with 15N spectra from erythrocyte suspensions containing 15N4Cl revealed that the intracellular [14N]ammonia signals were 100% NMR visible. 14N and 15N saturation transfer NMR experiments showed similar influx rates and permeabilities, indicating no loss of saturation transfer due to quadrupolar relaxation of 14N nuclei upon membrane passage. Ammonia influx was directly proportional to concentration (0.39 +/- 0.012 fmol.cell-1.s-1.mM-1 at pH 7.0) and not saturable, which is consistent with passive diffusion. Apparent ammonia permeability increased with pH over the range of pH 6-8 as the fraction of free NH3 increased. However, diffusion through unstirred layers became increasingly rate limiting. The permeability of the unstirred layers (1.1 +/- 0.45 x 10(-3) cm/s) was considerably lower than that of NH3 (0.21 +/- 0.014 cm/s). The Arrhenius activation energy for NH3 permeability was 49.5 +/- 11.8 kJ/mol. No evidence for NH+4 influx over the time domain of these experiments was found.
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- Richardson, Paul G., et al.
(författare)
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Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
- 2021
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 39:22, s. 2430-2442
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
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