CNS drug reviews
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Review
Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists.
Binding studies initially suggested that the muscarinic agonist, xanomeline, was a subtype selective muscarinic M(1) receptor agonist, and a potential new treatment for Alzheimer's disease. However, later in vitro and in vivo functional studies suggest that this compound is probably better described as a subtype selective M(1)/M(4) muscarinic receptor agonist. This subtype selectivity profile has been claimed to explain the limited classical cholinomimetic side effects, particularly gastrointestinal, seen with xanomeline in animals. ⋯ This data suggest that xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects. The preclinical data on the whole are promising for an antipsychotic-like profile. If in a new formulation (i.e., transdermal) xanomeline has less adverse effects, this drug may be valuable in the treatment of patients with psychosis.
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Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38-7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. ⋯ In this article we review the in vitro and in vivo pharmacology of BAY 38-7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38-7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h. As the doses of BAY 38-7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.
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Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. ⋯ On the basis of animal data the combined use of moclobemide with pethidine or dextropropoxyphene should be avoided. There is no evidence that moclobemide would increase body weight or produce seizures. Some preclinical data suggest that moclobemide may have anticonvulsant property.
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Review
The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.
Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. ⋯ Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
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Review
A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist.
The selective kappa-opioid receptor agonist spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly mu receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the kappa receptor with K(i) of 8.6 nM in guinea pig. Examination of the enantiomers of spiradoline, showed the (-)enantiomer to be responsible for the kappa agonist properties. ⋯ The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline-like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system. Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.