Curr Opin Invest Dr
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Curr Opin Invest Dr · May 2006
The therapeutic potential of TREM-1 modulation in the treatment of sepsis and beyond.
The triggering receptor expressed on myeloid cells (TREM)-1 is a recently identified molecule that is involved in monocytic activation and the inflammatory response. It belongs to a family related to natural killer cell receptors, and is expressed on neutrophils, mature monocytes and macrophages. The engagement of TREM-1 synergizes with the activation of several toll-like receptors in amplifying the inflammatory response mediated by microbial components. The modulation of the TREM-1 signaling pathway, by the use of small synthetic peptides derived from its extracellular domain, confers interesting survival advantages during experimental murine septic shock, even when administered late after the onset of sepsis.
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Clazosentan, an endothelin ETA antagonist, is under development by Actelion (formerly Axovan), under license from F Hoffman-La Roche, for the potential prevention of cerebral infarction and ischemia induced by cerebral vasospasm following subarachnoid hemorrhage. Results from the phase IIb portion of a phase IIb/III clinical study are expected in the first half of 2006.
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Neuropathic pain is a common and potentially treatable cause of considerable lifelong morbidity. Effective pharmacological treatments are scarce, but one group of drugs that has shown promise is the antiepileptics. ⋯ This review discusses the available evidence for the postulated mechanisms of action of gabapentin. Understanding the mechanism of action of this agent may well lead to the development of safer and more effective antineuropathic drugs.
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Curr Opin Invest Dr · Jan 2006
Review5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief.
Guided by an understanding of signal transduction in pain-processing systems, high-efficacy 5-hydroxytryptamine (5HT)1A receptor activation, by means of F-13640, has been discovered as a new molecular mechanism of pain relief in laboratory animals, inducing two neuroadaptive phenomena. Firstly, this activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and secondly, inverse tolerance develops so that the resulting analgesia grows rather than decays. ⋯ Indeed, F-13640 produces long-lasting, preemptive and, most remarkably, curative-like actions in neuropathic allodynia. Although awaiting proof-of-concept evidence in humans, high-efficacy 5-HT(1A) receptor activation may uniquely challenge the opioids for pain therapy.
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The development of new drugs for the treatment of childhood cancer presents novel challenges, and pediatric clinical trials of a new agent are often initiated many years after testing in adults. It is estimated that there are over 400 new entities being developed as cancer treatments, although few of these have been developed specifically for the treatment of childhood malignancies. This raises the question of how agents can be prioritized for pediatric clinical testing. In this review, the molecular characteristics of childhood cancers that may be valuable in steering choices for rational or molecularly targeted treatments are described, and the Pediatric Preclinical Testing Program, a National Cancer Institute initiative to identify agents that should be prioritized for clinical evaluation against childhood cancer, is presented.