Current topics in medicinal chemistry
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Sepsis is a common clinical problem that is responsible for an increasing number of deaths. Many new therapies for severe sepsis have been developed but few have shown benefit in rigorous clinical trials. To date the most successful therapies are relatively simple clinical interventions: appropriate broad spectrum antibiotics; early goal directed therapies to restore tissue oxygen delivery; physiological dose hydrocortisone in patients with relative adrenal insufficiency; intensive insulin therapy to maintain normoglycemia; and lung-protective ventilation strategies. ⋯ Statins may be beneficial in prevention of sepsis and as adjunctive treatments. Reconstitution of the immune response with interferon-gamma or granulocyte-macrophage colony stimulating factor may reverse immunoparesis in severe sepsis. Many other molecular targets have been identified for possible therapeutic intervention, but there are still fundamental difficulties to be overcome in demonstrating efficacy in clinical trials.
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The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. ⋯ In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
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NMDA receptors are known to be involved in nociceptive transmission and pain processing. Many structurally diverse NMDA antagonists have been reported to have activity in both animal models and clinical models of neuropathic pain. ⋯ These types of compounds may hold potential promise for future pain therapies. This review covers reported pain data surrounding representative examples of NMDA antagonists and provides a current assessment of potential clinical utility.
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Management of pain is an essential aspect of medicine; however, current therapies are frequently insufficient owing to severe side effects or limited effectiveness. Therefore, the discovery of new analgesics is needed, especially to treat the proportion of painful patients poorly improved by available analgesics. The transmission of nociceptive stimuli in primary afferent neurons critically depends on a peculiar repertoire of various types of ion channels such as a number of TRP channels, persistent sodium channels, inwardly rectifying potassium channels and voltage-gated calcium channels that either detect noxious stimuli, or regulate cellular excitability and synaptic transmission. ⋯ Hence, these channels are considered key targets for the development of analgesics. The nervous system expresses multiple types of calcium channels with specialized roles in neurophysiology. Here, we review the role of these channels and their accessory subunits in nociceptive signaling, and their potential as targets for development of innovative analgesics.