Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pharmacochemistry for the synthesis of new antirhinoviruses

Ce travail de pharmacochimie est consacré à la synthèse de nouvelles molécules benzéniques en vue d’étudier leurs propriétés pharmacologiques in vitro sur le Rhinovirus humain 14 mais également d’en déduire des relations de structure activité. En effet, le fil conducteur du projet de thèse est un travail de pharmacomodulation en collaboration avec le Rega Institute for Medical Research de Louvain. La méthode principale de synthèse de ces structures est basée sur la méthodologie TDAE ou Tétrakis(DiméthylAmino)Ethylène, appliquée sur des substrats dérivés du chlorure de nitrobenzyle. La synthèse et l’évaluation biologique de plus de 100 molécules a permis de décrire 5 hits dérivés du 4,5-diméthoxybenzène présentant des activités biologiques intéressantes in vitro (Concentration Effective Médiane de 1,5 à 4,3 μM ; index de sélectivité de 6 à 92). Les différentes stratégies adoptées lors de ce travail de pharmacochimie ont permis d’étendre l’étude des réactions par transfert monoélectronique sur de nouveaux substrats. Ainsi, le 1-(3-chloroprop-1-ynyl)-4-nitrobenzène a fait l’objet d’une étude en méthodologie LD-SRN1 avec des nitroalcanes, nitrocycloalcanes ainsi qu’avec des anions sulfinates ; ces travaux ont permis de décrire de nouveaux substrats insaturés originaux avec de bons rendements. De plus, la réactivité de ce substrat original a été évaluée en méthodologie TDAE avec des aldéhydes aromatiques. Ces travaux ont été valorisés par la synthèse de diarylbutynols originaux et ouvrent de nombreuses perspectives de recherche sur ce même noyau.This pharmacochemistry work aims at synthesizing of new benzenic derivatives molecules with the scope to study both the chemical and antirhinoviruses 14 pharmacological properties in vitro. In fact, this work was focused on the pharmacomodulation of benzonitrile derivatives in collaboration with Rega Institute for Medical Research group. One hundred structural analogues were synthesized and a structure-activity-relationship was established. Biological assays showed five molecules with interesting anti-hRV 14 activities (EC50 from 1.5 to 4.3 and selectivity index from 6 to 92).These products derived from the TDAE-initiated reaction of various nitrobenzyl chloride analogues. Different strategies directed toward this pharmacochemistry project permitted to study single electron transfer (SET) reaction on original substrates. In this way, we explored the concept of LD-SRN1 on a propargylic chloride derivative such as 1-(3-chloroprop-1-ynyl)-4-nitrobenzene with nitronate and sulfinate anions. This latter compound also constitutes a potential substrate for the preparation of a propargylic anion using the TDAE strategy. So, we examined the use of TDAE methodology in alkyne series with various aromatic aldehydes in the presence of TDAE. These last works opened the scope of single electron transfer (SET) reactions

Microcosting en radiologie interventionnelle (intervention du pharmacien dans la valorisation d'une spécialité nouvelle)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

First Long-Distance S(RN)1 on a propargylic chloride

International audienceWe report here the first example of a Long-Distance S(RN)1 (LD-S(RN)1) reaction on a propargylic chloride. The reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene (1) with nitronate anions led to both the formation of the C-alkylation product through an LD-S(RN)1 mechanism and the ethylenic compound resulting from nitrous acid elimination on the C-alkylation product 2. In contrast with previous work on LD-S(RN)1 reactivity, no O-alkylation product was observed. Only one original product 4 was isolated under phase transfer conditions, resulting from a nucleophilic attack by 2-nitropropane anion on the electrophilic allcyne. This LD-S(RN)1 reactivity did not extend to sulfinate anions: the reaction of 1 with sulfinate anions yielded original ethylenic disulfone compounds which were formed via an ionic process. (C) 2012 Elsevier Ltd. All rights reserved

Original TDAE Strategy Using Propargylic Chloride: Rapid Access to 1,4-Diarylbut-3-ynol Derivatives

We report herein the first synthesis of propargylic alcohols using an organic reducing agent. Diarylbutynol derivatives are formed in moderate to good yields under mild conditions from the reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene with various aromatic aldehydes using tetrakis(dimethylamino)ethylene (TDAE) as reductant

Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Real Life: One-Year Clinical and Economic Outcomes

International audienceBackground: Recombinant factor VIII Fc fusion protein (rFVIIIFc) is the first extended half-life (EHL) recombinant clotting factor with marketing authorization; it has been available in France since October 2016. However, data and literature about rFVIIIFc in clinical practice are scarce.Objective: We propose a 1-year clinical and economic outcome evaluation in patients with hemophilia A taking into consideration treatment adherence.Patients and methods: We reviewed the diaries of all patients treated with rFVIIIFc at Marseille Hemophilia Center for 1 year. All the data were related to the patients' infusion (i.e., annual number of infusions, weekly dose/kg, and annual consumption) and bleeding reports. The clotting factor costs were considered, whereas additional costs (e.g., infusion devices and nurse intervention) were neglected.Results: A total of 34 patients were evaluated. Their median age was 18 years (IQR = 18). Treatment adherence was observed in 62% for FVIII and 66% for rFVIIIFc. The analysis revealed a negligible decrease in the annual clotting factor consumption following the switch (- 2%, p = 0.7339). These data were combined with a significant reduction in the annual number of infusion (- 22.5%, median = 138.5, IQR = 65.8 for FVIII; median = 105, IQR = 24 for rFVIIIFc, p < 0.0001) and bleeding (- 50%, median = 5, IQR = 7.5 for FVIII; median = 1, IQR = 4 for rFVIIIFc, p < 0.0001). With regard to the cost, a decreasing trend was observed (- 8%, p = 0.1300).Conclusion: The analysis in a real-life setting revealed that the input of switches toward rFVIIIFc in different treatment (age of patients and regimen) patterns seems to corroborate previous studies. The results suggest that switches have a beneficial effect in terms of efficacy, clotting factor consumption, and cost

Efficacy and safety of plasma exchange using a double viral inactivated and prion reduced solvent/detergent fresh frozen plasma for the treatment of thrombotic microangiopathy: The first French experience in a single center.

MEDLINE:31331708BACKGROUND: Octaplas LG is the first plasma with marketing authorisation, available in France only since February 2016. This is a double viral inactivated and prion reduced solvent/detergent fresh frozen plasma. Clinical data on Octaplas LG use in thrombotic microangiopathy (TMA) remains very limited. In May 2017, we were the first hospital in France to benefit of this new plasma product now dispensed by hospital pharmacies. We present a prospective review of all therapeutic plasma exchange (TPE) procedures for TMA patients in our hospital to evaluate the new delivery circuit, the efficacy and the adverse events (AE) related to this plasma. STUDY DESIGN AND METHODS: We prospectively reviewed 166 TPE procedures where Octaplas LG was used as replacement fluid in 15 consecutive TMA patients required TPE in our hospital from May 2017 until December 2018. RESULTS: The total replacement plasma volume administered was 763 L (3818 units) with a median on 32 L (range 6-157) per episode. Remission was achieved in all cases after a median of 7 TPE per patient's episode. No exacerbation nor relapse were noted. One patient presented a grade 1 citrate reaction, and another patient an allergic reaction. We deplored pulmonary embolism in 2 patients. CONCLUSION: In our experience OctaplasLG was well-tolerated and was effective at inducing a full clinical remission. Although two PE were noted, the relationship to OctaplasLG in unclear. The new dispensing circuit through the hospital pharmacy has proven to be safe and efficient

Environmental monitoring by surface sampling for cytotoxics: a review

International audienceObject: Environmental monitoring is usually conducted by surface sampling to detect and quantify the presence of cytotoxic drugs after their reconstitution and administration. This technique reveals the origins of residual contamination and is an important component in order to protect healthcare workers from the potential risk of occupational exposure. The aim of this work is to compare various techniques and results of surface sampling for cytotoxics.Materials and methods: For each technique, sample processing methods and their analysis were compared from literature data. Sampling is often performed by the wiping technique. After treatment, various single or multi-compound technical analyses are used, in particular liquid or gas chromatography involving different detection methods: ultraviolet, mass spectrometry, plasma torch, voltammetry. Some methods are validated to ensure reliability.Results: Despite published guidelines and the use of isolator technology for the preparation of cytotoxic drugs, workplace contamination persists, leading to chemotherapeutic agents’ exposure of healthcare workers. Efforts need to be maintained with particular emphasis on harmonization and on determining alert level for cytotoxic contamination

Misuse of antibiotics reserved for hospital settings in outpatients: a ă prospective clinical audit in a university hospital in Southern France

26th European Congress of Clinical Microbiology and Infectious Diseases ă (ECCMID), Amsterdam, NETHERLANDS, APR 09-12, 2016International audienceSome antibiotics are reserved essentially for hospital settings owing to ă cost effectiveness and in order to fight the emerging antibiotic ă resistance crisis. In some cases, antibiotics reserved exclusively for ă use in hospitals may be prescribed in outpatients for serious infections ă or in the absence of a therapeutic alternative. A 30-day prospective ă audit of outpatient prescriptions of antibiotics reserved exclusively ă for use in hospitals was performed. The objective of this study was to ă evaluate the relevance of outpatient antibiotic prescriptions by ă measuring appropriateness according to guidelines. During the study ă period, 53 prescriptions were included, only 40% of which were ă appropriate. Among the 32 inappropriate prescriptions, 4 cases lacked ă microbial arguments, 1 case was not adequate for the infection type, 1 ă case involved an incorrect antibiotic dosage, 1 case involved an ă incorrect interval of dose administration, 3 cases had a therapeutic ă alternative and 22 cases were not recommended. Of the 53 prescriptions, ă 66% were started in hospital and 34% in outpatients. Only 25% of ă cases were prescribed with infectious diseases specialist (IDS) advice, ă 64% were based on microbiological documentation and 13% had a negative ă bacterial culture. Inappropriate prescriptions were usually observed in ă antibiotic lock therapy, skin infections, Clostridium difficile colitis, ă intra-abdominal infections and intravascular catheter-related ă infections. Outpatient prescriptions of antimicrobial drugs reserved ă exclusively for use in hospitals are frequently inappropriate. We ă recommend a real-time analysis algorithm with the involvement of an IDS ă for monitoring prescriptions to improve the quality of these ă prescriptions and possibly to prevent antibiotic resistance. (C) 2016 ă Elsevier B. V. and International Society of Chemotherapy. All rights ă reserved

The T3SS-1 : not the only way for Salmonella to invade non phagocytic cells

International audienc