Expert review of neurotherapeutics
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Expert Rev Neurother · Nov 2008
ReviewA new tr(i)p to sense pain: TRPA1 channel as a target for novel analgesics.
Pain sensation occurs at multiple levels of the nervous system, involving a myriad of molecules and signaling pathways that contribute to the detection of noxious stimuli, and the modulation, initiation and propagation of electrical activity in nociceptors, a subset of primary sensory neurons. The fact that several types of ion channels or their splice variants are highly expressed in nociceptors and are critical for pain transduction has prompted scientists to examine their physiological roles in order to better understand the neuromolecular mechanisms of the pain pathway. Recent reports have demonstrated that TRPA1, a member of the mammalian transient receptor potential cation channel family, acts as a key chemical nocisensor in response to diverse chemical stimuli. The TRPA1 channel represents a new target for novel analgesics to specifically eliminate pain sensation of various stimuli.
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Lacosamide is a novel chemical entity with anticonvulsant and analgesic properties that is being developed to treat epilepsy and neuropathic pain conditions. Lacosamide has shown efficacy in many animal models of chronic pain and in several short- and long-term Phase II/III clinical trials in humans with diabetic neuropathic pain. The mechanism of action of lacosamide differs from other drugs used to treat neuropathic pain in that it selectively enhances sodium channel slow inactivation without affecting fast inactivation, and may modulate collapsin-response mediator protein 2. The pharmacokinetic properties of lacosamide include a fast rate of absorption, little or no interaction with cytochrome P450 isoenzymes, limited effect of age and gender on plasma levels and low potential for drug-drug interactions.
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X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. ⋯ Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies.
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Expert Rev Neurother · Sep 2008
ReviewProinflammatory mediators and migraine pathogenesis: moving towards CGRP as a target for a novel therapeutic class.
Migraine is a complex neurological disorder in which genetic and environmental factors interact. At present, frontline therapies in migraine's acute treatment include the use of NSAIDS and triptans. Restrictions in the use of frontline drugs for migraine treatment and evidence concerning CGRP's key role led research towards new pathways involved in migraine pathophysiology. ⋯ This development can be considered the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are important since they confirm the current pathophysiological concept of migraine. The future introduction of CGRP antagonists in clinical practice could represent a progress for migraine therapy.
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Expert Rev Neurother · Sep 2008
ReviewLaser-evoked potentials in primary headaches and cranial neuralgias.
Using neurophysiological methods to explore nociceptive pathways may improve knowledge of the functional changes subtending pain processing in the different forms of headache and facial pain. Laser-evoked potentials (LEPs) are a reliable neurophysiological assay for the clinical assessment of pain syndromes. ⋯ In migraine, a normal amplitude of basal LEPs with reduced habituation and altered attentive modulation seems to express a general dysfunction of cortical pain processing, which may also contribute, other than to predispose, to the persistence of migraine. LEPs may be employed in the clinical evaluation of the neurophysiological and psychophysiological aspects of pain in the different forms of headaches and facial pain to improve the therapeutic approach and provide an objective measure of treatment efficacy.