Drug-Drug Interactions in Patients with Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug-drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations of coronavirus disease 2019 (COVID-19) as an underlying cause of ARDS and treatment with extracorporeal membrane oxygenation (ECMO) with the occurrence of pDDIs. This retrospective study included patients ≥18 years of age diagnosed with ARDS between January 2010 and September 2021. The Janusmed database was used for the identification of pDDIs. A total of 2694 pDDIs were identified in 189 patients with a median treatment duration of 22 days. These included 323 (12%) clinically relevant drug combinations that are best avoided, corresponding to a median rate of 0.05 per day. There was no difference in the number of pDDIs between COVID-19- and non-COVID-19-associated ARDS. In patients treated with ECMO, the rate of the most severely graded pDDIs per day was significantly higher compared with those who did not require ECMO. PDDIs occur frequently in patients with ARDS. On average, each patient may encounter at least one clinically relevant drug combination that should be avoided during their intensive care unit stay.

Progress in von Willebrand Disease Treatment: Evolution towards Newer Therapies.

von Willebrand disease (VWD) is a very heterogenous disease, resulting in different phenotypes and different degrees of bleeding severity. Established therapies (i.e., desmopressin, antifibrinolytic agents, hormone therapy for heavy menstrual bleeding, and von Willebrand factor [VWF] concentrates) may work in some subtypes, but not in all patients. In recent years, progress has been made in improving the diagnosis of VWD subtypes, allowing for more specific therapy. The impact of VWD on women's daily lives has also come to the fore in recent years, with hormone therapy, tranexamic acid, or recombinant VWF as treatment options. New treatment approaches, including the replacement of lacking factor VIII (FVIII) function, may work in those subgroups affected by severe FVIII deficiency. Reducing the clearance of VWF is an alternative treatment pathway; for example, rondaptivon pegol is a VWFA1 domain-binding aptamer which not only improves plasma VWF/FVIII levels, but also corrects platelet counts in thrombocytopenic type 2B VWD patients. These approaches are currently in clinical development, which will be the focus of this review. In addition, half-life extension methods are also important for the improvement of patients' quality of life. Targeting specific mutations may further lead to personalized treatments in the future. Finally, a few randomized controlled trials, although relatively small, have been published in recent years, aiming to achieve a higher level of evidence in future guidelines.

A randomized, double-blind study on the safety and immunogenicity of rTSST-1 variant vaccine: phase 2 results.

Background: Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus that causes the life-threatening toxic shock syndrome. The development of a safe and immunogenic vaccine against TSST-1 remains an unmet medical need. We investigated the safety, tolerability and immunogenicity of a recombinant TSST-1 variant vaccine (rTSST-1v) after 1-3 injections in healthy volunteers. Methods: In this randomised, double-blind, adjuvant-controlled, parallel-group, phase 2 trial, healthy adults aged 18-64 were randomly allocated to undergo 1-3 injections of either 10 or 100 µg rTSST-1v or Al(OH)3. The primary endpoint was safety and tolerability of rTSST-1v in the intention-to-treat population. The per-protocol population was used for the immunogenicity analysis. The trial is registered with EudraCT#: 2015-003714-24; ClinicalTrials.gov#: NCT02814708. Findings: Between April and November 2017,140 subjects were enrolled and 126 completed the trial. rTSST-1v showed a good safety and tolerability profile. A total of 855 systemic adverse events occurred, 280 of which were suspected related adverse events, without dose dependency. Two participants were discontinued early because of allergic reactions. Seroconversion occurred in >81% of subjects within 3 months of the first immunisation which was sustained until 18 months after the third immunisation in over 70% of subjects in the pooled low-dose group and in over 85% in the pooled high-dose group. Interpretation: rTSST-1v in cumulative doses of up to 300 µg was safe, well-tolerated and highly immunogenic. Two immunisations with 100 µg rTSST-1v provided the most persistent immune response and may be evaluated in future trials. Funding: Biomedizinische Forschung & Bio-Produkte AG funded this study.

Disseminated Intravascular Coagulation in Anaphylaxis.

Anaphylaxis is a life-threatening condition that involves severe cutaneous, respiratory, and cardiovascular symptoms. Disseminated intravascular coagulation (DIC) is an acquired, widespread activation of coagulation that can be caused by infectious conditions (e.g., sepsis) and noninfectious conditions. The onset of DIC following anaphylaxis is not commonly known, and information regarding the pathomechanism linking anaphylaxis to DIC is scarce. Further, demographic and clinical data in anaphylaxis-induced DIC are still missing to this day. Triggered by a case of anaphylaxis-induced DIC that seamlessly transitioned to lethal sepsis-induced DIC, we aimed to characterize the patient population affected by anaphylaxis-induced DIC by performing a review of existing literature and expand the discussion to underlying mechanisms. The overall mortality of the patient cohort (n = 30) identified by the literature review was 50%. All patients that died either suffered a bleeding event or a thrombotic event. The majority of patients (n = 25/30; 83%) had bleeding events; thrombotic events were only reported in nonsurvivors (n = 9/15 or 60% of nonsurvivors; vs. n = 0/15 in survivors; p < 0.001). Nonsurvivors of anaphylaxis-induced DIC were on average 25 years older than survivors (p = 0.068). In conclusion, DIC can complicate anaphylaxis and is expected to contribute to poor microvascular perfusion after anaphylaxis. Particularly, elderly patients with known cardiovascular disease and patients who develop thrombotic events are susceptible to lethal outcomes. As a rare and largely uncharacterized disease entity, further research is needed to investigate the link between DIC and anaphylaxis and to potentially identify better treatment strategies.

Renin-angiotensin system inhibitor discontinuation in COVID-19 did not modify systemic ACE2 in a randomized controlled trial.

Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.

The Pharmacokinetics of Individual Conjugated Xanthohumol Metabolites Show Efficient Glucuronidation and Higher Bioavailability of Micellar than Native Xanthohumol in a Randomized, Double-Blind, Crossover Trial in Healthy Humans.

SCOPE: Prenylated chalcones and flavonoids are found in many plants and are believed to have beneficial effects on health when consumed. Xanthohumol is present in beer and likely the most consumed prenylated chalcone, but poorly absorbed and rapidly metabolized and excreted, thus limiting its bioavailability. Micellar formulations of phytochemicals have been shown to improve bioavailability. METHODS AND RESULTS: In a randomized, double-blind, crossover trial with five healthy (three males and two females) volunteers, a single dose of 43 mg was orally administered as a native or micellar formulation. The major human xanthohumol metabolites are quantified in plasma. Unmetabolized free xanthohumol makes 1% or less of total plasma xanthohumol. The area under the plasma concentration-time curve of xanthohumol-7-O-glucuronide following the ingestion of the micellular formulation is 5-fold higher and its maximum plasma concentration is more than 20-fold higher compared to native xanthohumol. CONCLUSION: Metabolism of orally ingested xanthohumol is complex and efficiently converts the parent compound to predominantly glucuronic acid and to a lesser extent sulfate conjugates. The oral bioavailability of micellar xanthohumol is superior to native xanthohumol, making it a useful delivery form for future human trials.

Effect of the human endotoxin challenge on tedizolid tissue penetration.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fCmax (0.15 [0.14-0.19] vs. 0.19 [0.18-0.24] mg/L, P = .0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration-time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics.

The von Willebrand factor-binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A.

Factor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

Applicability of Vasopressor Trials in Adult Critical Care: A Prospective Multicentre Meta-Epidemiologic Cohort Study.

Objective: To assess the applicability of evidence from landmark randomized controlled trials (RCTs) of vasopressor treatment in critically ill adults. Study Design and Setting: This prospective, multi-center cohort study was conducted at five medical and surgical intensive care units at three tertiary care centers. Consecutive cases of newly initiated vasopressor treatment were included. The primary end point was the proportion of patients (≥18 years) who met the eligibility criteria of 25 RCTs of vasopressor therapy in critically ill adults included in the most recent Cochrane review. Multilevel Poisson regression was used to estimate the eligibility proportions with 95% confidence intervals for each trial. Secondary end points included the eligibility criteria that contributed most to trial ineligibility, and the relationship between eligibility proportions and (i) the Pragmatic-Explanatory Continuum Indicator Summary-2 (PRECIS-2) score, and (ii) the recruitment-to-screening ratio of each RCT. The PRECIS-2 score was used to assess the degree of pragmatism of each trial. Results: Between January 1, 2017, and January 1, 2019, a total of 1189 cases of newly initiated vasopressor therapy were included. The median proportion of cases meeting eligibility criteria for all 25 RCTs ranged from 1.3% to 6.0%. The eligibility criteria contributing most to trial ineligibility were the exceedance of a specific norepinephrine dose, the presence of a particular shock type, and the drop below a particular blood pressure value. Eligibility proportions increased with the PRECIS-2 score but not with the recruitment-to-screening ratio of the trials. Conclusion: The applicability of evidence from available trials on vasopressor treatment in critically ill adults to patients receiving vasopressors in daily practice is limited. Applicability increases with the degree of study pragmatism but is not reflected in a high recruitment-to-screening ratio. Our findings may help researchers design vasopressor trials and promote standardized assessment and reporting of the degree of pragmatism achieved.

Micellar Curcumin: Pharmacokinetics and Effects on Inflammation Markers and PCSK-9 Concentrations in Healthy Subjects in a Double-Blind, Randomized, Active-Controlled, Crossover Trial.

SCOPE: Preclinical models have demonstrated the anti-inflammatory and lipid-lowering effects of curcumin. Innovative formulations have been developed to overcome the poor bioavailability of native curcumin. The study hypothesizes that the bioavailability of micellar curcumin is superior to native curcumin and investigates the potential anti-inflammatory and proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration lowering effects. METHODS AND RESULTS: In this double-blind, randomized, crossover trial, 15 healthy volunteers receive micellar or native curcumin (105 mg day-1 ) for 7 days with a ≥7 days washout period. Curcumin and metabolite concentrations are quantified by high-performance liquid chromatography with fluorescence detection (HPLC-FD), and pharmacokinetics are calculated. To analyze anti-inflammatory effects, blood samples (baseline, 2 h, 7 days) are stimulated with 50 ng mL-1 lipopolysaccharides (LPS). Interleukin (IL)-6, tumor-necrosis factor (TNF-α), and PCSK9 concentrations are quantified. Micellar curcumin demonstrates improved bioavailability (≈39-fold higher maximum concentrations, ≈14-fold higher area-under-the-time-concentration curve, p < 0.001) but does not reduce pro-inflammatory cytokines in the chosen model. Subjects receiving micellar curcumin have significantly lower PCSK9 concentrations (≈10% reduction) after 7 days compared to baseline (p = 0.038). CONCLUSION: Micellar curcumin demonstrates an improved oral bioavailability but does not show anti-inflammatory effects in this model. Potential effects on PCSK9 concentrations warrant further investigation.

The difference between arterial pCO2 and etCO2 after cardiac arrest - Outcome predictor or marker of unfavorable resuscitation circumstances?

INTRODUCTION: In former studies, the arterio-alveolar carbon dioxide gradient (ΔCO2) predicted in-hospital mortality after initially survived cardiac arrest. As early outcome predictors are urgently needed, we evaluated ΔCO2 as predictor for good neurological outcome in our cohort. METHODS: We retrospectively analyzed all patients ≥18 years of age after non-traumatic in- and out of hospital cardiac arrest in the year 2018 from our resuscitation database. Patients without advanced airway management, incomplete datasets or without return of spontaneous circulation were excluded. The first arterial pCO2 after admission and the etCO2 in mmHg at the time of blood sampling were recorded from patient's charts. We then calculated ΔCO2 (pCO2 - etCO2). For baseline analyses, ΔCO2 was dichotomized into a low and high group with separation at the median. Good neurological outcome on day 30, expressed as Cerebral Performance Category 1-2, defined our primary endpoint. Survival to 30 days was used as secondary endpoint. RESULTS: Out of 302 screened patients, 128 remained eligible for analyses. ΔCO2 was lower in 30-day survivors with good neurological outcome (12.2 mmHg vs. 18.8 mmHg, p = 0.009) and in 30-day survivors (12.5 mmHg vs. 20.0 mmHg, p = 0.001). In patients with high ΔCO2, a cardiac etiology of arrest was found less often. They had a higher body mass index, longer duration of resuscitation, higher amounts of epinephrine, lower pO2 levels but both higher pCO2 and blood lactate levels, resulting in lower blood pH and HCO3- levels at admission. In a crude binary logistic regression analysis, ΔCO2 was associated with 30-day neurological outcome (OR = 1.041 per mmHg of ΔCO2, 95% CI 1.008-1.074, p = 0.014). This association persisted after the adjustment for age, sex, witnessed arrest and shockable first rhythm. However, after addition of the duration of resuscitation or the cumulative epinephrine dosage to the model, ΔCO2 lost its association. CONCLUSION: ΔCO2 at admission after a successfully resuscitated cardiac arrest is associated with 30 days survival with good neurological outcome. However, a higher ΔCO2 may rather be a surrogate for unfavorable resuscitation circumstances than an independent outcome predictor.

Multi-phasic life-threatening anaphylaxis refractory to epinephrine managed by extracorporeal membrane oxygenation (ECMO): A case report.

We present a case of a 52-year-old patient suffering from multi-phasic life-threatening anaphylaxis refractory to epinephrine treatment. Extracorporeal membrane oxygenation (ECMO) therapy was initiated as the ultima ratio to stabilize the patient hemodynamically during episodic severe bronchospasm. ECMO treatment was successfully weaned after 4 days. Mastocytosis was diagnosed as the underlying condition. Although epinephrine is recommended as a first-line treatment for anaphylaxis, this impressive case provides clear evidence of its limited therapeutic success and emphasizes the need for causal therapies.

Disseminated Intravascular Coagulation Score Predicts Mortality in Patients with Liver Disease and Low Fibrinogen Level.

BACKGROUND: Alongside its original diagnostic intention, the International Society on Thrombosis and Haemostasis' (ISTH) disseminated intravascular coagulation (DIC) score predicts mortality in various patient groups. OBJECTIVES: We investigated whether coagulopathy quantified by the DIC score can predict 30-day mortality in patients with liver disease and low fibrinogen levels. METHODS: We retrospectively analyzed all patients admitted to the Vienna General Hospital between 2003 and 2014 with a fibrinogen level of <150 mg/dL, a history of liver disease, and ≥2 pathological DIC parameters. We used a Cox regression and receiver operating characteristic analysis to assess the predictive value of the ISTH DIC score in its original (DIC-2001) and revised form (DIC-2018). RESULTS: A total of 1,333 patients were screened, and 388 of these patients (38% female, median age: 58 years, interquartile range: 48-66 years) were analyzed. The DIC-2001 (hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.78-2.59, p < 0.001) and DIC-2018 (HR: 1.73, 95% CI: 1.51-2.05, p < 0.001) predicted 30-day mortality. The results remained robust in several sensitivity analyses. CONCLUSION: The ISTH DIC-2001 and DIC-2018 scores predicted 30-day mortality in patients with liver disease and low fibrinogen levels. The DIC score deserves further investigation in this population as it likely reflects different dimensions of the underlying disease.

Performance of a Qualitative Point-of-Care Strip Test to Detect DOAC Exposure at the Emergency Department: A Cohort-Type Cross-Sectional Diagnostic Accuracy Study.

An accurate point-of-care test for detecting effective anticoagulation by direct oral anticoagulants (DOACs) in emergencies is an unmet need. We investigated the accuracy of a urinary qualitative strip test (DOAC Dipstick) to detect relevant DOAC exposure in patients who presented to an emergency department. In this prospective single-center cohort-type cross-sectional study, adults on DOAC treatment were enrolled. We assessed clinical sensitivity and specificity of DOAC Dipstick factor Xa and thrombin inhibitor pads to detect DOAC plasma levels ≥30 ng/mL using urine samples as the testing matrix. Liquid chromatography coupled with tandem-mass spectrometry was used as the reference standard method for plasma and urine measurement of DOAC concentrations. Of 293 patients enrolled, 265 patients were included in the analysis, of whom 92 were treated with rivaroxaban, 65 with apixaban, 77 with edoxaban, and 31 with dabigatran. The clinical sensitivity and specificity of the dipstick on urine samples to detect ≥30 ng/mL dabigatran plasma levels were 100% (95% confidence interval [CI]: 87-100%) and 98% (95% CI: 95-99%), respectively. The sensitivity and specificity of the dipstick to detect ≥30 ng/mL factor Xa inhibitor plasma levels were 97% (95% CI: 94-99%) and 69% (95% CI: 56-79%), respectively. The DOAC Dipstick sensitively identified effective thrombin and factor Xa inhibition in a real-world cohort of patients presenting at an emergency department. Therefore, the dipstick might provide a valuable test to detect relevant DOAC exposure in emergencies, although further studies will be needed to confirm these findings.

Out-of-Sample Validity of the PROLOGUE Score to Predict Neurologic Function after Cardiac Arrest.

BACKGROUND: The clinical value of a prognostic score depends on its out-of-sample validity because inaccurate outcome prediction can be not only useless but potentially fatal. We aimed to evaluate the out-of-sample validity of a recently developed and highly accurate Korean prognostic score for predicting neurologic outcome after cardiac arrest in an independent, plausibly related sample of European cardiac arrest survivors. METHODS: Analysis of data from a European cardiac arrest center, certified in compliance with the specifications of the German Council for Resuscitation. The study sample included adults with nontraumatic out-of-hospital cardiac arrest admitted between 2013 and 2018. Exposure was the PROgnostication using LOGistic regression model for Unselected adult cardiac arrest patients in the Early stages (PROLOGUE) score, including 12 clinical variables readily available at hospital admission. The outcome was poor 30-day neurologic function, as assessed using the cerebral performance category scale. The risk of a poor outcome was calculated using the PROLOGUE score regression equation. Predicted risk deciles were compared to observed outcome estimates in a complete-case analysis, a best-case analysis, and a multiple-data-imputation analysis using the Markov chain Monte Carlo method. RESULTS: A total of 1051 patients (median 61 years, IQR 50-71; 29% female) were analyzed. A total of 808 patients (77%) were included in the complete-case analysis. The PROLOGUE score overestimated the risk of poor neurologic outcomes in the range of 40% to 100% predicted risk, involving 63% of patients. The model fit did not improve after missing data imputation. CONCLUSIONS: In a plausibly related sample of European cardiac arrest survivors, risk prediction by the PROLOGUE score was largely too pessimistic and failed to replicate the high accuracy found in the original study. Using the PROLOGUE score as an example, this study highlights the compelling need for independent validation of a proposed prognostic score to prevent potentially fatal mispredictions.

Synthesis of Human Phase I and Phase II Metabolites of Hop (Humulus lupulus) Prenylated Flavonoids.

Hop prenylated flavonoids have been investigated for their in vivo activities due to their broad spectrum of positive health effects. Previous studies on the metabolism of xanthohumol using untargeted methods have found that it is first degraded into 8-prenylnaringenin and 6-prenylnaringenin, by spontaneous cyclisation into isoxanthohumol, and subsequently demethylated by gut bacteria. Further combinations of metabolism by hydroxylation, sulfation, and glucuronidation result in an unknown number of isomers. Most investigations involving the analysis of prenylated flavonoids used surrogate or untargeted approaches in metabolite identification, which is prone to errors in absolute identification. Here, we present a synthetic approach to obtaining reference standards for the identification of human xanthohumol metabolites. The synthesised metabolites were subsequently analysed by qTOF LC-MS/MS, and some were matched to a human blood sample obtained after the consumption of 43 mg of micellarised xanthohumol. Additionally, isomers of the reference standards were identified due to their having the same mass fragmentation pattern and different retention times. Overall, the methods unequivocally identified the metabolites of xanthohumol that are present in the blood circulatory system. Lastly, in vitro bioactive testing should be applied using metabolites and not original compounds, as free compounds are scarcely found in human blood.

Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial.

BACKGROUND: High on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers. METHODS: We conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P) and the platelet function analyzer. In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor. RESULTS: All cangrelor bolus infusions resulted in immediate and pronounced platelet inhibition. Bolus infusions of cangrelor 20 mg resulted in sufficient platelet inhibition assessed by MEA for 20 min in 90% of subjects. Infusion of cangrelor via the IV flow regulator resulted in sufficient platelet inhibition throughout the course of administration. Ex vivo epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner. CONCLUSIONS: Weight-adapted bolus infusions followed by a continuous infusion of cangrelor via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as weight-adapted bolus infusion followed by a continuous infusion using an IV flow regulator may be a viable treatment approach for effective and well controllable prehospital platelet inhibition. TRIAL REGISTRATION: EC (Medical University of Vienna) 1835/2019 and EudraCT 2019-002792-34 .

Corticosteroid Treatment Prevents Lipopolysaccharide-Induced Increase of ACE2 and Reduces Fibrin Degradation Products in Bronchoalveolar Lavage Fluid.

The assessment of systemic corticosteroid effects on intrapulmonary disease biomarkers is challenging. This retrospective evaluation of a human endotoxemia model quantified ACE2 and fibrin degradation product (FDP) concentrations in bronchoalveolar lavage fluid (BALF) samples from a randomized, double-blind, placebo-controlled study (NCT01714427). Twenty-four healthy volunteers received either 2 × 40 mg intravenous dexamethasone or placebo. These doses were administered 12 h apart prior to bronchoscopy-guided intrabronchial lipopolysaccharide (LPS) stimulation (control: saline into the contralateral lung segment). We quantified ACE2 concentration, the Angiotensin-II-to-Angiotensin-1-7 conversion rate as well as FDP in BALF 6 h after LPS instillation. In placebo-treated subjects, LPS instillation increased ACE2 concentrations compared to unstimulated lung segments [1,481 (IQR: 736-1,965) vs. 546 (413-988) pg/mL; p = 0.016]. Dexamethasone abolished the increase in ACE2 concentrations (p=0.13). Accordingly, LPS instillation increased the Angiotensin-II-to-Angiotensin-1-7 conversion capacity significantly in the placebo cohort, indicating increased enzymatic activity (p = 0.012). FDP increased following LPS-instillation [8.9 (2.7-12.2) vs. 6.6 (0.9-9.6) ng/mL, p = 0.025] in the placebo group, while dexamethasone caused a shut-down of fibrinolysis in both lung segments. LPS instillation increased ACE2 concentration, its enzymatic activity and FDP, which was mitigated by systemic dexamethasone treatment. Our results strengthen previously published findings regarding the efficiency of corticosteroids for the treatment of COVID-19-induced acute lung injury.