Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers

Aims: To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re-exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter-individual variation in response to dapagliflozin with regard to multiple renal risk markers. Methods: Data were used from a crossover randomized clinical trial that assessed the albuminuria-lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed-effects models were used to quantify the exposure–response relationships. Results: The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log-transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001). Conclusion: An individual's exposure to dapagliflozin is consistent upon re-exposure and correlates with pharmacodynamic response in renal risk markers

Optimized labeling of NOTA-conjugated octreotide with F-18

We recently reported a facile method based on the chelation of [18F]aluminum fluoride (Al18F) by NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Here, we present a further optimization of the 18F labeling of NOTA-octreotide (IMP466). Octreotide was conjugated with the NOTA chelate and was labeled with 18F in a two-step, one-pot method. The labeling procedure was optimized with regard to the labeling buffer, ionic strength, peptide concentration, and temperature. Radiochemical yield, specific activity, in vitro stability, and receptor affinity were determined. Biodistribution of 18F-IMP466 was studied in AR42J tumor-bearing mice. In addition, microPET/CT images were acquired. IMP466 was labeled with Al18F in a single step with 97% yield in the presence of 80% (v/v) acetonitrile or ethanol. The labeled product was purified by HPLC to remove unlabeled peptide and unbound Al18F. The radiolabeling, including purification, was performed for 45 min. Specific activities of 48,000 GBq/mmol could be obtained. 18F-IMP466 showed a high tumor uptake and excellent tumor-to-blood ratios at 2 h post-injection. In addition, the low bone uptake indicated that the Al18F–NOTA complex was stable in vivo. PET/CT scans revealed excellent tumor delineation and specific accumulation in the tumor. Uptake in receptor-negative organs was low. NOTA-octreotide could be labeled with 18F in quantitative yields using a rapid two-step, one-pot, method. The compound was stable in vivo and showed rapid accretion in SSTR2-receptor-expressing AR42J tumors in nude mice. This method can be used to label other NOTA-conjugated compounds such as RGD peptides, GRPR-binding peptides, and Affibody molecules with 18F

An approach to the use of indices-based analysis subject to money laundering and terrorist financing national risk assessment

The core aim of this study is to propose an approach to quantitate estimation of indices-based information subject to necessities of the National Risk Assessment (NRA) of money laundering and terrorist financing (ML/TF) risks. Mathematical formalization analysis for Ukraine based on 11 indices and indicators for years 2011-2015 subject to core areas of the overall situation in a country considered within its National Risk Assessment was carried out. Authors’ contribution covers scientific novelty that is a first-time analysis of a general situation in a jurisdiction in light of the National Risk Assessment’s requirements based on joint consideration of various indices and setting priority to areas of the overall country’s situation in the framework of conducted calculations. It was concluded that proposed approach is a valuable instrument for assessing priority of areas of the overall situation in the country for the National Risk Assessment’s purposes through a formalized mechanism ensuring high objectiveness. Practical significance of this study is a possibility to reach higher efficiency in allocation of available resources for the participants of the National Risk Assessment, to reduce some costs considering flexibility of the approach allowing consideration of significant volumes of information, its updating and comparison. This research could become a starting point for further research. Considering complexity of existing indices, there is a necessity to study a mechanism of their correlation and mutual influence, analyze elasticity and joint behavior, and discover the areas of preferable influence on large range of purposes not only limited to the MRA of ML/TF risks

Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors

Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides

Clinical Practice Audit on the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis in the Netherlands

Introduction: Managing complex and rare systemic autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can be challenging and is often accompanied by undesirable variations in clinical practice. Adequate understanding of clinical practice can help identify essential issues to improve the care for AAV patients. Therefore, we studied the real-life management and outcomes of AAV patients in the Netherlands. Methods: In this cohort study, we investigated clinical practice in university and nonuniversity teaching hospitals with respect to patients with a clinical diagnosis of AAV. We retrospectively collected clinical data encompassing clinical variables, medication details, and outcome parameters. Results: Data of 230 AAV patients were collected in 9 Dutch hospitals. Of these, 167 patients (73%) were diagnosed with granulomatosis with polyangiitis, 54 (24%) with microscopic polyangiitis and 9 (4%) with eosinophilic granulomatosis with polyangiitis. One hundred sixty-six patients (72%) had generalized disease. The median year of diagnosis was 2013 (range 1987–2018). Besides steroids, oral cyclophosphamide was the most used drug (50%) for induction therapy and azathioprine (68%) for maintenance therapy. Adverse outcomes were major infections in 35%, major relapses in 23%, malignancy in 10%, major cardiovascular events in 8%, and end-stage renal disease in 7%. Conclusion: Oral cyclophosphamide was the most frequently used induction therapy, azathioprine for maintenance therapy; over time, the use of rituximab is increasingly employed. Major infection and relapses are the most prevalent adverse outcomes. This audit resulted in important indicators for treatment of AAV patients that can be implemented for future, national audits to improve the outcomes of AAV patients

Identifying relevant determinants of in-hospital time to diagnosis for ANCA-associated vasculitis patients

OBJECTIVES: Diagnosing patients with ANCA-associated vasculitis (AAV) can be challenging owing to its rarity and complexity. Diagnostic delay can have severe consequences, such as chronic organ damage or even death. Given that few studies have addressed diagnostic pathways to identify opportunities to improve, we performed a clinical audit to evaluate the diagnostic phase. METHODS: This retrospective, observational study of electronic medical records data in hospitals focused on diagnostic procedures during the first assessment until diagnosis. RESULTS: We included 230 AAV patients from nine hospitals. First assessments were mainly performed by a specialist in internal medicine (52%), pulmonology (14%), ENT (13%) or rheumatology (10%). The overall median time to diagnosis was 13 [interquartile range: 2–49] days, and in patients primarily examined by a specialist in internal medicine it was 6 [1–25] days, rheumatology 14 [4–45] days, pulmonology 15 [5–70] days and ENT 57 [16–176] days (P = 0.004). Twenty-two of 31 (71%) patients primarily assessed by a specialist in ENT had non-generalized disease, of whom 14 (64%) had ENT-limited activity. Two hundred and nineteen biopsies were performed in 187 patients (81%). Histopathological support for AAV was observed in 86% of kidney biopsies, 64% of lung biopsies and 34% of ENT biopsies. CONCLUSION: In The Netherlands, AAV is diagnosed and managed predominantly by internal medicine specialists. Diagnostic delay was associated with non-generalized disease and ENT involvement at presentation. Additionally, ENT biopsies had a low diagnostic yield, in contrast to kidney and lung biopsies. Awareness of this should lead to more frequent consideration of AAV and early referral for a multidisciplinary approach when AAV is suspected

Correlations between plasma strontium concentration, components of calcium and phosphate metabolism and renal function in type 2 diabetes mellitus

BACKGROUND: Renal function decline in diabetic kidney disease is accompanied by calcium and phosphate metabolism alterations. Whereas Strontium (Sr2+ ) has many similarities with calcium, little is known about Sr2+ in this respect. We studied the association of plasma Sr2+ concentration and parameters associated with an altered calcium and phosphate metabolism in diabetic kidney disease. MATERIALS AND METHODS: Plasma Sr2+ concentration was measured in 450 patients included in the DIAbetes and LifEstyle Cohort Twente-1. Patients were classified based on chronic kidney disease (CKD) stages: stages 1-2, stage 3 and stages 4-5 (estimated glomerular filtration rate of ≥60 mL·min-1 ·1.73m-2 , 30-59 mL·min-1 ·1.73m-2 and ≤29 mL·min-1 ·1.73m-2 , respectively). The associations between log-transformed plasma Sr2+ concentration and parameters of calcium and phosphate metabolism were studied using multivariate linear regression analysis. RESULTS: Overall, median plasma Sr2+ concentration was in normal range, 269 nmol/L, but was progressively higher in patients with lower renal function, i.e. 246 nmol/L (CKD 1-2), 347 nmol/L (CKD 3) and 419 nmol/L (CKD 4-5). In multivariate analysis, independent associations were found between plasma Sr2+ concentration and both eGFR (β=-0.401, p<0.001) and plasma fibroblast growth factor 23 (FGF23) concentration (β=0.087, p=0.04). CONCLUSIONS: We found an independent inverse association between eGFR and plasma Sr2+ concentration and an independent association between plasma Sr2+ concentration and plasma FGF23 concentration, a marker of deranged calcium and phosphate metabolism. Further research is needed to determine the mechanisms behind these associations and the impact of an elevation in plasma Sr2+ concentration on bone mineralization and calcification. This article is protected by copyright. All rights reserved