Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro.

Nitric oxide (NO) has been shown to have antimicrobial activity in vitro and in some in vivo models, while the virucidal activity of NO remains elusive. Some studies using NO donors have suggested that NO could be a potential candidate to treat SARS-CoV infection. The Covid-19 pandemic raised the hypothesis that NO gas might have an impact on Sars-CoV-2 replication cycle and might be considered as a candidate therapy to treat COVID-19. To our knowledge, there are no in vitro preclinical studies demonstrating a virucidal effect of gaseous NO on SARS-CoV-2. This study aims to determine whether gaseous NO has an impact on the replication cycle of SARS-CoV-2 in vitro. To that end, SARS-CoV-2 infected epithelial (VeroE6) and pulmonary (A549-hACE2) cells were treated with repeated doses of gaseous NO at different concentrations known to be efficient against bacteria. Our results show that exposing SARS-CoV-2 infected-cells to NO gas even at high doses (160 ppm, 6 h) does not influence the replication cycle of the virus in vitro. We report here that NO gas has no antiviral properties in vitro on SARS-COV-2. Therefore, there is no rationale for its usage in clinical settings to treat COVID-19 patients for direct antiviral purposes, which does not exclude other potential physiological benefits of this gas.

Healthcare costs of a telemonitoring programme for heart failure: indirect deterministic data linkage analysis.

AIMS: We aim to evaluate the costs associated with healthcare resource consumption for chronic heart failure (HF) management in patients allocated to telemonitoring versus standard of care (SC). METHODS AND RESULTS: OSICAT-ECO involved 745 patients from the OSICAT trial (NCT02068118) who were successfully linked to the French national healthcare database through an indirect deterministic data linkage approach. OSICAT compared a telemonitoring programme with SC follow-up in adults hospitalized for acute HF ≤ 12 months. Healthcare resource costs included those related to hospital and ambulatory expenditure for HF and were restricted to direct costs determined from the French health data system over 18 months of follow-up. Most of the total costs (69.4%) were due to hospitalization for HF decompensation, followed by ambulatory nursing fees (11.8%). During 18-month follow-up, total costs were 2% lower in the telemonitoring versus the SC group, due primarily to a 21% reduction in nurse fees. Among patients with NYHA class III/IV, a 15% reduction in total costs (€3131 decrease) was observed over 18-month follow-up in the telemonitoring versus the SC group, with the highest difference in hospital expenditure during the first 6 months, followed by a shift in costs from hospital to ambulatory at 12 months. CONCLUSIONS: HF hospitalization and ambulatory nursing fees represented most of the costs related to HF. No benefit was observed for telemonitoring versus SC with regard to cost reductions over 18 months. Patients with severe HF showed a non-significant 15% reduction in costs, largely related to hospitalization for HF decompensation, nurse fees, and medical transport.

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses.

ABSTRACT: Experimental studies have suggested that nitrous oxide-induced analgesia depends on interactions with opioids. On the basis of these results, we hypothesized that the effects of inhaled nitrous oxide/oxygen (N 2 O/O 2 ) 50%-50% equimolar mixture (EMONO) on patients with neuropathic pain would be higher in those receiving concomitant opioids. To test this hypothesis, we did exploratory post hoc analyses of our recently published ProtoTOP study to compare the effects of EMONO and placebo in patients with or without concomitant opioid treatment. A total of 92 patients of the 221 (ie, 41.6%) included in the ProtoTOP study were concomitantly treated with opioids. In contrast with our previous analyses, average pain intensity was significantly decreased in comparison with placebo one week after the last treatment administration in patients treated with opioids, but not in those treated without opioid, and this effect was maintained over the 4-week follow-up period. Neuropathic pain symptom inventory (NPSI total and subscores) was also significantly more decreased after inhalation of EMONO in comparison with placebo only in patients receiving opioids. The proportion of patients with at least 30% pain reduction and of those reporting an overall improvement with the Patient Global Impression of Change were significantly higher only in this population of patients. In conclusion, these results complement our previous analyses with the identification of a specific population of responders to EMONO inhalation in patients with neuropathic pain. As suggested by experimental studies, we hypothesized that these long-lasting analgesic effects could depend on the anti-N-methyl-D-aspartate properties of N 2 O.

Evaluation of antihyperalgesic and analgesic effects of 35% nitrous oxide when combined with remifentanil: A randomised phase 1 trial in volunteers.

BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ±â€Š9.25 and 24.4 ±â€Š7.3 cm2, respectively) compared with remifentanil (51.0 ±â€Š17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION: EudraCT-No.: 2011-000966-37.

Safety and efficacy of an equimolar mixture of oxygen and nitrous oxide: a randomized controlled trial in patients with peripheral neuropathic pain.

ABSTRACT: Nitrous oxide (N2O) is an odorless and colorless gas routinely used as an adjuvant of anesthesia and for short-duration analgesia in various clinical settings mostly in the form of an N2O/O2 50%-50% equimolar mixture (EMONO). Experimental studies have suggested that EMONO could also induce long-lasting analgesic effects related to the blockade of N-methyl-D-aspartate receptors. We designed the first international multicenter proof of concept randomized, placebo-controlled study to assess the efficacy and safety of a 1-hour administration of EMONO or placebo (medical air) on 3 consecutive days up to 1 month after the last administration in patients with chronic peripheral neuropathic pain. A total of 240 patients were recruited in 22 centers in France and Germany and randomly assigned to 1 study group (120 per group). Average pain intensity (primary outcome), neuropathic pain characteristics (Neuropathic Pain Symptom Inventory), Patient Global Impression of Change, anxiety, depression, and quality of life were systematically assessed before and after treatment. The changes in average pain intensity between baseline and 7 days after the last administration were not significantly different between the 2 groups. However, evoked pain intensity (predefined secondary endpoint) and Patient Global Impression of Change (exploratory endpoint) were significantly improved in the EMONO group, and these effects were maintained up to 4 weeks after the last treatment administration. Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further investigation of the long-term analgesic effects of EMONO in patients with neuropathic pain.

Telemonitoring versus standard care in heart failure: a randomised multicentre trial.

AIMS: The aim was to assess the effect of a telemonitoring programme vs. standard care (SC) in preventing all-cause deaths or unplanned hospitalisations in heart failure (HF) at 18 months. METHODS AND RESULTS: OSICAT was a randomised, multicentre, open-label French study in 937 patients hospitalised for acute HF ≤12 months before inclusion. Patients were randomised to telemonitoring (daily body weight measurement, daily recording of HF symptoms, and personalised education) (n = 482) or to SC (n = 455). Mean ± standard deviation number of events for the primary outcome was 1.30 ± 1.85 for telemonitoring and 1.46 ± 1.98 for SC [rate ratio 0.97, 95% confidence interval (CI) 0.77-1.23; P = 0.80]. In New York Heart Association (NYHA) class III or IV HF, median time to all-cause death or first unplanned hospitalisation was 82 days in the telemonitoring group and 67 days in the SC group (P = 0.03). After adjustment for known predictive factors, telemonitoring was associated with a 21% relative risk reduction in first unplanned hospitalisation for HF [hazard ratio (HR) 0.79, 95% CI 0.62-0.99; P = 0.044); the relative risk reduction was 29% in patients with NYHA class III or IV HF (HR 0.71, 95% CI 0.53-0.95; P = 0.02), 38% in socially isolated patients (HR 0.62, 95% CI 0.39-0.98; P = 0.043), and 37% in patients who were ≥70% adherent to body weight measurement (HR 0.63, 95% CI 0.45-0.88; P = 0.006). CONCLUSION: Telemonitoring did not result in a significantly lower rate of all-cause deaths or unplanned hospitalisations in HF patients. The pre-specified subgroup results suggest the telemonitoring approach improves clinical outcomes in selected populations but need further confirmation.

Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases.

Using midbrain cultures, we previously demonstrated that the noble gas xenon is robustly protective for dopamine (DA) neurons exposed to L-trans-pyrrolidine-2,4-dicarboxylate (PDC), an inhibitor of glutamate uptake used to generate sustained, low-level excitotoxic insults. DA cell rescue was observed in conditions where the control atmosphere for cell culture was substituted with a gas mix, comprising the same amount of oxygen (20%) and carbon dioxide (5%) but 75% of xenon instead of nitrogen. In the present study, we first aimed to determine whether DA cell rescue against PDC remains detectable when concentrations of xenon are progressively reduced in the cell culture atmosphere. Besides, we also sought to compare the effect of xenon to that of other noble gases, including helium, neon and krypton. Our results show that the protective effect of xenon for DA neurons was concentration-dependent with an IC50 estimated at about 44%. We also established that none of the other noble gases tested in this study protected DA neurons from PDC-mediated insults. Xenon's effectiveness was most probably due to its unique capacity to block NMDA glutamate receptors. Besides, mathematical modeling of gas diffusion in the culture medium revealed that the concentration reached by xenon at the cell layer level is the highest of all noble gases when neurodegeneration is underway. Altogether, our data suggest that xenon may be of potential therapeutic value in Parkinson disease, a chronic neurodegenerative condition where DA neurons appear vulnerable to slow excitotoxicity.