The ongoing pandemic of COVID-19 has forced governments to impose a lockdown, and many people have suddenly found themselves having to reduce their social relations drastically. Given the exceptional nature of similar situations, only a few studies have investigated the negative psychological effects of forced social isolation and how they can be mitigated in a real context. In the present study, we investigated whether the amount of digital communication technology use for virtual meetings (i.e., voice and video calls, online board games and multiplayer video games, or watching movies in party mode) during the lockdown promoted the perception of social support, which in itself mitigated the psychological effects of the lockdown in Italy. Data were collected in March 2020 (N = 465), during the lockdown imposed to reduce the COVID-19 spread. The results indicated that the amount of digital technology use reduced feelings of loneliness, anger/irritability, and boredom and increased belongingness via the perception of social support. The present study supported the positive role of digital technologies in maintaining meaningful social relationships even during an extreme situation such as a lockdown. Implications such as the need to reduce the digital divide and possible consequences of the ongoing pandemic are discussed.

A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki>100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.

Experimental evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy derivative 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compound, evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.

Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with 111In and 68Ga, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC50 values for natIn-NOTA-DUPA-RM26 were 4 ± 1 nM towards GRPR and 824 ± 230 nM towards PSMA. An in vivo binding specificity 1 h pi of 111In-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of 111In-NOTA-DUPA-RM26 and 68Ga-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 ± 2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12 ± 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for 111In-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that 68Ga-NOTA-DUPA-RM26 and 111In-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration.

Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present phase I, open-label, two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH), acid (BRV-AC), and hydroxy acid (BRV-OHAC) metabolites. Twenty-six healthy subjects received BRV (150-mg single oral dose) either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (C max ) of BRV, but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (253%), but had little effect on BRV-OHAC (210%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all of the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant).

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Tuberculosis (TB) is a slow growing, potentially debilitating disease that has plagued humanity for centuries and has claimed numerous lives across the globe. Concerted efforts by researchers have culminated in the development of various strategies to combat this malady. This review aims to raise awareness of the rapidly increasing incidences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, highlighting the significant modifications that were introduced in the TB treatment regimen over the past decade. A description of the role of pathogen–host immune mechanisms together with strategies for prevention of the disease is discussed. The struggle to develop novel drug therapies has continued in an effort to reduce the treatment duration, improve patient compliance and outcomes, and circumvent TB resistance mechanisms. Herein, we give an overview of the extensive medicinal chemistry efforts made during the past decade toward the discovery of new chemotypes, which are potentially active against TB-resistant strains.

ABSTRACT:Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-␤-glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two-period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately ؊40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (K i 12 M) while having a marginal effect on BRV-OH formation (K i >153 M). Gemfibrozil-1-O-␤-glucuronide had no relevant effect on either reaction (K i >200 M). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9.