ObjectivesThe outbreak of COVID-19 posed the issue of urgently identifying treatment strategies. Colchicine was considered for this purpose based on well-recognised anti-inflammatory effects and potential antiviral properties. In the present study, colchicine was proposed to patients with COVID-19, and its effects compared with ‘standard-of-care’ (SoC).MethodsIn the public hospital of Esine, northern Italy, 140 consecutive inpatients, with virologically and radiographically confirmed COVID-19 admitted in the period 5–19 March 2020, were treated with ‘SoC’ (hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir). They were compared with 122 consecutive inpatients, admitted between 19 March and 5 April 2020, treated with colchicine (1 mg/day) and SoC (antiviral drugs were stopped before colchicine, due to potential interaction).ResultsPatients treated with colchicine had a better survival rate as compared with SoC at 21 days of follow-up (84.2% (SE=3.3%) vs 63.6% (SE=4.1%), p=0.001). Cox proportional hazards regression survival analysis showed that a lower risk of death was independently associated with colchicine treatment (HR=0.151 (95% CI 0.062 to 0.368), p<0.0001), whereas older age, worse PaO2/FiO2, and higher serum levels of ferritin at entry were associated with a higher risk.ConclusionThis proof-of-concept study may support the rationale of use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.

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BACKGROUND AND PURPOSEIntrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and m opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ m opioid receptor agonist. EXPERIMENTAL APPROACHThe following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [ ]N/OFQ(1-13)-NH2 was able to elicit robust and long-lasting antinociceptive effects. CONCLUSIONS AND IMPLICATIONSCollectively, these results demonstrate that [Dmt 1 ]N/OFQ(1-13)-NH2 behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics. AbbreviationsN/OFQ, nociceptin/orphanin FQ; NOP receptor, N/OFQ peptide receptor

BACKGROUND AND PURPOSENociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists have been proposed as a novel therapeutic approach to Parkinson's disease. Main limitations of previous studies were the use of structurally similar compounds and the evaluation of their acute effects only. We report here on the acute and long-term antiparkinsonian effects of the novel compound 2-[3-[4-(2-chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl]-2-(morpholine-4-carbonyl)-indol-1-yl]-acetamide (NiK-21273) in comparison with the potent and selective NOP receptor antagonist SB-612111. EXPERIMENTAL APPROACHBasic pharmacological properties of NiK-21273 were studied in cell lines and isolated tissues (mouse and rat vas deferens). Antiparkinsonian effects were studied in reserpinized mice and 6-hydroxydopamine hemilesioned rats under both acute and chronic administration protocols. KEY RESULTSIn vitro, NiK-21273 behaved as a potent (pA2 7.7) and selective NOP receptor antagonist. In vivo, it reduced hypokinesia in reserpinized mice at 0.1 and 1 but not 10 mg·kg ) provided a dose-dependent antiparkinsonian effect. NiK-21273 ameliorated motor performance in 6-hydroxydopamine hemilesioned rats at 0.5 and 5 but not 15 mg·kg . SB-612111 replicated these effects in the 0.01-1 mg·kg -1 range without loss of efficacy. Both antagonists synergized with L-DOPA at subthreshold doses. Chronic administration of NiK-21273 provided delayed improvement in baseline activity at 0.5 and 1.5 mg·kg , although tolerance to the higher dose was observed. Conversely, SB-612111 (1 mg·kg -1 ) maintained its effects over time without modifying baseline activity. CONCLUSIONS AND IMPLICATIONSNOP receptor antagonists provide motor benefit in parkinsonism models although the 'therapeutic' window and long-term effects may vary between compounds.