Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complicationsSimilarly, serum ferritin decreased significantly compared with placebo by LSM ؊235 and ؊337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n ‫؍‬ 11; 6.6%), rash (n ‫؍‬ 8; 4.8%), and diarrhea (n ‫؍‬ 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo. (Blood. 2012;120(5): 970-977)

Experiments were carried out to test the hypothesis that lactate reduces the neurotoxicity of glutamate in vivo. MAP2 immunohistochemistry was used to measure lesion size, and microdialysis to measure the changes in glucose and lactate in the extracellular compartment. After implantation of a microdialysis probe 100 mM glutamate with or without 6 mM lactate was added to the perfusion medium and infused into the cortex of unanesthetized rats. Infusion of 100 mM glutamate for a period of 30 min produced a lesion of 6.05 +/- 0.64 mm(3), an increase in lactate of 124 +/- 19% above basal and a 21 +/- 9% reduction of glucose below basal level. When 6mM L-lactate was perfused together with 100 mM glutamate there was a significant reduction in the size of the lesion and there was no reduction in dialysate glucose. When L-lactate was replaced with D-lactate the lesion size and the increase in dialysate lactate were greater than after glutamate alone. The neuroprotective role of L-lactate is attributed to its ability to meet the increased energy demands of neurones exposed to high concentrations of glutamate.

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-013-1808-z) contains supplementary material, which is available to authorized users.

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Abstract:These experiments for the first time examine simultaneous changes in glucose and lactate in unanaesthetised animals during moderate hypoxia. Unanaesthetised rats were exposed to moderate hypoxia for a period of 15 min by reducing inspired oxygen to 8%. Changes in glucose and lactate were monitored in rat cortex using microdialysis and a novel dual enzyme-based assay. Samples of dialysate collected at 3-min intervals were assayed for both glucose and lactate. There was an early rapid rise of lactate that reached a peak at the end of the period of hypoxia followed by a steep decline. Glucose showed a very much smaller delayed increase that started during the period of hypoxia and continued beyond it. The origin of the rise in glucose is discussed, using the temporal relationship between the lactate and glucose changes. Key Words: Glucose-Lactate-Hypoxia. J. Neurochem. 75, 1703Neurochem. 75, -1708Neurochem. 75, (2000.There is now extensive evidence for the relation between glucose and lactate in brain metabolism and the role of astrocytes in the supply of energy substrates for neuronal metabolism (Tsacopoulos and Magistretti, 1996). We have previously used neuronal activation (Fray et al., 1996) and brief periods of hypoxia and hyperoxia to study changes in brain glucose and lactate. To examine the relation between glucose and lactate in greater detail in this study, we have used a more prolonged period of hypoxia to challenge brain metabolism.Although the effects of ischaemia have been studied quite extensively, these have to be distinguished from the effects of hypoxia, as the loss of blood supply in ischaemia means a complete absence of both oxygen and glucose delivery. The reduction of P a O 2 in hypoxia leads to a number of compensatory changes, which include an increase in ventilation rate and in regional cerebral blood flow (rCBF) (Siesjö, 1978). The latter maintains availability of oxygen to the tissue. Thus, results in both humans (Cohen et al., 1967) and animals (Johannsson and Siesjö, 1975) showed no change in cerebral oxygen consumption even during severe hypoxia.The hypoxia induced in previous studies ranged from periods of severe hypoxia, caused by decreasing inspired oxygen to 3% (Silver and Erecinska, 1994; Ronne-Engström et al., 1995), to mild hypoxia, carried out at 10% oxygen (Kogure et al., 1970;Davis and Carlsson, 1973;Kintner et al., 1983). Changes in EEG or somatosensory evoked potentials were seen only when inspired oxygen was reduced to 4% (Smith et al., 1989). As the presence of anaesthesia has effects on both brain glucose and rCBF and may therefore affect the response to hypoxia, we have used freely moving rats in the present study. The animals were given a 15-min period of hypoxia. Inspired oxygen levels were reduced to 8%, which reduces P a O 2 from the normal level of 90 mm Hg to ϳ30 mm Hg (Lewis et al., 1973). Neurochemical changes were monitored using microdialysis. With our recently developed dual on-line assay, we were able to simultaneously measure glucose and lacta...