Current medicinal chemistry
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The increase in diagnostic imaging procedures that require infusion of intravenous radiographic contrast has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Since CIN accounts for a significant increase of hospital-acquired renal failure, length of stay and mortality, several additive strategies to prevent CIN are presently advocated, including N-acetylcysteine (NAC), sodium bicarbonate, theophylline or fenoldopam, and peri-procedural hemofiltration/hemodialysis. ⋯ Since NAC has only few side-effects, we presently advise NAC as an additive preventive measure in the intensive care setting. Theophylline or sodium bicarbonate hydration are viable options, either in conjunction NAC or as alternatives.
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Review
Recent advances in computational prediction of drug absorption and permeability in drug discovery.
Approximately 40%-60% of developing drugs failed during the clinical trials because of ADME/Tox deficiencies. Virtual screening should not be restricted to optimize binding affinity and improve selectivity; and the pharmacokinetic properties should also be included as important filters in virtual screening. ⋯ Recent developments in the prediction of drug absorption, especially with the application of new machine learning methods and newly developed software are also discussed. Future directions for research are outlined.
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The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. ⋯ Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer's disease.
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The three isotypes of peroxisome proliferator-activated receptors (PPARs), PPARalpha, beta/delta and gamma, are ligand-inducible transcription factors that belong to the nuclear hormone receptor family. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and thus, can be defined as metabolic and anti-inflammatory transcription factors. ⋯ This review discusses the molecular mechanisms by which PPARs and their ligands modulate the inflammatory response. In addition, it presents recent developments implicating PPAR specific ligands in potential treatments of inflammation-related diseases, such as atherosclerosis, inflammatory bowel diseases, Parkinson's and Alzheimer's diseases.
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The cytochrome P450 monooxygenase enzyme system is involved in the synthesis and/or degradation of a large number of endogenous compounds and in the biotransformation of drugs and other xenobiotics. 17alpha-Hydroxylase-C17,20-lyase (P450 17, CYP 17) is the key enzyme of the androgen biosynthesis. As androgens have been implicated in the development and progression of prostate cancer, this enzyme has become a promising therapeutic target. This paper will review the possible approaches dealing with P450 17 inhibition as a chemotherapeutic strategy in the struggle against prostate cancer.