Metabolic syndrome among individuals with heroin use disorders on methadone therapy: Prevalence,characteristics, and related factors

ABSTRACT

Background: Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy. Methods: A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Results: One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m² (interquartile range [IQR]: 21.2–28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5–20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6–31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m² increase odds ratio [OR]: 1.49, 95% CI: 1.27–1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28–1.48) were associated with metabolic syndrome. Conclusions: Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be recommended to prevent metabolic syndrome in subjects on methadone therapy.     

Confronting Ceftolozane-Tazobactam Susceptibility in Multidrug-Resistant Enterobacterales Isolates and Whole-Genome Sequencing Results (STEP Study)

Ceftolozane-tazobactam (C/T) is frequently used for infections caused by multidrug-resistant (MDR)-Enterobacterales isolates. Whole-genome sequencing (WGS, Illumina-Hiseq 4000/NovaSeq 6000, OGC, UK) was used to study the population structure, the resistome and the virulome of C/T-susceptible and -resistant MDR Escherichia spp. (n=30) and Klebsiella spp. (n=78) isolates, recovered from lower respiratory, intra-abdominal and urinary tract infections of ICU patients from 11 Portuguese Hospitals (STEP study, 2017-2018). Minimum inhibitory concentrations (MICs) were determined (ISO-broth microdilution, breakpoints EUCAST-2020). In Escherichia spp., a weak concordance between the phenotypic and the WGS method (P=0.051) was observed in the carbapenemase detection (3/30) [bla_VIM-2 (2/3), bla_KPC-3 (1/3)]; VIM-2-Escherichia coli isolates were C/T-susceptible and only the KPC-3-Escherichia marmotae producer showed C/T-resistance. Overall, CTX-M-15-E. coli-ST131-O25:H4-H30-Rx (11/30) was the most frequent subclone, followed by CTX-M-27-E. coli-ST131-O25:H4-H30 (4/4). Moreover, a wide resistome and virulome were detected in all E. coli isolates. Among Klebsiella spp. isolates [K. pneumoniae (67/78), K. aerogenes (7/78), K. oxytoca (2/78), K. variicola (2/78)], concordance (P<0.001) was observed between the phenotypic and the genomic carbapenemase detection (21/78) [bla_KPC-3 (14/21), bla_OXA-48 (3/21), bla_OXA-181 (3/21)]. A high correlation between C/T-resistance and carbapenemase detection was established (P<0.05). Overall, a high clonal diversity was observed, mainly in KPC-3-producing K. pneumoniae isolates. An extensive resistome was detected in Klebsiella spp. isolates, whereas virulence determinants were mostly identified in carbapenemase producers (P<0.001). WGS is a powerful tool for typing characterization and microbiological study of MDR-Enterobacterales pathogens. Furthermore, carbapenemase genes are associated with C/T-resistance in Klebsiella spp., but other mechanisms might also be involved.     

1,2,4-Oxadiazole-Bearing Pyrazoles as Metabolically Stable Modulators of Store-Operated Calcium Entry

Store-operated calcium entry (SOCE) is a pivotal mechanism in calcium homeostasis, and, despite still being under investigation, its dysregulation is known to be associated with severe human disorders. SOCE modulators are therefore needed both as chemical probes and as therapeutic agents. While many small molecules have been described so far, their poor properties in terms of drug-likeness have limited their translation into the clinical practice. In this work, we describe the bioisosteric replacement of the ester moiety in pyrazole derivatives with a 1,2,4-oxadiazole ring as a means to afford a class of modulators with high metabolic stability. Moreover, among our derivatives, a compound able to increase the calcium entry was identified, further enriching the library of available SOCE activators.     

Development of an Emergency Revisit Score for Patients With Drug-Related Problems

Background: Drug-related problems (DRPs) are a frequent reason for emergency departments (EDs) visits. However, data about the risk factors associated with EDs revisits are limited. Objective: To develop and validate a predictive model indicating the risk factors associated with EDs revisit within 30 days of the first visit. Methods: A retrospective cohort study was conducted involving patients who attended an ED for DRPs related to cardiovascular drugs. A 30-day prediction model was created in a derivation cohort by logistic regression. An integer score proportional to the regression coefficient was assigned to the variables with P < .100 in the multivariate analysis. Results: 581 patients (mean age: 80.0 [12.6] years) were included, 133 (22.9%) revisited the ED within 30 days from discharge. Six factors (chronic kidney disease, chronic heart failure, visit to an ED in the preceding 3 months, high anticholinergic burden, DRPs associated with heparin, and safety-related DRPs) were identified as risk factors and combined into a final score, termed the DREAMER score. The model reached an area under the receiver operating curve values of 0.72 (95% confidence interval [CI] = 0.67-0.77) in the referral cohort and 0.71 (95% CI = 0.65-0.74) in the validation cohort (P = .273). Three risk categories were generated, with the following scores and estimated risks: low risk (0-8 points): 11.6%; intermediate risk (9-14 points): 21.3%; and high risk (>14 points): 41.2%. Conclusion and Relevance: The DREAMER score identifies patients at high risk for ED revisit within 30 days from the first visit for a DRPs, being a useful tool to prioritize interventions on discharge.     

Involvement of cholinergic receptors in the different stages of memory measured in the modified elevated plus maze test in mice

Background and MethodsSeveral lines of evidence support a strong relationship between cholinergic pathways and memory. The aim of our experiments was to examine the mechanisms involved in the formation of different memory stages, to evaluate the impact of substances, which affect the cholinergic system in mice, with an employment of the modified elevated plus maze (mEPM) test. This test allows examining different processes of memory (acquisition, consolidation and retrieval), depending on the time of drug treatment. The time period, necessary for mice to move from the opened arm to the enclosed arm (i.e., transfer latency, TL) was used as an index of memory.ResultsOur findings revealed that in both memory acquisition and consolidation, nicotine, an agonist of cholinergic receptors (0.035 and 0.175 mg/kg, free base, sc), reduced TL on the second day of the experiment (TL2), thus improving memory. In turn, scopolamine, an antagonist of cholinergic receptors (0.3 and 1.0 mg/kg, ip), significantly increased TL2 values, impairing cognition. Subsequently, we evaluated the influence of mecamylamine, a non-selective antagonist of nicotinic cholinergic receptors (nAChRs) and of varenicline, an α4β2 partial nAChRs agonist, on memory-related behaviors induced by nicotine and scopolamine. Acute injections of mecamylamine (0.5 and 1.0 mg/kg, ip) and varenicline (0.5 and 1.0 mg/kg, ip), prior to the injections of nicotine (0.035 mg/kg) or scopolamine (1.0 mg/kg), significantly suppressed nicotine-induced memory improvement or scopolamineinduced memory impairment.ConclusionOur studies indicate that the cholinergic system plays a crucial role in memory processes. Pharmacological manipulation of cholinergic transmission can be the base to develop more effective pharmacotherapies for these memory disturbances in which cholinergic receptors are involved.     

Antagonism of Sigma-1 Receptors Blocks Compulsive-Like Eating

Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder.     

Stimulatory effect of antidepressants on the production of IL-6

A body of evidence indicates that the therapeutic activity of antidepressants is connected with their modulatory effect on the inflammatory response system and cell-mediated immunity. The present study was carried out to examine the effects of antidepressant agents, such as imipramne, venlafaxine, l-5-hydroxytryptophan, fluoxetine and a combination of l-5-hydroxytryptophan and fluoxetine, on the production of the pleotrophic cytokines TNF-alpha and IL-6. Diluted whole blood from fluoxetine-treated patients with treatment-resistant depression (TRD) (mean age: 50.6+/-3.9 years), age-matched healthy controls (mean age: 51.6+/-1.7 years) and younger healthy volunteers (mean age: 35.4+/-1.7 years) was stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) for 48 h with or without incubation with the antidepressants at 10(-6) and 10(-5) M. The major findings of this study are: (1). imipramine and venlafaxine (at the higher concentration), 5-HTP (at lower and higher concentrations) and a combination of 5-HTP and fluoxetine (both at the lower concentration) increased the production of IL-6; (2). all drugs used did not affect TNF-alpha production. IL-6 production was significantly higher in depressed patients than in age-matched volunteers, whereas TNF-alpha production was significantly higher in older volunteers than in younger ones. We speculate that the therapeutic activity of these antidepressants is at least partly connected with their effect on the cytokine network and IL-6 production.     

Biochemical aspects of nitric oxide

Nitric oxide (NO), a free radical molecule, produced by NO synthase (NOS) in the body exerts a number of pathophysiological actions due to its chemical reactivity. Low amounts of NO (nM) normally produced by constitutive NOS play a critical role in different physiological events such as vasodilation and neurotransmission. Higher amounts of NO ( micro M) locally and spatially produced by inducible NOS during inflammation act as double-edged sword exerting either beneficial or detrimental effects. Recently, new vision on the biological role of NO has been proposed based on the possible cross-talk between constitutive and inducible NOS. Accordingly, normally produced low amounts of NO may be involved in the regulation of NF-kappaB activation and successively the expression of inducible NOS. Under normal conditions NF-kappaB activation is suppressed by low amounts of NO. Under conditions in which massive amounts of NO produced by inducible NOS act detrimentally, NO-elicited down-regulation of NF-kappaB activation is compromised due to the drop in NO at the early phase of inflammation caused by inactivation of constitutive NOS. Any treatment which counterparts the drop in NO, therefore, may present a new approach either in preventing or in treating inflammatory diseases.