A randomized double‐blind, placebo‐controlled study was conducted in 37 asymptomatic HIV‐infected individuals (mean CD4 count 707 cells/mm 3 ) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L‐2‐oxothiazolidine‐4‐carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single‐dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 ± 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.
Serotonin 5HT6 receptors are almost exclusively located in the CNS with high expression in the hippocampus, cerebral cortex, nucleus accumbens and striatum. The presence of this receptor in brain areas known to be involved in learning and memory, coupled with the finding that 5HT6 receptor antagonists stimulate acetylcholine and glutamate release, suggests an important role in cognition and restoration of cognitive impairment. Behavioral data using a variety of cognitive tasks strongly supports this contention. Improved episodic memory performance has been observed in the novel object recognition task in young rats following a 48 hour delay with several 5HT6 antagonists including MEM 34551. In the aged-impaired rat Morris water maze task, significant improvements in spatial memory performance has been observed with several 5HT6 receptor antagonists. Similar findings were also observed in the passive avoidance task using aged animals. These later studies support a role for 5HT6 receptor antagonists in enhancing cognitive deficits associated with age-related mild cognitive impairment (MCI) and Alzheimer's disease. Interestingly, 5HT6 receptor density was shown to be very low in a variety of mouse strains including the C57/BL6 mouse. We tested several 5HT6 antagonist compounds in our aged-impaired C57/BL6 mouse Morris water maze task and saw no cognitive restoration effects, thus supporting the neuroanatomical observations. Taken together, these data support a role for 5HT6 receptor antagonists in learning and memory processing and highlight their potential as therapeutic agents in MCI and Alzheimer's disease patients.
Neurons must maintain appropriate ion gradients in order to function properly; as they age, or are affected by toxins such as beta amyloid peptides, neurons lose this ability. An increase in Ca2+ entry into the cell alters activity of Ca2+–dependent proteins such as ion channels and proteolytic enzymes which may adversely affect many cell functions. Excessive Ca2+ entry may be exacerbated by an increase in density of L–type Ca2+–channels reported to occur in aging and in Alzheimer's disease. Blocking voltage–regulated calcium channels may facilitate the ability of neurons to maintain appropriate calcium levels and function properly. Memory Pharmaceuticals is developing MEM1003, a dihydropyridine (DHP) Ca2+ channel modulator, for Alzheimer's disease. MEM1003 is equipotent to nimodipine, another DHP, in blocking L–type Ca2+currents in CA1 hippocampal neurons, but it is 4 to 15–fold less potent in relaxing rat thoracic smooth muscle when compared to other DHPs like nimodipine, nitrendipine or felodipine. This suggests that MEM1003 may have a superior safety profile. MEM1003 is a single enantiomer, unlike nimodipine and many other DHP drugs, and may lack potential off–target pharmacological activities present in racemic mixtures. We will present data showing the effectiveness of MEM1003 in improving cognitive performance in multiple preclinical behavior models at plasma exposure levels consistent with its affinity for the DHP binding site. One proposed mechanism for the procognitive effects of MEM1003 is that it mediates a reduction in the slow afterhypolarization (sAHP) of CA1 pyramidal neurons. An enlarged sAHP, functionally linked to L–type Ca2+channels, may interfere with cognitive behaviors. Our recent findings have demonstrated that sAHP amplitude co–varies with spatial learning ability in aged rats (Tombaugh et al., 2005). The pharmacokinetic and safety profiles of MEM1003 were recently studied in double–blind, randomized, placebo–controlled Phase 1A and Phase 1B clinical trials. MEM1003 was well tolerated up to the highest dose tested of 180 mg twice daily. The safety data and pharmacokinetics of MEM1003 in these studies will be presented and the relevance of the exposure levels to preclinical animal efficacy models and toxicology studies will be discussed. MEM1003 is currently in a Phase 2A clinical trial for Alzheimer's disease.
Increasing evidence links chronically elevated glucocorticoid levels and cognitive impairments in a subpopulation of aged rodents and humans. Antidepressant drugs improve hypothalamic-pituitary-adrenal axis feedback regulation and reduce plasma glucocorticoid levels. Decreasing the cumulative lifetime exposure to glucocorticoid excess by long-term exposure to antidepressants may prevent the emergence of cognitive impairments in aged rats. To test this hypothesis, we treated middle-aged male Lister hooded rats (16 months) with amitriptyline until they were 24 months of age, and their cognitive function was assessed in the water maze. Performance in the spatial learning task declined significantly with aging (p < 0.01), with 33% of aged controls showing poorer (<2.5 SD) probe test performance than young controls. Amitriptyline treatment from midlife preserved water maze performance with aging (p < 0.01 compared with aged controls) and significantly (p < 0.01) reduced the proportion of poor performers (7%). Measures of anxiety-related behaviors in the elevated plus-maze were significantly (p < 0.05) decreased in the aged rats after amitriptyline. Furthermore, evening plasma corticosterone levels were reduced (30% decrease; p < 0.01 compared with aged controls) after 6 months of amitriptyline. These data suggest that long-term treatment with amitriptyline decreases the prevalence of cognitive impairment in aged rats and that this may, in part, be a consequence of reduced plasma corticosterone levels and reduced anxiety.
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