Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma.

Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC(sorafenib) and AUC(N-oxide), respectively). Inter-group comparison revealed that AUC(N-oxide) and AUC ratio (AUC(N-oxide)/AUC(sorafenib)) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC(N-oxide) and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC(N-oxide:) 2.0 µg ∙ day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) ≤ 2.0 µg ∙ day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement.

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.

Arsenic trioxide poisoning: a description of two acute overdoses.

Arsenic is a traditional poison that has a history extending back into ancient times, as a medicinal agent, a homicidal poison and more recently in deliberate and unintentional self-poisoning. We report two cases of acute poisoning with an unwettable formulation of arsenic trioxide. Both patients had early gastrointestinal toxicity and were treated with early whole bowel irrigation (WBI). Chelation therapy with dimercaptosuccinic acid (dimercaptosuccinate, DMSA) was commenced within 24 hours and serial blood and urine arsenic concentrations were measured. Neither patient suffered any adverse outcome in spite of very high blood and urine concentrations of arsenic. Arsenic quantification in blood, urine and faeces suggested that enhanced gastrointestinal decontamination was minimally effective for decontamination and that DMSA for at least two weeks was required.

Titration of the BOLD effect: separation and quantitation of blood volume and oxygenation changes in the human cerebral cortex during neuronal activation and ferumoxide infusion.

Most functional magnetic resonance imaging (fMRI) techniques are sensitive to susceptibility variations and rely on the change in blood oxygenation level in response to neuronal activation (BOLD). The BOLD effect is accompanied by a change in cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Intravascular contrast agents, such as magnetite nanoparticles, can be used to measure changes in rCBV. A new measuring protocol has been developed that enables the separate quantification of changes in blood volume and oxygenation levels. A combination of alternating acoustic stimulation blocks and infusion of a superparamagnetic contrast agent offers the possibility to disentangle the competing influences of oxygenation and blood volume changes. Serial blood sampling during infusion was used to assess the actual contrast agent concentration during infusion in order to calculate absolute blood volume changes during neuronal resting and activation states. Magn Reson Med 42:829-836, 1999.

Evaluation of the in vitro stability of gadolinium (III) polyoxometalates.

The gadolinium chelates of lacunary polyoxometalates were evaluated for in vitro stability against rat serum, diethylenetriaminepentaacetic acid (DTPA), endogenous metal cations, and DTPA-doped rat serum. The chelates dissociated rapidly in rat serum. Challenges by DTPA gave relatively slower dissociation rates, whereas challenges by endogenous metal cations (Fe(III), Zn(II), and Cu(II)) occurred at a rate comparable to the serum challenge, suggesting the instability in serum is due to a transmetalation mechanism. Challenges by DTPA-doped serum gave slower rates of dissociation than in native serum, verifying the transmetalation mechanism.

Erythrocyte 2,3-DPG, PO2 50% and available O2 during the early post-natal fall in hemoglobin in rabbits.

Erythrocyte 2,3-DPG, PO2 50%, whole blood hemoglobin and available O2, and fixed acid Bohr effect were studied during the first 10 days after birth in rapidly growing suckling rabbits. The post-natal fall in hemoglobin concentration was accompanied by a marked rise in erythrocyte 2,3-DPG and a gradual increase in PO2 50%. The rise in PO2 50% was sufficient to keep the available O2 of the blood unchanged throughout the observation period. The observations show that a 2,3-DPG mediated rise in PO2 50% very effectively contributes to maintenance of adequate tissue oxygenation during the post-natal fall in hemoglobin. The rise in 2,3-DPG and and PO2 50% may be due to the ordinary hypoxia-induced shift to the right of the hemoglobin O2 dissociation curve, as observed under other circumstances when blood hemoglobin is rapidly reduced, but the very marked rise in 2,3-DPG and the very low delta PO2 50%/delta 2,3-DPG ratio suggest that the rise may as well be due to hypoxia independent, pre-programmed processes. The fixed acid Bohr effect was essentially the same in newborn and adult rabbits, and was uninfluenced by large variations in 2,3-DPG.