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The search for novel drug delivery systems (DDSs) able to improve the performance of old-generation antibiotics is a topic of great interest due to overcoming problems associated with antibiotic resistance [1]. Polycationic calixarene derivatives able to self-assemble in nanoaggregates are promising novel nanocontainers for delivering antibiotics to bacteria due to their ability to establish electrostatic interactions with the negatively charged bacterial membranes [2]. In particular, a polycationic amphiphilic calix[4]arene, bearing choline groups and dodecyl aliphatic chains at the cavity upper and lower rim respectively, proved to be a promising nanocarrier for drug delivery [3]. The determination of the strength and nature of drug-micelle interactions is crucial for the design of novel medicines and the modification or selection of suitable shuttles for target-oriented drug delivery. However, despite the wide interest in the examination of these interactions, a quantitative analysis of the species, binding constants and thermodynamic parameters for the recognition/inclusion of a drug with(in) micellar assemblies has rarely been addressed. The present work deals with the study of the binding features of polycationic calix[4]arene derivatives (CholineC4dod, MedeaC4dod and MedeaC4prop) with ofloxacin, chloramphenicol or tetracycline in neutral aqueous solution for investigating the capability of micellar aggregates to recognize and host three old generation antibiotics. These molecules were selected as models of antibiotics affected by the onset of resistance phenomena with the aim of contributing to the design and development of effective DDSs for the repurposing of old-fashioned drugs. The study of the solution equilibria and the determination of the binding parameters in neutral aqueous solution were carried out using nano-isothermal titration calorimetry, that allows obtaining both stability constant and enthalpy change values for host-guest complex formation [4] and/or selforganization of surfactants into micelles by a single experiment [5,6]. ITC measurements showed that the formation of the chloramphenicol-micelle adduct is always an enthalpically driven process while the adducts with ofloxacin and tetracycline are always entropically driven and enthalpically unfavored. NMR experiments confirmed the picture on the positioning of the antibiotics within the micellar backbone provided by the ITC data [7]. [1] R. K. Kobayashi, G. Nakazato, Front. Microbiol. 2020, 11, 1421. [2] I. Di Bari, R. Picciotto, G. Granata, A. R. Blanco, G. M. L. Consoli, S. Sortino, Org. Biomol. Chem. 2016, 14(34), 8047. [3] G. Granata, S. Petralia, G. Forte, S. Conoci, G. M. L. Consoli, Mater. Sci. Eng. C 2020, 111, 110842. [4] C. Bonaccorso, R. Migliore, M. A. Volkova, G. Arena, C. Sgarlata, Thermochim. Acta 2017, 656, 47. [5] W. Loh, C. Brinatti, K. C. Tam, Biochim. Biophys. Acta 2016, 1860(5), 999. [6] R. Migliore, PhD Thesis, University of Catania, 2019. [7] R. Migliore, G. Granata, A. Rivoli, G. M. L. Consoli, C. Sgarlata, Front. Chem. 2021, 8, 626467.

In the search of innovative agents able to combat the antibiotic resistance phenomenon which is a serious threat for public health in the world, nitric oxide (NO) and singlet oxygen (1O2) radicals are very interesting "non-conventional" drugs. They elicit a significant broad spectrum toxicity against virus, bacteria, fungi, yeast, and protozoa by oxidation of cell components as proteins, lipids, and DNA. A growing interest there is for new compounds generating NO and 1O2 in a controlled fashion due to the high cytotoxicity, short half-life and diffusion in the cellular environment over short distances of these radicals. Light is a biofriendly stimulus that offers advantages in terms of precise spatiotemporal control and powerful trigger, it is does not affect physiological parameters such as temperature, pH, and ionic strength. Therefore, among the variety of NO and 1O2 generators, photochemical compounds are particularly appealing to confine the cytotoxic action in the area of interest sparing healthy cells. In this contribute, we exploited the calix[4]arene macrocycle to realize new nanoconstructs for photodisinfection and antibacterial phototherapy by using both a covalent and non-covalent approach. In the first case, multiple units of a NO photodonor have been clustered and spatially organized onto a polycationic calix[4]arene scaffold; in the second case multiple units of insoluble or scarcely water soluble NO and 1O2 photodonors have been entrapped into a polycationic calix[4]arene spontaneously self-assembling in micellar nanoaggregates. The calixarene-based nanoconstructs as nanocontainers and nanocarriers enhanced solubility and local concentration of the photodonors and as a nanoreactor increased the release of NO under the exclusive control of visible light inputs. The light-stimulated bactericidal effect was successfully tested on Gram positive and Gram negative bacteria.

Self-assembled structures built from amphiphilic molecules find application in different fields. a The synthetic versatility of calixarene macrocycles, whose skeleton can be differently functionalized with a variety of hydrophilic and hydrophobic moieties, allows the development of amphiphilic derivatives able to aggregate in different higher order supramolecular architectures. b, c Here we describe the capability of an amphiphilic calix[4]arene derivative, bearing four carboxylic acid groups at the calixarene upper rim and four dodecyl chains at the lower rim, to form discrete and stable multilamellar vesicles in aqueous medium by using an emulsion/solvent evaporation method. Dynamic Light Scattering (DLS) measurements, Field Emission Scanning Electron Microscopy (FE-SEM) and Transmission Electron Microscopy (TEM) images provided information about size, size distribution and morphology of the nanostructured assemblies. The vesicular nature was confirmed by entrapment of a hydrophilic dye such as rodhamine B in aqueous lumen. A preliminary study showed that the self-assembled structures of the carboxy-calix[4]arene can entrap also a hydrophobic drug such as curcumin. The amphiphilic carboxy-calix[4]arene represents the first example of calix[4]arene derivative assembling in very stable multilamellar vesicles in aqueous medium with a narrow polydispersity. Suitable nanometer-size, very size narrow distribution, well-defined spherical shape, negatively charged hydrophilic multilamellar wall, high size stability (more than two years), and guest encapsulation ability make the vesicles of the carboxy-calix[4]arene derivative appealing in the research of drug delivery systems. Acknowledgment: Research funded by PON R&C 02_00355_2964193 (MIUR, Rome). References: a) Hill, J. P.; Shrestha, L. K.; Ishihara, S.; Ji, Q.; Ariga, K. Molecules 2014, 19, 8589-8609. b) Helttunen, K.; Shahgaldian, P. New J. Chem. 2010, 34, 2704-2714. c) Consoli, G. M. L.; Granata, G.; Lo Nigro, R.; Malandrino, G.; Geraci, C. Langmuir 2008, 24, 6194-6200.

We aimed at investigating the impact of lifetime manic spectrum symptoms on the severity of pain and the health-related quality of life (HRQoL) in patients with fibromyalgia (FM).One hundred and sixty-seven patients with FM, assessed according to the ACR criteria, were consecutively enrolled. Psychiatric diagnoses were carried out following the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV-TR). The severity of pain and the HRQoL of FM patients was measured by means of the Fibromyalgia Impact Questionnaire (FIQ) and the Medical Outcomes Study Short Form-36 Health Survey (MOS SF-36); the mood spectrum symptomatology by means of the Mood Spectrum-Self Report (MOODS-SR).A high rate of lifetime manic symptoms was detected and resulted as related to the Pain Visual Analogic Scale ("pain VAS") of the FIQ and the FIQ total scores as well as to the "bodily pain", and to the physical and mental component summary scores of the MOS SF-36, both in the whole sample (n=167) and in FM patients without bipolar disorder (n=160).Our results highlight the need to pay more attention to manic spectrum symptoms and features in FM patients, because of their relationship with the severity of pain and with a worse HRQoL.

Introduction: The rabbit syndrome (RS) is a rare movement disorder generally associated with prolonged use of antipsychotics and characterized by inwilling, rhythmic, fast and fine movements of oral and masticatory muscles along the vertical axis of the mouth. Prevalence: The prevalence of RS ranges between 1.5% and 4.4%; middle and elderly ages, the female gender, aswell as past brain injuries are considered risk factors for its development. Pathophysiology: Although a dysbalance of the cholinergic and dopaminergic neurotransmission in the basal ganglia seems to be involved in the pathophysiology of RS, its precise mechanisms need to be clarified as yet. Relationships with antipsychotics: Fifty cases of RS have been published up-to-now: 34 and 10 occurred during treatments with typical and atypical antipsychotics, respectively, while 6 seemed unrelated to these drugs. Differential diagnosis: The differential diagnosis between RS and tardive dyskinesias involving the mouth may be based mainly on the evidence that in these last conditions the movements of the mouth are less regular and slower and involve the tongue. Treatment strategy: The available data suggest that RS responds favourably to anticholinergic drugs and to the change of the antipsychotic.

Reaction of p-tert-butylcalix[8]arene 1 with adipoyl chloride in the presence of NaH as the base yielded singly and doubly intrabridged esters 2-4 and 6. Surprisingly, calix[8]arene monospirodienone derivative 7 was also isolated, which was originated by O2 oxidation. The conditions of this oxidation were optimized leading to a novel synthetic approach to calixarene monospirodienones based on the O2/NaH/acyl-chloride oxidizing system. Xantheno calix[8]arenes 8-8a were obtained by rearrangement of 7.

The first example of two discrete calix[8]arene conformational isomers, has been obtained by exhaustive benzylation of 1,5-tetramethylene-bridged calix[8]arene. It is demonstrated, with the aid of X-ray cristallography, that these atropisomers have two 3/4-cone halves oriented syn or anti with respect to the bridge/bridgeheads moiety. VT NMR studies indicate that the tert-butyl-through-the-annulus inversion is inhibited, while groups larger than n-hexyl or benzyl are required for curtailing the O-through-the- annulus route.

The structure of the 1:3 complex between 5,5'-biscalix[4]arene- hexabenzoate and toluene has been determined by a single crystal X-ray diffraction study. The two calix[4]arene subunits of the 5,5'-biscalix[4] arene system are related by an inversion center and are joined by an eclipsed biphenyl para-para linkage. Each calix[4]arene moiety dispalys a 1,3-alternate conformation and includes a toluene molecule within two opposite benzoate groups, while a third toluene molecule lies close to a crystallographic inversion center.

The family connection of diabetes was examined from the clinical records of 3,372 subjects who were seen, as an out patient population, within the frame of a Regional Health Program in Taranto, South Italy. The family connection of diabetes resulted from a questionnaire in which the subjects had to give informations about their disease, if present, and degrees of relationship that were directly verified by us with the examination (clinic and laboratory) of relatives said to have diabetes. From the analysis of records, it emerged that 112 patients were affected by insulin-dependent-diabetes mellitus (IDDM): 54 of them were related with at least one subject suffering from noninsulin-dependent diabetes mellitus (NIDDM), 13 with at least one subject affected by IDDM and the remaining 45 did not show any family connection. The corresponding figures found in a group of healthy control subjects, matched to IDDM patients for age, sex and BMI, were 19, 2 and 84, respectively (p less than 0.001). 34 IDDM patients were related with a first degree of relationship (parents, sons, sibs) to diabetic subjects (IDDM or NIDDM), but only 4 controls showed such a degree (p less than 0.001). These results seem to indicate that patients with IDDM have an increased family history of NIDDM.

8 cases of Hodgkin's disease, 1 case of chronic myeloid leukemia and 1 case of reticulosarcoma have been treated with sarcochlorine (DL-para-bis (β-chloroethyl) aminophenylalanine). A marked cytostatic action of the compound, effectively influencing the general conditions, the febrile course and the zonal manifestations of the disease, was observed in all patients. Two negative aspects were demonstrated, i.e. a marked leukopenic influence of the cytostatic substance and a short duration of the clinical remissions.

The effect of rapid daily variation of glycemia and labile HbA1 on both antithrombin III (ATIII) activity and plasma concentration in ten insulin dependent diabetics has been evaluated. The variations of both plasma glucose and labile HbA1 were inversely correlated to the alterations of ATIII activity (r = -0.71 and r = -0.73, respectively, p less than 0.001), while no change in ATIII plasma concentration was present. These data suggest a direct role of glucose in determining rapid alteration of ATIII biologic activity, in vivo, in diabetes, probably mediated by labile non-enzymatic glycation.