Pharmacokinetics of iron isomaltoside 1000 in patients with inflammatory bowel disease

Kim Nordfjeld, Hans Andreasen, Lars L ThomsenPharmacosmos A/S, Holbaek, DenmarkBackground: Iron isomaltoside 1000 is a novel injectable iron compound which offers potential advantages in the treatment of subjects with iron-deficiency anemia. We studied the pharmacokinetics (PK) of this novel compound in subjects with mild-to-moderate inflammatory bowel disease (IBD).Methods: This open-label, crossover, single-center trial was conducted in 12 subjects with IBD who were allocated to one of the two single intravenous (IV) bolus sequences of iron isomaltoside 1000: 100 mg followed by 200 mg, or vice-versa. PK variables were analyzed according to a single-compartment model.Results: The concentration-versus-time relationship for isomaltoside-bound iron (IBI) and total iron (TI) showed first-order kinetics with small deviations from dose-linearity. The area under the concentration-time curve (AUC) values in h * µg/mL for IBI following 100 mg and 200 mg doses were 888 and 2141 respectively, and for TI following 100 mg and 200 mg doses, the AUC values were 1010 and 2319 respectively. The corresponding maximum serum concentration (Cmax) values in µg/mL were 35.6 and 68.6 for IBI, and 37.3 and 71.1 for TI. The half-life (T½) values for IBI and TI were between 20.8–23.5 hours. The apparent volume of distribution (VD) ranged from 3.0–3.5 L. Only approximately 1% of the doses administered were excreted in the urine. No serious adverse event (SAE) was reported. One subject was withdrawn after the 100 mg dose due to abdominal pain and flushing.Conclusion: At the administered doses, iron isomaltoside 1000 showed first-order PK, and did not raise safety concerns in patients with IBD. The PK parameters for IBI were close to those of TI.Keywords: inflammatory bowel disease, iron deficiency anemia, iron treatment, iron isomaltoside, pharmacokinetic

Long-term risk of gastrointestinal cancers in persons with gastric or duodenal ulcers

Peptic ulcer predicts gastric cancer. It is controversial if peptic ulcers predict other gastrointestinal cancers, potentially related to Helicobacter pylori or shared lifestyle factors. We hypothesized that gastric and duodenal ulcers may have different impact on the risk of gastrointestinal cancers. In a nationwide cohort study using Danish medical databases 1994-2013, we quantified the risk of gastric and other gastrointestinal cancers among patients with duodenal ulcers (dominantly H. pylori-related) and gastric ulcers (dominantly lifestyle-related) compared with the general population. We started follow-up 1-year after ulcer diagnosis to avoid detection bias and calculated absolute risks of cancer and standardized incidence ratios (SIRs). We identified 54,565 patients with gastric ulcers and 38,576 patients with duodenal ulcers. Patient characteristics were similar in the two cohorts. The 1-5-year risk of any gastrointestinal cancer was slightly higher for gastric ulcers patients (2.1%) than for duodenal ulcers patients (2.0%), and SIRs were 1.38 (95% CI: 1.31-1.44) and 1.30 (95% CI: 1.23-1.37), respectively. The SIR of gastric cancer was higher among patients with gastric ulcer than duodenal ulcer (1.92 vs. 1.38), while the SIRs for other gastrointestinal cancers were similar (1.33 vs. 1.29). Compared with gastric ulcer patients, duodenal ulcer patients were at lower risk of smoking- and alcohol-related gastrointestinal cancers. The risk of nongastric gastrointestinal cancers is increased both for patients with gastric ulcers and with duodenal ulcers, but absolute risks are low. H. pylori may be less important for the development of nongastric gastrointestinal cancer than hypothesized

The role of guidelines and the patient's life-style in GPs' management of hypercholesterolaemia

BACKGROUND: Recent Swedish and joint European guidelines on hyperlipidaemia stress the high coronary risk for patients with already established arterio-sclerotic disease (secondary prevention) or diabetes. For the remaining group, calculation of the ten-year risk for coronary events using the Framingham equation is suggested. There is evidence that use of and adherence to guidelines is incomplete and that tools for risk estimations are seldom used. Intuitive risk estimates are difficult and systematically biased. The purpose of the study was to examine how GPs use knowledge of guidelines in their decisions to recommend or not recommend a cholesterol-lowering drug and the reasons for their decisions. METHODS: Twenty GPs were exposed to six case vignettes presented on a computer. In the course of six screens, successively more information was added to the case. The doctors were instructed to think aloud while processing the cases (Think-Aloud Protocols) and finally to decide for or against drug treatment. After the six cases they were asked to describe how they usually reason when they meet patients with high cholesterol values (Free-Report Protocols). The two sets of protocols were coded for cause-effect relations that were supposed to reflect the doctors' knowledge of guidelines. The Think-Aloud Protocols were also searched for reasons for the decisions to prescribe or not to prescribe. RESULTS: According to the protocols, the GPs were well aware of the importance of previous coronary heart disease and diabetes in their decisions. On the other hand, only a few doctors mentioned other arterio-sclerotic diseases like stroke and peripheral artery disease as variables affecting their decisions. There were several instances when the doctors' decisions apparently deviated from their knowledge of the guidelines. The arguments for the decisions in these cases often concerned aspects of the patient's life-style like smoking or overweight- either as risk-increasing factors or as alternative strategies for intervention. CONCLUSIONS: Coding verbal protocols for knowledge and for decision arguments seems to be a valuable tool for increasing our understanding of how guidelines are used in the on treatment of hypercholesterolaemia. By analysing arguments for treatment decisions it was often possible to understand why departures from the guidelines were made. While the need for decision support is obvious, the current guidelines may be too simple in some respects

Benefit of respiratory gating in the Danish Breast Cancer Group partial breast irradiation trial

Background and purpose: Partial breast irradiation (PBI)has beenthe Danish Breast Cancer Group(DBCG) standard for selected breast cancer patients since 2016 based onearlyresults from the DBCG PBI trial.During trial accrual, respiratory-gated radiotherapy was introduced in Denmark. This study aims to investigate the effect of respiratory-gating on mean heart dose (MHD).Patients and methods: From 2009 to 2016 the DBCG PBI trial included 230 patientswith left-sided breast cancer receiving external beam PBI, 40 Gy/15 fractions/3 weeks.Localization of the tumor bed on the planning CT scan, the use of respiratory-gating, coverage of the clinical target volume (CTV), and doses to organs at risk were collected.Results: Respiratory-gating was used in 123 patients (53 %). In 176 patients (77 %) the tumor bed was in the upper and in 54 patients (23 %) in the lower breast quadrants. The median MHD was 0.37 Gy (interquartile range 0.26-0.57 Gy), 0.33 Gy (0.23-0.49 Gy) for respiratory-gating, and 0.49 Gy (0.31-0.70 Gy) for free breathing, p < 0.0001. MHD was < 1 Gy in 206 patients (90 %) and < 2 Gy in 221 patients (96 %). Respiratory-gating led to significantly lower MHD for upper-located, but not for lower-located tumor beds, however, all MHD were low irrespective of respiratory-gating. Respiratory-gating did not improve CTV coverage or lower lung doses.Conclusions: PBI ensured a low MHD for most patients. Adding respiratory-gating further reduced MHD for upper-located but not for lower-located tumor beds but did not influence target coverage or lung doses. Respiratory-gating is no longer DBCG standard for left-sided PBI

An asymmetric electron-scattering photosphere around optical tidal disruption events

A star crossing the tidal radius of a supermassive black hole will be spectacularly ripped apart with an accompanying burst of radiation. A few tens of such tidal disruption events (TDEs) have now been identified in the optical wavelengths, but the exact origin of the strong optical emission remains inconclusive. Here we report polarimetric observations of three TDEs. The continuum polarization is independent of wavelength, while emission lines are partially depolarized. These signatures are consistent with optical photons being scattered and polarized in an envelope of free electrons. An almost axisymmetric photosphere viewed from different angles is in broad agreement with the data, but there is also evidence for deviations from axial symmetry before the peak of the flare and significant time evolution at early times, compatible with the rapid formation of an accretion disk. By combining a super-Eddington accretion model with a radiative transfer code we generate predictions for the degree of polarization as a function of disk mass and viewing angle, and we show that the predicted levels are compatible with the observations, for extended reprocessing envelopes of $\sim$1000 gravitational radii. Spectropolarimetry therefore constitutes a new observational test for TDE models, and opens an important new line of exploration in the study of TDEs.Comment: Author's version of paper to appear in Nature Astronomy. In the journal version the detailed discussion on the ISP determination will be moved from the Methods section to a Supplementary Information section. 58 pages in double spacing format, including 5 Figures, 10 Extended Data Figures and 2 Table

Self-Assembly of ABC Bottlebrush Triblock Terpolymers with Evidence for Looped Backbone Conformations

Bottlebrush block copolymers offer rich opportunities for the design of complex hierarchical materials. As consequences of the densely grafted molecular architecture, bottlebrush polymers can adopt highly extended backbone conformations and exhibit unique physical properties. A recent report has described the unusual phase behavior of ABC bottlebrush triblock terpolymers bearing grafted poly(dl-lactide) (PLA), polystyrene (PS), and poly(ethylene oxide) (PEO) blocks (LSO). In this work, a combination of resonant soft X-ray reflectivity (RSoXR), near-edge X-ray absorption fine structure spectroscopy (NEXAFS), and self-consistent field theory (SCFT) was used to provide insight into the phase behavior of LSO and underlying backbone chain conformations. Consistent with SCFT calculations, RSoXR measurements confirm a unique mesoscopic ACBC domain connectivity and decreasing lamellar periods (d0) with increasing backbone length of the PEO block. RSoXR and NEXAFS demonstrate an additional unusual feature of brush LSO thin films: when the overall film thickness is ∼3.25d0, the film–air interface is majority PS (>80%). Because PS is the midblock, the triblocks must adopt looping configurations at the surface, despite the preference for the backbone to be extended. This result is supported by backbone concentrations calculated through SCFT, which suggest that looping midblocks are present throughout the film. Collectively, this work provides evidence for the flexibility of the bottlebrush backbone and the consequences of low-χ block copolymer design. We propose that PEO blocks localize at the PS/PLA domain interfaces to screen the highest χ contacts in the system, driving the formation of loops. These insights introduce a potential route to overcome the intrinsic penalties to interfacial curvature imposed by the bottlebrush architecture, enabling the design of unique self-assembled materials