CNS drug reviews
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KTX 0101 is the sodium salt of the physiological ketone, D-beta-hydroxybutyrate (betaOHB). This neuroprotectant, which has recently successfully completed clinical Phase IA evaluation, is being developed as an intravenous infusion fluid to prevent the cognitive deficits caused by ischemic foci in the brain during cardiopulmonary bypass (CPB) surgery. KTX 0101 maintains cellular viability under conditions of physiological stress by acting as a "superfuel" for efficient ATP production in the brain and peripheral tissues. ⋯ In models of chronic neurodegenerative disorders, KTX 0101 protects neurons against damage caused by dopaminergic neurotoxins and by the fragment of beta-amyloid, Abeta(1-42), implying possible therapeutic applications for ketogenic strategies in treating Parkinson's and Alzheimer's diseases. Major obstacles to the use of KTX 0101 for long term therapy in chronic disorders, e.g., Parkinson's and Alzheimer's diseases, are the sodium loading problem and the need to administer it in relatively large amounts because of its rapid mitochondrial metabolism. These issues are being addressed by designing and synthesizing orally bioavailable multimers of betaOHB with improved pharmacokinetics.
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Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. ⋯ At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.