Cyclic AMP enhancing drugs modulate eicosanoid release from human alveolar macrophages

The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control-respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55–93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 106 cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3–4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions

Identification of β2-adrenoceptors on guinea pig alveolar macrophages using (-)-3-[125I]iodocyanopindolol

The β-adrenoceptor antagonist (-)-3-[125I]iodocyanopindolol ([125I]ICYP) binds with high affinity and in a saturable way to membranes of guinea pig alveolar macrophages. The equilibrium dissociation constant for [125I]ICYP is 24.3 ± 1.2 pM, and the number of binding sites is 166.3 ± 13.7 fmol/mg protein (N=4, ±SEM). Displacement studies with selective antagonists showed that [125I]ICYP labels β2-adrenoceptors on guinea pig alveolar macrophages

Stimulation of cyclic AMP production in human alveolar macrophages induced by inflammatory mediators and β-sympathicomimetics

Abstract We have investigated the effects of inflammatory mediators and β-adrenoceptor agonists on the adenylyl cyclase responsiveness in alveolar macrophages from control subjects, patients suffering from chronic obstructive pulmonary disease (COPD) and asthmatics. Basal cyclic AMP (cAMP) levels in alveolar macrophages from COPD patients were significantly elevated (plus 42%) as compared to controls. In addition, the adenylyl cyclase responsiveness to prostaglandin E2, histamine and the β-adrenoceptor agonist salbutamol was significantly impaired in alveolar macrophages from COPD patients and asthmatics. The lipid mediator platelet activating factor showed no effect on cAMP production in all three alveolar macrophage populations. Furthermore, the cAMP-enhancing effects of isoprenaline, salbutamol and histamine appeared to be mediated via β2-adrenoceptors and histamine H2-receptor subtypes respectively. Taken together, these data suggest an intrinsic desensitization phenomenon in alveolar macrophages from COPD patients and asthmatics

Risk Factors of γ-Hydroxybutyrate Overdosing

The aim of this study was to identify in recreational drug users the factors which increase the risk of overdosing (OD) with γ-hydroxybutyrate (GHB). A purposive sample of 45 experienced GHB users was interviewed, equally divided into three groups (never OD, occasional OD, and repeat OD). The repeat OD group scored highest on many risk factors regarding GHB use, the occasional OD group scored intermediate, and the never OD group scored lowest. Participants, whether or not they had overdosed on GHB, most often perceived GHB use (e.g. using more GHB than usual, using GHB doses too closely together) as the main reason for GHB OD, and many participants who had overdosed on GHB reported that they had taken more GHB than usual at their most recent occasion of GHB OD. No significant differences in co-use of GHB with other substances were found between the three groups. Our findings indicate that using GHB in the company of groups of friends probably reduces, but does not eliminate, the risk of OD

Is Europe facing an opioid crisis like the United States? An analysis of opioid use and related adverse effects in 19 European countries between 2010 and 2018

Background: Given the ongoing opioid crisis in the United States (US), we investigated the opioid situation in Europe. The aims of the study are to provide an overview of trends in prescription opioid (PO) use and opioid-related adversities between 2010 and 2018 for different opioids in 19 European countries and to present a comparison with similar data from the US. Methods: A multisource database study with national data from 19 European countries evaluating trends between 2010 and 2018 in (a) PO consumption, (b) high-risk (HR) opioid users, (c) opioid-related hospital admissions, (d) opioid-related overdose deaths, (e) opioid use disorder treatment entries, and (f) patients in opioid substitution therapy (OST). Within and between-country comparisons and comparisons with data from the US were made. Results: There was considerable variation between European countries. Most countries showed increased PO consumption with the largest increase and the highest consumption in the United Kingdom (UK) compared to the rest of Europe and the US in 2018 (UK: 58,088 defined daily doses for statistical purposes/1000 population/day). In 2018, Scotland had the highest rates (per 100,000 population) of HR opioid users (16·2), opioid-related hospital admissions (118), opioid-related deaths (22·7), opioid use disorder treatment admissions (190), and OST patients (555) of all included European countries. These rates were similar or even higher than those in the US in 2018. Other countries with high rates of opioid-related adversities were Northern Ireland (synthetic and "other" opioids), Ireland (heroin and methadone), and England (all opioids). All other countries had no or little increase in opioid-related adversities. Conclusions: Apart from the British Isles and especially Scotland, there is no indication of an opioid crisis comparable to that in the US in the 19 European countries that were part of this study. More research is needed to identify drivers and develop interventions to stop the emerging opioid crisis in the UK and Ireland