Current medicinal chemistry
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The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- α and γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. ⋯ Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.
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Cardiac troponins (cTn) are considered to be the 'gold standard' biomarker for the diagnosis of acute coronary syndrome (ACS); a pathological spectrum which includes cardiac ischemia, angina, myocardial infarction and ultimately cardiac failure. The growing evidence base for the diagnostic and prognostic use of cTn in ACS has resulted in a universal redefinition of acute myocardial infarction (AMI). Recently a number of immunoassays with claims of superior sensitivity have been produced. ⋯ It is unknown if such mild elevations in cTn detected by sensitive assays are of clinical concern. What is certain is that AMI remains a clinical not a biochemical diagnosis and interpretation of cTn concentrations should be made according to the clinical context. This review highlights the development of the sensitive assays, documents their analytical and clinical performance and reviews the usefulness of cTn elevation in non-ACS conditions.
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Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of pain, fever and inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal bleeding. ⋯ Either naproxen and diclofenac hybrids have been reported to cause less gastrointestinal injury than parent NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H₂S and/or by exerting anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study.
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Enzymes belonging to the PLA(2) superfamily catalyze the hydrolysis of unsaturated fatty acids from the sn-2 position of glycerol moiety of neural membrane phospholipids. The PLA(2) superfamily is classified into cytosolic PLA(2) (cPLA(2)), calcium-independent PLA(2) (iPLA(2)), plasmalogen-selective PLA(2) (PlsEtn-PLA(2)) and secretory PLA(2) (sPLA(2)). PLA(2) paralogs/splice variants/isozymes are part of a complex signal transduction network that maintains cross-talk among excitatory amino acid and dopamine receptors through the generation of second messengers. ⋯ In contrast, studies using a selective iPLA(2) inhibitor, bromoenol lactone, or antisense oligonucleotide indicate that iPLA(2) is an important "housekeeping" enzyme under basal conditions, whose activity is required for the prevention of vacuous chewing movements, a rodent model for tardive dyskinesia, and deficits in the prepulse inhibition of the auditory startle reflex, a common finding in schizophrenia. These studies support the view that PLA(2) activity may not only play a crucial role in neurodegeneration but depending on the isoform, could also be essential in prevention of neuropsychiatric diseases. The findings could open new doors for understanding and treatment of neurodegenerative and neuropsychiatric diseases.