In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention

Red luminescence in H-doped beta-Ga2O3

The effects of hydrogen incorporation into beta-Ga2O3 thin films have been investigated by chemical, electrical and optical characterization techniques. Hydrogen incorporation was achieved by remote plasma doping without any structural alterations of the film; however, X-ray photoemission reveals major changes in the oxygen chemical environment. Depth-resolved cathodoluminescence (CL) reveals that the near-surface region of the H-doped Ga2O3 film exhibits a distinct red luminescence (RL) band at 1.9 eV. The emergence of the H-related RL band is accompanied by an enhancement in the electrical conductivity of the film by an order of magnitude. Temperature-resolved CL points to the formation of abundant H-related donors with a binding energy of 28 +/- 4 meV. The RL emission is attributed to shallow donor-deep acceptor pair recombination, where the acceptor is a VGa-H complex and the shallow donor is interstitial H. The binding energy of the VGa-H complex, based on our experimental considerations, is consistent with the computational results by Varley et al [J. Phys.: Condens. Matter, 23, 334212, 2011].Comment: 3 figure

Pollen morphology of Fridericia Mart. (Bignoniaceae) from Brazilian forest fragments

A pollen morphology study of 10 Brazilian native species of Fridericia (Bignoniaceae) from forest fragments was performed using light microscopy and scanning electron microscopy, in search of new characters that might increase knowledge of pollen morphology of the species, and also to help the taxonomic characterization of the genus. The pollen grains were acetolysed, measured, photographed, and described qualitatively. The quantitative data were analyzed by descriptive statistics and multivariate statistics. Non-acetolysed pollen grains were observed under scanning electron microscopy for further details of exine and pollen surface. The pollen grains are isopolar, medium to large, with circular to subcircular amb, oblate-spheroidal to subprolate, tricolporate, with long colpi, constricted or not, sometimes with margo, rounded or truncated at the polar ends, endoaperture lalongate, and microreticulate to reticulate exine, sexine thicker than nexine. The results indicate a stenopalynous genus, however, in some cases, it is possible to identify the studied species by the pollen morphology. Morphological considerations are also discussed.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Estadual Paulista, FCAV, Dept Biol Aplicada Agr, BR-14884900 Jaboticabal, SP, BrazilUniv Estadual Paulista, FCAV, Dept Biol Aplicada Agr, BR-14884900 Jaboticabal, SP, BrazilFAPESP: 12/09942-