Summary
Deferasirox is a once‐daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open‐label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine. Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.
Purpose
We aimed to determine the agreement between quantitative susceptibility mapping (QSM)-based biomagnetic liver susceptometry (BLS) and confounder-corrected R2* mapping with superconducting quantum interference device (SQUID)-based biomagnetic liver susceptometry in patients with liver iron overload.
Methods
Data were acquired from two healthy controls and 22 patients undergoing MRI and SQUID-BLS as part of routine monitoring for iron overload. MR imaging was performed on a 3T system using a 3D multi-echo, gradient-echo acquisition. Both magnetic susceptibility and R2* of the liver were estimated from this acquisition. Linear regression was used to compare estimates of QSM-BLS and R2* to SQUID-BLS.
Results
Both QSM-BLS and confounder-corrected R2* were sensitive to the presence of iron in the liver. Linear regression between QSM-BLS and SQUID-BLS demonstrated the following relationship: QSM-BLS = (−0.22 ± 0.11) + (0.49 ± 0.05) · SQUID-BLS with r2 = 0.88. The coefficient of determination between liver R2* and SQUID-BLS was also r2 = 0.88.
Conclusion
We determined a strong correlation between both QSM-BLS and confounder-corrected R2* to SQUID-BLS. This study demonstrates the feasibility of QSM-BLS and confounder-corrected R2* for assessing liver iron overload, particularly when SQUID systems are not accessible.
Serum ferritin (SF) and liver iron concentration (LIC), as measured by SQUID biosusceptometry, were assessed in a convenience sample of transfusion independent thalassemia patients (nTx-Thal, n=26), regularly transfused thalassemia (Tx-Thal, n=89), or sickle cell patients (SCD, n=45) to investigate the severity of iron overload and the relationship between SF and LIC in nTx-Thal compared to SCD and Tx-Thal. SF correlated with LIC (RS=0.53, P<0.001), but was found to be a poor predictor for LIC. SF was significantly lower (P<0.001) in nTx-Thal patients than in other groups, despite similar LIC values. The SF-to-LIC ratio was significantly lower in nTx-Thal compared to Tx-Thal and SCD patients (median of 0.32, 0.87, and 1.2, respectively: P<0.001). Due to underestimation of LIC by ferritin levels, chelation treatment may be delayed or misdirected in patients with thalassemia intermedia.
Summary. In this non‐randomized prospective study, liver and spleen iron concentrations were monitored annually over a 4‐year period by non‐invasive Superconducting Quantum Interference Device biomagnetometry in 54 β‐thalassaemia major patients (age, 7–22 years) receiving treatment with deferiprone (75 mg/kg/d). Median liver iron concentrations increased significantly from 1456 to 2029 and 2449 µg/gliver at baseline, after 2·0 and 3·2 years respectively. Another group of 51 thalassaemic patients (aged 4–34 years) who received desferrioxamine s.c. for 1·9 years increased their liver iron concentration from 1076 to 1260 µg/gliver. Taking into account the increase of the daily iron input from transfusions of 3·6 mg/d, caused by weight gain in 67% of the patients treated with deferiprone, a larger total body iron elimination rate was achieved after 2 years than at baseline. A negative ferritin change was observed in 51% of the patients. In 15 non‐splenectomized patients, liver iron significantly increased from 1260 to 1937 µg/gliver (P < 0·01), but serum ferritin remained stable at 2100 µg/l, as did the spleen iron concentration at 1200 µg/gspleen. A two‐compartment model may predict an average chelation efficacy for desferrioxamine and deferiprone, with a saturation effect of the latter, for a certain chelation and transfusion regimen by a single liver iron quantification.
In this age so concerned with travel in outer as well as inner-space, it is strange that, while we have detailed charts of the moon, we have no cartography of the varieties of human experience. In order to draft a map of inner space, I am ready to be your travel guide and take you on two voyages: one along the perceptionhallucination continuum of increasing ergotropic (1) arousal, which includes creative, psychotic, and ecstatic experiences; and another along the perceptionmeditation continuum of increasing trophotropic (1) arousal, which encompasses the hypoaroused states of Zazen and Yoga samadhi.Along the perception-hallucination continuum of increasing arousal of the sympathetic nervous system (ergotropic arousal), man--the self-referential system--perceptually-behaviorally (cortically) interprets the change (drug-induced or "natural") in his subcortical activity as creative, psychotic, and ecstatic experiences (2). These states are marked by a gradual turning inward toward a mental dimension at the expense of the physical. The normal state of daily routine, our point of departure, is followed by an aroused, creative state, which can be characterized by an increase in both data content (a description of space) and rate of data processing ["flood of inner sensation' (3), or most intense time (4)]. However, in the next aroused state on the continuum, acute schizophrenic [or rather "hyperphrenic" (5)] state, further increase in data content may not be matched by a corresponding increase in the rate of data processing. While the creative state is conducive to the evolution of novel relations and new meaning, the psychotic "jammed computer" state interferes with the individual's creative interpretation of the activity of his central nervous system (CNS). At the peak of ecstatic rapture, the outside (physical) world "retreats to the fringe of
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