Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers

The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined

Correction of anemia by dapagliflozin in patients with type 2 diabetes

Aims: Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia. Methods: Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated. Results: At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR Conclusions: Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition. (c) 2020 Published by Elsevier Inc

The concept of negative pressure wound therapy (NPWT) after poststernotomy mediastinitis – a single center experience with 54 patients

Deep sternal infections, also known as poststernotomy mediastinitis, are a rare but often fatal complication in cardiac surgery. They are a cause of increased morbidity and mortality and have a significant socioeconomic aspect concerning the health system. Negative pressure wound therapy (NPWT) followed by muscular pectoralis plasty is a quite new technique for the treatment of mediastinitis after sternotomy. Although it could be demonstrated that this technique is at least as safe and reliable as other techniques for the therapy of deep sternal infections, complications are not absent. We report about our experiences and complications using this therapy in a set of 54 patients out of 3668 patients undergoing cardiac surgery in our institution between January 2005 and April 2007

Dapagliflozin versus metolazone in heart failure resistant to loop diuretics

Background and Aims: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods: A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results: 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier: NCT04860011

Present state and future perspectives of using pluripotent stem cells in toxicology research

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed

Proteoglycans, group IIA phospholipase A2, and lipoproteins.Potential involvement in atherogenesis

Atherosclerosis is a multifactorial complex disease characterized by a focal accumulation of ApoB-100 containing lipoproteins, extracellular matrix (ECM), and cells in the arterial intima accompanied by an inflammatory reaction. In vivo and in vitro data supports the hypothesis that sulfated extracellular proteoglycans may be responsible for the selective retention of low density lipoproteins (LDL) in the arterial wall. Once retained in the intima, the lipoproteins are the targets for subsequent modifications that may lead to formation of large extracellular lipid aggregates and uptake by macrophages. Group IIA secretory non-pancreatic phospholipase A2 (snpPLA2) is a key enzyme involved in inflammatory processes with the specific function of hydrolyzing the sn-2 acyl group in phosphoglycerides and thereby liberating non-esterified fatty acids and lyso-phospholipids. Lipoproteins contain in their surface a substantial amount of phosphoglycerides and they may serve as physiological substrates for snpPLA2. Immunohistochemical studies have demonstrated abundant snpPLA2 associated with the ECM in human atherosclerotic lesions.The focus of this study was to investigate the interactions between snpPLA2 and proteoglycans synthesized by vascular cells as an attempt to characterize the molecular basis for the association of snpPLA2 with ECM components that are known to accumulate during atherosclerosis. In addition, the effects of sPLA2-modification of human plasma lipoproteins were analyzed. The results demonstrated that snpPLA2 binds differentially to proteoglycans and glycosaminoglycans and that these interactions modulate the enzyme activity. Specifically it was demonstrated that chondroitin-6-sulfate increased snpPLA2 activity, while heparin/heparan sulfate inhibited the enzyme. In addition, snpPLA2 bound efficiently to the core protein of decorin, a low molecular weight dermatan sulfate proteoglycan. Interestingly, this interaction appeared to mediate snpPLA2 association with collagen fibers, an observation supported by immunohistochemical analysis of human atherosclerotic tissue. Furthermore, sPLA2-modification of LDL in vitro lead to the formation of small, high density particles with increased affinity for proteoglycans. Hydrolysis of lipoproteins in human plasma by sPLA2 in vitro also generated smaller lipoprotein particles and large subfractions of LDL and high density lipoproteins were preferentially hydrolyzed by sPLA2.These results support the argument that the local snpPLA2-activity in the arterial wall may be modulated by the composition of the ECM with which snpPLA2 is associated. In addition, snpPLA2 may possibly be an important player involved in lipoprotein modification, and may by its action generate atherogenic lipoprotein particles (i.e. small dense LDL particles with increased affinity for proteoglycans). As a consequence, snpPLA2 may contribute to atherogenesis by generating pro-inflammatory lipid mediators and modifying lipoproteins in the arterial wall and in the circulation

Employment of the Triple Helix concept for development of regenerative medicine applications based on human pluripotent stem cells

Using human pluripotent stem cells as a source to generate differentiated progenies for regenerative medicine applications has attracted substantial interest during recent years. Having the capability to produce large quantities of human cells that can replace damaged tissue due to disease or injury opens novel avenues for relieving symptoms and also potentially offers cures for many severe human diseases. Although tremendous advancements have been made, there is still much research and development left before human pluripotent stem cell derived products can be made available for cell therapy applications. In order to speed up the development processes, we argue strongly in favor of cross-disciplinary collaborative efforts which have many advantages, especially in a relatively new field such as regenerative medicine based on human pluripotent stem cells. In this review, we aim to illustrate how some of the hurdles for bringing human pluripotent stem cell derivatives from bench-to-bed can be effectively addressed through the establishment of collaborative programs involving academic institutions, biotech industries, and pharmaceutical companies. By taking advantage of the strengths from each organization, innovation and productivity can be maximized from a resource perspective and thus, the chances of successfully bringing novel regenerative medicine treatment options to patients increase.CC BY 2.0</p