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Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter. [ABSTRACT FROM AUTHOR]

Previous flow cytometry studies showed that platelet activation may occur during cytapheresis, cardiopulmonary bypass and hemodialysis. The aim of this pilot study was to determine if the impact of plasmapheresis leads to alterations in platelet hemostatic capacity. Plasmapheresis was carried out in 30 volunteers using an Autopherese C™ (Baxter) and an MCS3p™ (Haemonetics). Blood samples were collected and analyzed immediately before and after plasmapheresis. As a result of the plasmapheresis on the Autopherese C™, the mean closure time (CT) for collagen/epinephrine (Col/Epi) increased from 118.2 ± 25.1 to 149.9 ± 35.0 s and from 88.7 ± 16.9 to 98.5 ± 26.3 s for collagen/ADP (Col/ADP), respectively. Seven subjects showed impaired CTs after plasmapheresis for Col/Epi. For Col/ADP, five subjects showed impaired CTs after apheresis. Statistical analysis (McNemar test) showed a significant difference before and after apheresis for Col/Epi (P = 0.024) but not for Col/ADP (P = 0.088). Similar results were shown for plasmapheresis carried out with the MCS3p™. These findings show that plasmapheresis can cause an impairment of platelet function in healthy volunteers as measured by the PFA-100™, an effect of so far unknown clinical significance. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the tolerability and efficacy of moxonidine in the treatment of arterial hypertension in patients with obstructive pulmonary disease. The ACE inhibitor ramipril was used as a reference agent. Patients and Methods: A group of 104 adult patients with arterial hypertension and respiratory disorders took part in a double-blind, randomised, parallel-group, single-centre study. During the eight-week treatment phase, patients received either moxonidine (0.2 or 0.4 mg/day) or the ACE inhibitor ramipril (2.5 or 5 mg/day). Results: Small, nonsignificant changes in arterial oxygen partial pressure (PaO) were observed during the treatment period with both moxonidine and ramipril. Forced expiratory volume in one second (FEV) remained constant during treatment with moxonidine. A slight decrease in FEV with ramipril was not statistically significant (p > 0.1). The 24-hour blood pressure measurements showed that systolic and diastolic blood pressures were reduced with moxonidine (p = 0.018 and p = 0.009, respectively) and with ramipril (p < 0.001 for both measurements). Conclusions: Moxonidine and ramipril exhibited comparable antihypertensive efficacy. Lung function was unchanged during treatment with moxonidine, suggesting that this new antihypertensive agent may be an appropriate choice of medication for patients with essential hypertension and concomitant obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

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Abstract Effective treatment of venous thromboembolism (VTE) strikes a balance between prevention of recurrence and bleeding complications. The current standard of care is heparin followed by a vitamin K antagonist such as warfarin. However, this option is not without its limitations, as the anticoagulant effect of warfarin is associated with high inter- and intra-patient variability and patients must be regularly monitored to ensure that anticoagulation is within the narrow target therapeutic range. Several novel oral anticoagulant agents are in the advanced stages of development for VTE treatment, some of which are given after an initial period of heparin treatment, in line with current practice, while others switch from high to low doses after the initial phase of treatment. In this review we assess the critical considerations for treating VTE in light of emerging clinical data for new oral agents and discuss the merits of novel treatment regimens for patients who have experienced an episode of deep vein thrombosis or pulmonary embolism.

Abstract Background There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. Methods Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. Results General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03–1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. Conclusions Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. Trial registration ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

Refractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development., Competing Interests: Competing interests: DS, HL, JH, MAK and CPRH are cofounders of Tubulis GmbH. DS, MAK, JH, SS, PO and IM are employees at Tubulis GmbH. The presented work is part of a pending patent application by DS, HL, AS, JS, MA, KS, JH, CPRH, MAK, IJ, and BV. The remaining authors declare no competing financial interests., (© 2025. The Author(s).)

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of 90 Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [ 90 Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Acute erythroid leukemia (AEL) is a disease continuum between Myelodysplastic syndrome (MDS) and Acute myeloid leukemia (AML) with the cellular hallmark of uncontrolled proliferation and impaired differentiation of erythroid progenitor cells. First described by Giovanni di Guglielmo in 1917 AEL accounts for less than 5% of all de novo AML cases. There have been efforts to characterize AEL at a molecular level, describing recurrent alterations in TP53, NPM1 and FLT3 genes. A genomic analysis of AEL cases confirmed its complexity. Despite these advances, the biology underlying erythroid proliferations remains unclear and the prognosis is dismal with a median survival of only 3 months for pure erythroid leukemia (PEL). Marker combinations suitable for the identification and characterization of leukemic stem cell (LSC) candidates, monitoring measurable residual disease (MRD) during chemotherapy treatment and the development of innovative targeted therapies are missing. Here, we developed a mass cytometry panel for an in-depth characterization of erythroid and myeloid blast cell populations from human AEL bone marrow samples in comparison to other AML subtypes and healthy counterparts. A total of 8 AEL samples were analyzed and compared to 28 AML samples from different molecular subtypes, healthy bone marrow counterparts (n = 5) and umbilical cord blood (n = 6) using high-dimensional mass cytometry. Identification of erythroid and myeloid blast populations in high-dimensional mass cytometry data enabled a refined view on erythroblast differentiation stages present in AEL erythroid blasts and revealed immunophenotypical profiles specific to AEL. Profiling of phenotypic LSCs revealed aberrant erythroid marker expression in the CD34 + CD38 - stem cell compartment. In addition, the identification of novel candidate surface marker combinations and aberrancies might enhance clinical diagnostics of AEL. We present a high-parameter mass cytometry approach feasible for immunophenotypical analysis of blast and stem cell populations in myeloid neoplasms with erythroid predominance laying the foundation for more precise experimental approaches in the future., (© 2023 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)

There are major challenges ahead for clinicians treating patients with atrial fibrillation (AF). The population with AF is expected to expand considerably and yet, apart from anticoagulation, therapies used in AF have not been shown to consistently impact on mortality or reduce adverse cardiovascular events. New approaches to AF management, including the use of novel technologies and structured, integrated care, have the potential to enhance clinical phenotyping or result in better treatment selection and stratified therapy. Here, we report the outcomes of the 6th Consensus Conference of the Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA), held at the European Society of Cardiology Heart House in Sophia Antipolis, France, 17-19 January 2017. Sixty-two global specialists in AF and 13 industry partners met to develop innovative solutions based on new approaches to screening and diagnosis, enhancing integration of AF care, developing clinical pathways for treating complex patients, improving stroke prevention strategies, and better patient selection for heart rate and rhythm control. Ultimately, these approaches can lead to better outcomes for patients with AF.

Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged <75 years and 603 aged ≥75 years. The primary efficacy outcome was symptomatic VTE/VTE-related death. Safety outcomes were centrally adjudicated major bleeding events (MBEs), MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeds. Baseline renal function was categorized as normal, mild RI or moderate RI. A total of 3,698 had normal renal function and 1,100 and 237 had mild and moderate RI, respectively (23 patients with severe RI and 49 with missing creatinine clearance data were not included). For dabigatran, VTE/VTE-related death decreased from 3.1% (normal renal function) to 1.9% for mild RI and to 0.0% for moderate RI. For warfarin, the event rates were 2.6, 1.6 and 4.1%, respectively. Overall, major bleeding increased with increasing RI ( p  = 0.0037) and with age ( p  = 0.4350), with no apparent difference between the dabigatran and warfarin patients. Dabigatran shows better efficacy than warfarin in RI and in the elderly patients, probably because of an increase in the concentration of dabigatran. However, bleeding risk increases with both dabigatran and warfarin in the presence of RI., Competing Interests: Conflicts of Interest: Samuel Z. Goldhaber receives honoraria for consulting activities from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, Portola and Zafgen. Dr. Goldhaber receives research support from BiO2 Medical, Boehringer Ingelheim, BMS, BTG EKOS, Daiichi, the National Heart, Lung, and Blood Institute of the National Institutes of Health, Janssen and the Thrombosis Research Institute.Henry Eriksson receives honoraria for lecturing and consulting activities from Boehringer Ingelheim, Bayer, Pfizer and LeoPharma.Ajay Kakkar receives honoraria for consulting activities from Boehringer Ingelheim, Bayer, Janssen, Daiichi Sankyo, and Sanofi. He receives research support from Bayer.Sebastian Schellong receives honoraria for lecturing and for consulting activities from Boehringer Ingelheim, Bayer, Bayer HealthCare, BMS, Daiichi Sankyo and Pfizer.Sam Schulman receives honoraria for consulting activities from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Bristol-Myers-Squibb, and research grants from Boehringer Ingelheim, Baxalta and Octapharma.Martin Feuring is an employee of Boehringer Ingelheim.Mandy Fraessdorf is an employee of Boehringer Ingelheim.Jörg Kreuzer is an employee of Boehringer Ingelheim.Elke Schueler is an employee of HMS Analytic Software Gmbh., (Schattauer GmbH Stuttgart.)

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0-3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68-0.95 and RE-MEDY, HR 0.73; 95% CI 0.59-0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.

It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER ® , RE-COVER ™ II, and RE-MEDY ™ were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER IDENTIFIER NCT00291330; RECOVER II IDENTIFIER NCT00680186; RE-MEDY IDENTIFIER NCT00329238., (© The Author(s) 2016.)

Dabigatran was non-inferior to warfarin for prevention of recurrent venous thromboembolism (VTE), and dabigatran had a lower rate of bleeding compared with warfarin in two large-scale randomised trials, RE-COVER and RE-COVER II. In this study, we investigate the efficacy and safety of dabigatran versus warfarin according to the index event that qualified the patient for enrollment, either symptomatic pulmonary embolism (PE) with or without deep-vein thrombosis (DVT), or DVT alone. We then analyse the anticoagulant effect of dabigatran vs warfarin on patients enrolled with PE. The pooled dataset for the efficacy analysis consisted of 2553 and 2554 patients who were randomised to dabigatran and warfarin, respectively. Recurrent VTE/VTE-related death during the study period and additional 30-day follow-up occurred in 2.7 % of all patients on dabigatran and in 2.4 % on warfarin (hazard ratio [HR] 1.09 [95 % confidence interval 0.77, 1.54]). In patients with PE as their index event, recurrent VTE/VTE-related death occurred in 2.9 % vs 3.1 % of patients (HR 0.93 [0.53, 1.64]). There were significantly fewer major bleeding events in patients treated with dabigatran than with warfarin (HR 0.60 [0.36, 0.99]). The pattern was similar both in patients with PE and in those with DVT alone as the index event. These analyses of the pooled dataset from the RE-COVER and RE-COVER II trials indicate that dabigatran is as effective as warfarin in preventing recurrent VTE, regardless of whether patients present with symptomatic PE (with or without DVT) or with symptomatic DVT alone. Dabigatran was also associated with a lower risk of bleeding than warfarin, regardless of the index event.