Pasty polymers offer a platform for injectable implants for drug delivery. A library of biodegradable pasty polymers was synthesized by bulk ring-opening polymerization of lactide, glycolide, trimethylene carbonate, or caprolactone using castor oil or 12-hydroxy stearic acid as hydroxyl initiators and stannous octoate as the catalyst. Some of the polymers behaved as Newtonian liquids. Pasty polymers of poly(caprolactone) and poly(trimethylene carbonate) were stable under physiologic conditions for over 1 month in vitro, whereas polymers of poly(lactic-co-glycolic acid) degraded within 10 days. These pasty polymers offer a platform for pasty injectable biodegradable carriers for drugs and fillers. Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
A. Keren, Gilhar, A. , Ullmann, Y. , Zlotkin-Frušić, M. , Soroka, Y. , Domb, A.J. , and Levite, M. . 2019.
“Instantaneous Depolarization Of T Cells Via Dopamine Receptors, And Inhibition Of Activated T Cells Of Psoriasis Patients And Inflamed Human Skin, By D1-Like Receptor Agonist: Fenoldopam”. Immunology, 158, 3, Pp. 171-193. doi:10.1111/imm.13109.
Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft-versus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (Vm) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R+ T cells than healthy human skin. In line with that, 25-fold more D1R+ T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam (Corlopam) – a D1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1β and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required. © 2019 John Wiley & Sons Ltd
Iron is a key element for every single living process. On a fundamental level, targeting iron is a valuable approach for the treatment of disorders caused by iron overload. Utilizing iron chelators as therapeutic agents has received expanding consideration in chelation therapy. Approved low molecular weight (MW) iron chelators to treat iron overload may experience short half-lives and toxicities prompting moderately high adverse effects. In recent years, polymeric/macromolecular iron chelators have received attention as therapeutic agents. Polymeric iron chelators show unique pharmaceutical properties that are different to their conventional small molecule counterparts. These polymeric iron chelators possess longer plasma half-lives and reduced toxicities, thus exhibiting a significant supplement to currently using low MW iron chelator therapy. In this review, we have briefly discussed polymeric iron chelators and factors to be considered when designing clinically valuable iron chelators. We have also discussed applications of polymeric iron chelators in the diseases caused by iron overload associated with transfusional hemosiderosis, neurodegenerative disorders, malaria and cancer. With this, research findings for new polymeric iron chelators are also covered. © 2019 Bentham Science Publishers.