Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group

Introduction: A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. Methods: The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. Results: This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. Conclusion: These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer

Potential of aryl-urea-benzofuranylthiazoles hybrids as multitasking agents in Alzheimer's disease

PMID = 2624499

Development and Validation of Molecular Overlays Derived from Three-Dimensional Hydrophobic Similarity with PharmScreen

Molecular alignment is a standard procedure for three-dimensional (3D) similarity measurements and pharmacophore elucidation. This process is influenced by several factors, such as the physicochemical descriptors utilized to account for the molecular determinants of biological activity and the reference templates. Relying on the hypothesis that the maximal achievable binding affinity for a drug-like molecule is largely due to desolvation, we explore a novel strategy for 3D molecular overlays that exploits the partitioning of molecular hydrophobicity into atomic contributions in conjunction with information about the distribution of hydrogen-bond (HB) donor/acceptor groups. A brief description of the method, as implemented in the software package PharmScreen, including the derivation of the fractional hydrophobic contributions within the quantum mechanical version of the Miertus-Scrocco-Tomasi (MST) continuum model, and the procedure utilized for the optimal superposition between molecules, is presented. The computational procedure is calibrated by using a data set of 402 molecules pertaining to 14 distinct targets taken from the literature and validated against the AstraZeneca test, which comprises 121 experimentally derived sets of molecular overlays. The results point out the suitability of the MST-based hydrophobic parameters for generating molecular overlays, as correct predictions were obtained for 94%, 79%, and 54% of the molecules classified into easy, moderate, and hard sets, respectively. Moreover, the results point out that this accuracy is attained at a much lower degree of identity between the templates used by hydrophobic/HB fields and electrostatic/steric ones. These findings support the usefulness of the hydrophobic/HB descriptors to generate complementary overlays that may be valuable to rationalize structure-activity relationships and for virtual screening campaigns

Inhibition of β-Amyloid Aggregation in Alzheimer's Disease: The Key Role of (Pro)electrophilic Warheads

Catechols have been largely investigated as anti-aggregating agents toward beta-amyloid peptide. Herein, as a follow up of a previous series of hydroxycinnamic derivatives, we synthesized a small set of dihydroxy isomers for exploring the role of the reciprocal position of the two hydroxyl functions at a molecular level. Para- and ortho-derivatives effectively reduced amyloid fibrillization, while the meta-analogue was devoid of any activity in this respect. Electrochemical analyses showed that the antiaggregating potency correlates with the oxidation potential, hence indicating the proelectrophilic character as a prerequisite for activity. Interestingly, mass spectrometry studies and quantum mechanical calculations revealed different modes of action for active para- and ortho-derivatives, involving covalent or noncovalent interactions with beta-amyloid. The distinctive mode of action is also translated into a different cytotoxicity profile. This work clearly shows how apparently minimal structural modifications can completely change the compound behavior and generate alternative mechanisms of action of proelectrophilic chemical probes

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead

Cancer immunotherapy–related adverse events: causes and challenges

Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint–targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.Fil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Choi, Jennifer Ailen. Northwestern University; Estados UnidosFil: Cooksley, Tim. University of Manchester; Reino UnidoFil: Dougan, Michael. Harvard Medical School; Estados UnidosFil: Glezerman, Ilya. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Ginex, Pamela. Oncology Nursing Society; Estados UnidosFil: Girotra, Monica. Weill Cornell Medicine; Estados Unidos. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Gupta, Dipti. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Johnson, Douglas. Vanderbilt University; Estados UnidosFil: Shannon, Vickie R.. University of Texas; Estados UnidosFil: Suarez Almazor, Maria. University of Texas; Estados UnidosFil: Rapoport, Bernardo L.. University of Pretoria; Sudáfrica. Medical Oncology Centre of Rosebank; SudáfricaFil: Anderson, Ronald. University of Pretoria; Sudáfric