4-[4-(Piperidin-1-yl)piperidin-1-yl]benzonitrile

In the title compound, C17H23N3, both piperidine rings adopt chair conformations. In the crystal packing, intermolecular C—H⋯N hydrogen bonds and C—H⋯π interactions are present

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognised in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine. Since this pathway – the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress it also stands in an unique position to mediate the effects of environmental factors on cognition and behaviour. Targetting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures

(E)-3-[(Dimethylamino)methylidene]-4-phenyl-1-(prop-2-ynyl)-1H-1,5-benzodiazepin-2(3H)-one

A new metal-organic framework compound, poly[[mu(7)-dihydrogen (4,5-dicyano1,2-phenylene) diphosphonato](oxonium) caesium], [Cs(C8H4N2O6P2)(H3O)](n) (I), based on Cs+ and the organic linker 4,5-dicyano-1,2-phenylene) bis(phosphonic acid, (H(4)cpp), containing two distinct coordinating functional groups, has been prepared by a simple diffusion method and its crystal structure is reported. The coordination polymeric structure is based on a CsO8N2 complex unit comprising a monodentate hydronium cation, seven O-atom donors from two phosphonium groups of the (H(2)cpp)(2-) ligand, and two N-atom donors from bridging cyano groups. The high level of connectivity from both the metal cation and the organic linker allow the formation of a compact and dense three-dimensional network without any crystallization solvent. Topologically (I) is a seven-connected uninodal network with an overall Schafli symbol of {4(17).6(4)}. Metal cations form an undulating inorganic layer, which is linked by strong and highly directional O-H center dot center dot center dot O hydrogen-bonding interactions. These metallic layers are, in turn, connected by the organic ligands along the [010] direction to form the overall three-dimensional framework structure

A perspective on multi-target drug discovery and design for complex diseases

Diseases of infection, of neurodegeneration (such as Alzheimer's and Parkinson's diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and post-translational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7

Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the α-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide

The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7–(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7–(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7–(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats

La presa di decisione nell'utilizzo del sistema di assorbenza. indagine presso l''unità operativa di medicina dell'azienda ulss 18 di rovigo.

Background Il sistema di assorbenza è un dispositivo che permette di contenere e assorbire le urine prevenendo la perdita sugli indumenti e nel letto, solitamente utilizzato in soggetti istituzionalizzati o ricoverati con incontinenza urinaria (IU). Questo presidio viene applicato anche a pazienti degenti che al momento dell’ingresso presentano un normale modello di eliminazione urinaria. Indagare le motivazioni in base alle quali l’infermiere decide di applicare o meno un pannolone e quali sono gli aspetti che l’infermiere considera per prendere tale decisione sono essenziali per la pratica clinica. Scopo dello studio Lo scopo dello studio è quello di indagare la presa di decisione dell’infermiere nel posizionare il sistema di assorbenza ad un paziente, sia esso continente o incontinente, ricoverato presso l’Unità Operativa di Medicina del Presidio Ospedaliero di Rovigo. Materiali e metodi Lo studio è stato condotto presso l’Unità Operativa di Medicina del Presidio Ospedaliero di Rovigo dal 15 luglio 2015 al 1 settembre 2015. Il campione è rappresentato da tutti i nuovi pazienti ricoverati presso l’Unità Operativa di Medicina in un determinato periodo di tempo (30 giorni) e dal personale infermieristico della medesima realtà operativa. La raccolta dati si è sviluppata in due momenti: in una prima fase è stata effettuata su tutti i nuovi pazienti ricoverati presso l’Unità Operativa di Medicina nell’arco di 30 giorni consultando fonti secondarie. Il secondo momento ha previsto la somministrazione di un questionario a domande predefinite si/no agli infermieri dell’Unità Operativa di Medicina che indagava aspetti infermieristici quali: l’accertamento del modello di eliminazione urinaria, la decisione dell’infermiere di posizionare o meno il pannolone al campione di pazienti individuato nell’arco dei 30 giorni, la collaborazione e la comunicazione con la figura dell’operatore socio - sanitario. Risultati Nell’arco di 30 giorni sono stati ricoverati 87 nuovi pazienti presso l’Unità Operativa di Medicina del Presidio Ospedaliero di Rovigo. Durante il ricovero il sistema di assorbenza è stato applicato a 43 pazienti incontinenti e a 21 pazienti che al momento del ricovero risultavano continenti. Le più frequenti motivazioni che hanno influito sulla decisione dell’infermiere di applicare il pannolone sono state: un’incontinenza determinata da un disorientamento spazio – temporale e da problemi esistenti (es. ictus, patologie degenerative), la presenza di perdita involontaria di urina non percepita dal paziente (IU), un’incontinenza fecale, la presenza di altri problemi (es. diarrea). Conclusioni L’uso del sistema di assorbenza non si limita al paziente con incontinenza urinaria, ma anche a pazienti che al momento del ricovero sono continenti. La decisione dell’infermiere di applicare il pannolone si dovrebbe basare su un accertamento iniziale completo del paziente che permetta di escludere altri interventi volti a gestire l’eliminazione urinaria (interventi di promozione alla continenza o contenitivi: posizionamento di un catetere vescicale, uso della padella, del pappagallo, della comoda o dell’uro – condom). L’uso discontinuo del sistema di assorbenza dovrebbe essere garantito tramite valutazioni intermedie del paziente, effettuate da un’equipe multidisciplinare durante il ricovero, per evitare l’insorgenza di complicanze che il sistema di assorbenza può determinare nel paziente