Current medicinal chemistry
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Temperature control, airway management and support of circulation remain the gold-standards for the majority of neonates requiring resuscitation at birth. For the minority of neonates in which the basic steps of resuscitation fail to reverse an adverse situation, drug administration is justifiable. The 2010 International Liaison Committee on Resuscitation (ILCOR) guidelines for newborn resuscitation state: "Drugs are rarely indicated in resuscitation of the newly born infant. ⋯ These are best given via an umbilical venous catheter". Even though drugs have been used in neonatal resuscitation for long, their doses, order and route of administration have been issues of debate among neonatologists, mainly due to the lack of data in human studies. This review will examine existing evidence behind the medications currently used in neonatal resuscitation.
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Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select chemotherapeutic agents and in non-malignant diseases. In this review article, we briefly review the mechanisms of DNA repair and pre-clinical development of PARP inhibitors before discussing the clinical development of the various PARP inhibitors in depth.
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microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. ⋯ Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.
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Glutamate has been implicated in the pathogenesis of several diseases on the central nervous system, but recent studies have also suggested that it can be involved also in the onset and course of peripheral neuropathies. Given the increasing evidence of this possibility, several attempts have been performed in order to modulate its activity. Among them, glutamate carboxypeptidase II (GCP II) inhibition demonstrated promising results in different models of peripheral nerve damage, including diabetic and toxic neuropathies.
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Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. ⋯ Zwitterionic 6-amino acid conjugates of 14-Oalkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.