Evaluation of Decontamination Efficacy of Cleaning Solutions on Stainless Steel and Glass Surfaces Contaminated by 10 Antineoplastic Agents

Objectives: The handling of antineoplastic agents results in chronic surface contamination that must be minimized and eliminated. This study was designed to assess the potential of several chemical solutions to decontaminate two types of work surfaces that were intentionally contaminated with antineoplastic drugs. Methods: A range of solutions with variable physicochemical properties such as their hydrophilic/hydrophobic balance, oxidizing power, desorption, and solubilization were tested: ultrapure water, isopropyl alcohol, acetone, sodium hypochlorite, and surfactants such as dishwashing liquid (DWL), sodium dodecyl sulfate (SDS), Tween 40, and Span 80. These solutions were tested on 10 antineoplastic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. To simulate contaminated surfaces, these molecules (200ng) were deliberately spread onto two types of work surfaces: stainless steel and glass. Recovered by wiping with a specific aqueous solvent (acetonitrile/HCOOH; 20/0.1%) and an absorbent wipe (Whatman 903®), the residual contamination was quantified using high-performance liquid chromatography (HPLC) coupled to mass spectrometry. To compare all tested cleaning solutions, a performance value of effectiveness was determined from contamination residues of the 10 drugs. Results: Sodium hypochlorite showed the highest overall effectiveness with 98% contamination removed. Ultrapure water, isopropyl alcohol/water, and acetone were less effective with effectiveness values of 76.8, 80.7, and 40.4%, respectively. Ultrapure water was effective on most hydrophilic molecules (97.1% for cytarabine), while on the other hand, isopropyl alcohol/water (70/30, vol/vol) was effective on the least hydrophilic ones (85.2% for doxorubicin and 87.8% for epirubicin). Acetone had little effect, whatever the type of molecule. Among products containing surfactants, DWL was found effective (91.5%), but its formulation was unknown. Formulations with single surfactant non-ionics (tween 40 and span 80) or anionic (SDS) were also tested. Finally, solutions containing 10-2 M anionic surfactants and 20% isopropyl alcohol had the highest global effectiveness at around 90%. More precisely, their efficacy was the highest (94.8%) for the most hydrophilic compounds such as cytarabine and around 80.0% for anthracyclines. Finally, the addition of isopropyl alcohol to surfactant solutions enhanced their decontamination efficiency on the least hydrophilic molecules. Measured values from the stainless steel surface were similar to those from the glass one. Conclusion: This study demonstrates that all decontamination agents reduce antineoplastic contamination on work surfaces, but none removes it totally. Although very effective, sodium hypochlorite cannot be used routinely on stainless steel surfaces. Solutions containing anionic surfactant such as SDS, with a high efficiency/safety ratio, proved most promising in terms of surface decontaminatio

A Method for the Simultaneous Determination of Chlorogenic Acid and Sesquiterpene Lactone Content in Industrial Chicory Root Foodstuffs

A method for the simultaneous determination of free chlorogenic acids (CGA) and sesquiterpene lactones (STL) in chicory root and its dried (flour) and roasted (grain) forms is described. The method uses one extraction and one analysis for all chicory root products. Various solvents with low to high polarity, such as methanol, chloroform, or n-hexane, were tested alone, in combination in different proportions or with acidified or neutral aqueous solvent. The water/chloroform/methanol (30/30/40, v/v/v) mixture generated the best extraction yield, 21% higher than alcohol mixtures. The profiling of CGA and STL content was performed through a conventional HPLC-DAD method using a PFP core shell column in a fast single run. Good retention time and area repeatability (RDD mean % 0.46 and 5.6, resp.) and linearity (R2≥0.96) were obtained. The STL and chlorogenic acids levels determined were 254.7 and 100.2 μg/g of dry matter in the root, 792.5 and 1,547 μg/g in flour, and 160.4 and 822.5 μg/g in the roasted grains, respectively. With an average recovery of 106% and precision of 90%, this method is rapid, reproducible, and straightforward way to quantify the chlorogenic acids and STL in chicory raw material and end products

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

Nouveaux agonistes des récepteurs aux cannabinoïdes CB , dérivés de 4-oxo-quinoléines, 4-oxo-naphtyridines et 4-oxo-cinnolines

Le cancer, deuxième cause de mortalité et de morbidité dans les pays développés après les maladies cardio-vasculaires, résulte d'un dérèglement du programme génétique de la cellule conduisant à son immortalité et à une prolifération anarchique. En France en 2004, 40 000 nouveaux cas de cancer de la prostate ont été diagnostiqués. Le cancer de la prostate touche an général le sujet âgé et représente la deuxième cause de décès par cancer chez l'homme, après le cancer du poumon. Du fait du vieillissement de la population des pays développés, le nombre de patients atteints par le cancer de la prostate ne va cesser d'augmenter. Afin de palier les problèmes liés à l'utilisation des anticancéreux classiques (manque de sélectivité, résistance, échappement...), le développement de nouvelles stratégies thérapeutiques pour traiter le cancer de la prostate s'avère indispensable.Depuis 1997, plusieurs états américains ont autorisé l'utilisation du 9-THC ( 9 tétrahydrocannabinol, principe actif du cannabis) et de l'un de ses dérivés dans le contrôle des nausées et des vomissements engendrés par la chimiothérapie anticancéreuse. Actuellement plusieurs dérivés du 9-THC sont en phase III de tests cliniques pour le traitement des douleurs associées aux cancers.Depuis la caractérisation du 9-THC dans les années 60, de nombreux progrès ont été réalisés dans la compréhension de la pharmacologie des cannabinoïdes, notamment par la découverte, au début des années 90, de deux récepteurs couplés à des protéines G: le récepteur CB1, principalement localisé au niveau du système nerveux central (SNC), et le récepteur CB2, présent au niveau périphérique. L'étude de ces récepteurs, rendue possible par le développement de ligands de synthèse, a permis de mettre en évidence des effets anticancéreux (antiprolifératif, proapoptotique...) liés à leur stimulation. Cependant la stimulation du récepteur CB1 pourrait être à l'origine d'effets secondaires du fait de sa localisation dans le SNC. Il serait dès lors intéressant d'étudier le potentiel anticancéreux de ligands sélectifs du récepteur CB2. Dans le cadre de nos recherches visant à élaborer de nouveaux ligands des récepteurs aux cannabinoïdes CB2, nous avons développé une chimiothèque de 98 composés autour d'un motif central hétérocyclique de type quinoléine, naphtyridine ou encore cinnoline substitué en position 3 par une fonction carboxamide.Lors des tests pharmacologiques, ces composés se sont révélés être des agonistes sélectifs du récepteur CB2. Différentes modulations structurales ont été envisagées, comme l'introduction de substituants en position 2, 5, 6, 7 et 8, le remplacement de la fonction carboxamide par son isomère rétroamide ou par une fonction cétone. La réduction en amine secondaire, ou encore le remplacement de la chaïne latérale hydrophobe par d'autres groupements plus hydrophiles ou aromatiques ont également été envisagés.Le potentiel antiprolifératif de ces ligands sélectifs du récepteur CB2 a ensuite été évalué sur différentes lignées cellulaires issues de cancers de la prostate.Cancer, second cause of mortality nad morbidity in the developed countries, just after cardiovascular diseases, results from a deregulation of the genetic cell program leading to its immortality and its uncontroled proliferation. In France in 2004, about 40,000 new cases of prostate cancer were diagnosed. Prostate cancer reaches in general old people and represents the second cause of death per cancer, after lung cancer.Because of the ageing of the population of developed countries, the number of prostate cancer patients will increase. In order to solve problems related to the use of traditional anti-cancer drugs (lack of selectivity, resistance...), the development of new therapeutic strategies to treat prostate cancer proves to be essential. Since 1997, 9-THC ( 9 tétrahydrocannabinol, the major psychoactive component of Cannabis sativa L.) is currently used to treat nausea and emesis in cancer patient undergoing extensive chemotherapy. Moreover some cannabis-based drugs are in phase three clinical trials for treating pain associated with cancer.Since 9-THC characterization in the sixties, many improvements have been made in cannabinoid pharmacology knowledge, particularly, in the nineties with the discovery of two G-protein coupled receptors : the CB1 receptor, which is mainly located in the central nervous system (CNS), and the CB2 receptor which is principally present in the immune system. Thanks to the development of a great variety of new synthetic ligands, the study of these receptors has revealed the anticancer potency of the cannabinoid receptors agonists. CB1 receptor stimulation could induce undesirable effects due to its CNS localization, so we proposed to study the anticancer potency of CB2-selective agonists.In order to develop new potent CB2-selective ligands, a 98-compound library was built using a central heterocyclic ring as quinoleine, naphthyridine or cinnoline, substitued in position 3 by various carboxamido substituents, and hydrophobic side chains in the N1-position. Pharmacological results revealed a strong CB2 selectivity, and an agonist profile for all compounds. Thus, some chemical modulations were next realized as : replacement of the carboxamide link, in position 3, by inverse amide analogue or its reduction in secondary amine ; introduction of differentsubstituents on the position 2, 5, 6, 7 and 8 ; modulation of the N1-position side chain. Anticancer potency of these new potent CB2 receptor ligands was investigated using different prostate cancer cell lines.LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF