A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

PURPOSE: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. METHODS: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. RESULTS: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004). CONCLUSIONS: Imatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered

Metabolic Syndrome Derived from Principal Component Analysis and Incident Cardiovascular Events: The Multi Ethnic Study of Atherosclerosis (MESA) and Health, Aging, and Body Composition (Health ABC).

Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54-1.90) (P &lt; 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39-1.94), Chinese, 1.39 (1.06-1.83), African, 1.67 (1.37-2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91-2.87) for MetS-PC versus 1.79 (1.46-2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12-1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12-1.39) and African Americans (HR = 1.16, 95%CI 1.01-1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17-1.64 compared with 1.46, 95%CI 1.23-1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort

Outcomes of acute intraoperative surgical conversion during endovascular aortic aneurysm repair

PurposeOutcomes and predictors of acute surgical conversion during endovascular aortic aneurysm repair (EVAR) were examined using the American College of Surgeons-National Safety and Quality Improvement Project (ACS-NSQIP) Database (2005 to 2008).MethodsAcute intraoperative surgical conversions occurring during elective EVAR were identified using Current Procedural Terminology codes. Nonemergent EVAR and primary open surgical repairs of infrarenal aneurysms were examined for comparison. Perioperative morbidity was categorized as wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, operative, and septic. Mortality, overall morbidity, and length of stay (LOS) were examined.ResultsWe identified 72 acute conversions, 2414 open repairs, and 6332 EVAR without acute conversion. Demographics and comorbidities were generally similar among operative groups. Mean operative time was 274 minutes for acute conversion vs 226 minutes for primary open repair and 162 minutes for EVAR (conversion vs EVAR and open repair vs EVAR P < .0001 for each; conversion vs open repair P = .0014; analysis on rank operative time). Blood transfusion was required in 69% of acute conversions (mean volume, 6.0 units) vs 73% of open repairs (mean volume, 3.3 units) and 12% of EVARs (mean volume, 2.6 units; P < .0001 for each pair-wise comparison; analysis on rank number of units among those transfused). Major morbidity was 28% for acute conversions, 28% for open repairs, and 12% for EVARs. Mortality was 4.2% for acute conversions, 3.2% for open repairs, and 1.3% for EVARs. Median (quartile 1, quartile 3) LOS was 7 (5, 9) days for acute conversion and open repair, and 2 (1, 3) days for EVAR. Morbidity and mortality were significantly higher for acute conversion and open repair vs EVAR. The OR (95% confidence interval) for morbidity was 2.9 (1.7-4.8) after conversion and 2.8 (2.5-3.2) after open repair (P < .0001 for both) and for mortality was 3.4 (1.0-10.9; P = .0437) for conversion and 2.5 (1.9-3.5; P < .0001) for open repair. Morbidity and mortality were similar between acute conversion and open repair. A similar pattern among repair groups was demonstrated for LOS, with similar LOS for acute conversions and open repair, which were significantly longer than those observed for EVAR. No significant demographic or medical risk factor predictors of acute conversion during EVAR were identified.ConclusionAcute surgical conversion was a rare complication affecting 1.1% of EVAR cases, with no broadly identifiable at-risk population. When conversion did occur, morbidity and mortality rates paralleled those observed for elective open repair

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Purpose: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. Methods: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. Results: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug con

Converting cyclosporine A from intravenous to oral administration in hematopoietic stem cell transplant recipients and the role of azole antifungals

Purpose: Cyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals. Methods: We retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration. Results: We included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration. Conclusions: In patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co-medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations

First Detection of Near-Infrared Line Emission from Organics in Young Circumstellar Disks

We present an analysis of high-resolution spectroscopy of several bright T Tauri stars using the VLT/CRIRES and Keck/NIRSPEC spectrographs, revealing the first detections of emission from HCN and C2H2 in circumstellar disks at near-infrared wavelengths. Using advanced data reduction techniques we achieve a dynamic range with respect to the disk continuum of ~500 at 3 microns, revealing multiple emission features of H2O, OH, HCN, and C2H2. We also present stringent upper limits for two other molecules thought to be abundant in the inner disk, CH4 and NH3. Line profiles for the different detected molecules are broad but centrally peaked in most cases, even for disks with previously determined inclinations of greater than 20 degrees, suggesting that the emission has both a Keplerian and non-Keplerian component as observed previously for CO emission. We apply two different modeling strategies to constrain the molecular abundances and temperatures: we use a simplified single-temperature LTE slab model with a Gaussian line profile to make line identifications and determine a best-fit temperature and initial abundance ratios, and we compare these values with constraints derived from a detailed disk radiative transfer model assuming LTE excitation but utilizing a realistic temperature and density structure. Abundance ratios from both sets of models are consistent with each other and consistent with expected values from theoretical chemical models, and analysis of the line shapes suggests the molecular emission originates from within a narrow region in the inner disk (R < 1 AU).Comment: Accepted to the Astrophysical Journa

The influence of exposure to maternal diabetes in utero on the rate of decline in β-cell function among youth with diabetes

A relationship between exposure to maternal diabetes in utero and a younger age at diagnosis of type 2 diabetes was detected in SEARCH for Diabetes in Youth Study, while no significant association was detected with paternal diabetes status, suggesting an independent effect of the intrauterine exposure to hyperglycemia. We assessed the influence of exposure to maternal diabetes in utero on beta cell decline measured using fasting C-peptide (FCP) among 1079 youth with diabetes, including 941 with type 1 and 138 with type 2, who were followed post-diagnosis for an average of 58 months. No significant relationship was detected between exposure to maternal diabetes in utero and change in FCP levels in youth with type 1 or type 2 diabetes. These findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term beta-cell function decline in youth with type 1 or type 2 diabetes

Deconstructing doing well; what can we learn from care experienced young people in England, Denmark and Norway?

This paper addresses the conceptualization of ‘outcomes’ for care experienced people through an in-depth longitudinal study of 75 young adults in Denmark, England and Norway. ‘Outcome’ studies have played a crucial role in raising awareness of the risk of disadvantage that care experienced people face, across a variety of domains including education and employment. These studies may have an unintended consequence, however, if care experienced people are predominantly viewed, and studied, through a problem-focused lens. The danger is that policy and research neglects other – perhaps less readily measurable – aspects of experience, including subjective understandings – what matters to care experienced people themselves. Our analyses are based on an in-depth qualitative longitudinal study, which explored meanings of ‘doing well’ over time among care experienced people (aged 16–32), all of whom were ‘successful’ in relation to traditional indicators of participation in education and/or employment (including voluntary work). Across countries, their accounts revealed the importance of attending to subjective and dynamic understandings of ‘doing well’, and the significance of ordinary, mundane and ‘do-able’ lives. Participants’ narratives highlight aspects of doing well that raise challenging questions about how traditional outcome indicators – and corresponding policy priorities – might better capture what young people themselves see as important. A narrow interpretation of outcomes may lead to misrecognition of what it means to do well, and so to a stigmatizing ‘way of seeing’ care experienced lives. A broader conceptualization of outcomes is necessary to recognize – and so to develop policy and services to support – the complex, dynamic relationality of doing well