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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Through the years, various chemical agents have been studied that are capable of producing the radiosensitization of hypoxic cells in vitro. One of the best-known classes of agent developed for this purpose is the nitroimidazoles, which produce sensitization by mimicking the presence of oxygen. Two nitroimidazole agents, misonidazole and pimonidazole (Figure 5.112), have been extensively studied since the late 1970s. They work, at least in vitro, due to their relatively high electron affinity which induces the formation of free radicals and depletes radioprotective thiols, thereby sensitizing hypoxic cells to the effects of ionizing radiation. This produces single-strand breaks in DNA, with subsequent inhibition of DNA synthesis and cell death. However, despite the promising in vitro results, the combination of misonidazole and radiation in several clinical trials (including a number of Phase III trials) since 1978 has failed to demonstrate improved survival. Furthermore, the potential clinical usefulness of misonidazole and a close analog (desmethylmisonidazole) was compromised by severe though reversible toxicities, including nausea, vomiting, and peripheral neuropathy. A number of agents, many based on the misonidazole structure, have been designed and investigated but none has reached the approval stage. Examples include etanidazole, efaproxiral, and nimorazole. Structures of the radiosensitizing agents misonidazole, pimonidazole, and amifostine (EthyolTM).
Effects of erythropoietin abuse on exercise performance
Published in The Physician and Sportsmedicine, 2018
Paolo Sgrò, Massimiliano Sansone, Andrea Sansone, Francesco Romanelli, Luigi Di Luigi
O2 blood carrying capacity is the easiest parameter that can be improved. This improvement may be achieved by increasing the Hb mass or by using artificial oxygen carriers. Different methods may be used to increase Hb mass, such as altitude training, hypoxic rooms, gene therapy, and blood transfusion, as well as the administration of several drugs: rHuEpo, Darbepoetin, Mircera, Epo mimetic peptide, and Hypoxia-Inducible Factor stabilizers (cobalt, desferrioxamine, and Prolyl-hydroxylases inhibitors). The misuse of artificial oxygen carriers includes several Hb-based oxygen carriers, commercially released as Hemopure and Oxyglobin, and Perfluorocarbon emulsion (PFC), which are able to dissolve great quantities of gases yet be completely biologically inert [46]. A further class of drugs is represented by the allosteric modulators of Hb which decrease the oxygen affinity of RBCs suspension through preferential binding to deoxy-Hb and act synergistically with 2,3-diphosphoglycerate (2,3-DPG) [47]. The RSR13, known as Efaproxiral is the prototype of this class of drugs and it is currently forbidden by World Antidoping Agency (WADA).
Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Erika Cione, Maria Cristina Caroleo, Hiroyuki Kagechika, Fabrizio Manetti
In a similar way, the two propionic acid derivatives efaproxiral and bezafibrate were found to increase insulin secretion in a dose-dependent manner. Efaproxiral is an investigational drug analogue of bezafibrate and binds to haemoglobin subunits33. It was applied as radio sensitiser in radiation anticancer therapy because of the non-covalent binding to haemoglobin results in facilitating the release of oxygen from the haemoglobin/oxygen complex, thus increasing the oxygen level in tumour cells (i.e. crucial for the effectiveness of radiation therapy), independently from blood–brain barrier penetration. However, results from a phase III trial led to study discontinuation34.