Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
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Migraine is a common neurological disease characterised by the presence of attacks of unilateral, severe head pain accompanied by other symptoms. Although it has been classified as the sixth most disabling disorder, the available therapeutic options to treat this condition have not progressed accordingly. The advance in the development of 5-HT1 receptor agonists for migraine, including 5-HT1B/D and 5-HT1F receptor agonists, has meant a major step forward towards the progression of a better treatment for migraine. ⋯ It is a well-tolerated compound that does not induce major adverse events. Although ongoing phase III clinical trials are needed to confirm its efficacy and safety, lasmiditan might offer an alternative to treat acute migraine with no associated cardiovascular risk. This review will focus on the characterisation of 5-HT1 receptor agonists and their effects as migraine therapies.
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Here, we review the role of pituitary adenylate cyclase-activating peptide-38 (PACAP38) in migraine pathophysiology and data implicating PAC1 receptor as a future drug target in migraine. Much remains to be fully elucidated about migraine pathophysiology, but recent attention has focused on signaling molecule PACAP38, a vasodilator able to induce migraine attacks in patients who experience migraine without aura. ⋯ The selective affinity of PACAP38 to the PAC1 receptor makes this receptor a highly interesting and potential novel target for migraine treatment. Efficacy of antagonism of this receptor should be investigated in randomized clinical trials.
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Randomized Controlled Trial
Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial.
This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. ⋯ Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.
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Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. ⋯ Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.
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Adult hippocampal neurogenesis (AHN) occurs in humans and every other mammalian species examined. Evidence that AHN is stimulated by a variety of treatments and behaviors with anxiolytic properties has sparked interest in harnessing AHN to treat anxiety disorders. However, relatively little is known about the mechanisms through which AHN modulates fear and anxiety. ⋯ Based on studies of the role of AHN in Pavlovian fear conditioning, we conclude that AHN modulates the consequences of aversive experience by influencing 1) the efficiency of hippocampus-dependent memory acquisition; 2) generalization of hippocampal fear memories; 3) long-term retention of hippocampal aversive memories; and 4) the nonassociative effects of acute aversive experience. The preclinical literature suggests that stimulation of AHN is likely to have therapeutically relevant consequences, including reduced generalization and long-term retention of aversive memories. However, the literature also identifies four caveats that must be addressed if AHN-based therapies are to achieve therapeutic benefits without significant side effects.