Efficient microwave combinatorial synthesis of novel indolic arylpiperazine derivatives as serotoninergic ligands

An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K2CO3. Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT1A, 5-HT2A and 5-HT2C receptors affinity and allowed to disclose three interesting compounds as 5-HT2C, mixed 5-HT2A/5-HT2C and 5-HT1A/5-HT2C ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profile

Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus.

A series of 4-substituted piperazine derivs. bearing a norbornene nucleus have been prepd. and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compds. showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (.alpha.1 and .alpha.2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be crit. in order to have affinity on serotonin receptors and the proper selection of substituents led to compds. with higher receptor specificity and affinity. In binding studies, several mols. showed affinity in nanomolar range towards 5-HT1A 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, .alpha.1 and .alpha.2). Compd. 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1 -yl]ethoxy]-4-aza-tricyclo[5.2. 1 .02,6]dec-8-ene-3,5- dione (Ki = 1.13 nM), was the most active and selective deriv. for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compd. 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy

Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors

Incidence and long-term functional outcome of neurologic disorders in hospitalized COVID-19 patients infected with pre-omicron variants

Background and objective: A variety of neurological disorders has been reported as presentations or complications of COVID-19 infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome. Methods: The Neuro-COVID Italy study was a multicentre, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurological disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020 to June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms or death. Results: Among 52759 hospitalized COVID patients, 1865 patients presenting 2881 new neurological disorders associated with COVID-19 infection (neuro-COVID) were recruited. Incidence of neuro-COVID cases significantly declined over time, comparing the first three pandemic waves (8.4%, 95% CI [7.9, 8.9]; 5.0%, 95% CI [4.7, 5.3]; 3.3%, 95% CI [3.0, 3.6], respectively; p = 0.027). The most frequent neurological disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%) and cognitive impairment (13.7%). The onset of neurological disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by the majority of neuro-COVID patients (64.6%) during follow-up (median 6.7 months) and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI [0.05, 0.50]; p = 0.019). Mild residual symptoms were frequently reported (28.1%), while disabling symptoms were common only in stroke survivors (47.6%). Discussion: Incidence of COVID-associated neurologic disorders decreased during the pre-vaccination phase of the pandemic. Long-term functional outcome was favourable in most neuro-COVID disorders, although mild symptoms commonly lasted over 6 months after infection