Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

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

Hypoglycaemic effect of quinolizidine alkaloids - lupanine and 2-thionosparteine on non-diabetic and streptozotocin-induced diabetic rats

The hypoglycaemic effects of two quinolizidine alkaloids: lupanine and 2-thionosparteine were examined in non-diabetic and in streptozotocin-induced diabetic rats. The model of experimental diabetes can be considered to be related to diabetes mellitus type 2 with regards to the impairment of beta-cells' secretory function. A single intraperitoneal injection of 2-thionosparteine at a dose of 8.6\ua0mg/kg lowered the blood glucose levels in diabetic rats at 90 and 120\ua0min after administration and showed similar hypoglycaemic effects to glibenclamide and sparteine, which were used as reference substances. In contrast to glibenclamide, 2-thionosparteine did not result in a significant increase in plasma insulin levels in diabetic rats; an increase was only observed in the non-diabetic group. It was found that lupanine did not exert hypoglycaemic potency in diabetic and in non-diabetic animals and did not significantly increase plasma insulin concentration independent of the group examined. From this study we can state that 2-thionosparteine, but not lupanine, is confirmed to be a possible plasma glucose lowering agent. It is possible that 2-thionosparteine-dependent decrease in blood glucose level is not the only result of this drug's related insulin secretion. © 2007 Elsevier B.V. All rights reserved

Images profiles voltages on RLC electric grid with frequency dependent

The hypoglycaemic effects of two quinolizidine alkaloids: lupanine and 2-thionosparteine were examined in non-diabetic and in streptozotocin-induced diabetic rats. The model of experimental diabetes can be considered to be related to diabetes mellitus type 2 with regards to the impairment of beta-cells' secretory function. A single intraperitoneal injection of 2-thionosparteine at a dose of 8.6 mg/kg lowered the blood glucose levels in diabetic rats at 90 and 120 min after administration and showed similar hypoglycaemic effects to glibenclamide and sparteine, which were used as reference substances. In contrast to glibenclamide, 2-thionosparteine did not result in a significant increase in plasma insulin levels in diabetic rats; an increase was only observed in the non-diabetic group. It was found that lupanine did not exert hypoglycaemic potency in diabetic and in non-diabetic animals and did not significantly increase plasma insulin concentration independent of the group examined. From this study we can state that 2-thionosparteine, but not lupanine, is confirmed to be a possible plasma glucose lowering agent. It is possible that 2-thionosparteine-dependent decrease in blood glucose level is not the only result of this drug's related insulin secretion. " 2007 Elsevier B.V. All rights reserved.",,,,,,"10.1016/j.ejphar.2007.02.032",,,"http://hdl.handle.net/20.500.12104/42020","http://www.scopus.com/inward/record.url?eid=2-s2.0-34249004601&partnerID=40&md5=7011c5f67be003bfacb0bf2c4a6a2963",,,,,,"01-mar",,"European Journal of Pharmacology",,"24

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin s

ABSTRACT Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs

Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats

The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotransmitter reuptake and behavioral effects in an assay of intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake inhibition, <i>S</i>(+)­MDPV (EC₅₀ = 2.13 nM) was more potent than either (±)­MDPV (EC₅₀ = 4.85 nM) or <i>R</i>(−)­MDPV (EC₅₀ = 382.80 nM); the three drugs were less potent at NET uptake inhibition, with the same rank order of potency. Neither racemic MDPV nor its optical isomers inhibited the reuptake of serotonin at concentrations up to 10 μM. <i>S</i>(+)­MDPV produced an abuse-related and dose-dependent facilitation of ICSS, and the potency of <i>S</i>(+)­MDPV (significant facilitation at doses ≥ 0.1 mg/kg) was greater than that of the racemate (significant facilitation at doses ≥ 0.32 mg/kg). <i>R</i>(−)­MDPV failed to alter ICSS at doses up to 100 times greater than the lowest effective dose of <i>S</i>(+)­MDPV. The results indicate that abuse-related neurochemical and behavioral effects of racemic MDPV reside primarily with its <i>S</i>(+) isomer