The Safety, Tolerability, Pharmacokinetics and Cognitive Effects of GSK239512, a Selective Histamine H₃ Receptor Antagonist in Patients with Mild to Moderate Alzheimer’s Disease: A Preliminary Investigation

Abstract

GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Further clinical trials have been completed, focused on evaluation of the efficacy and safety of GSK239512 in Alzheimer's disease, using a randomized, double-blind, placebo-controlled study and cognitive impairment in schizophrenia. The initial report showed that GSK239512 displayed appropriate tolerability up to a maximum dose of 80 mg/day in patients with Alzheimer's disease, with some preliminary evidence for positive effects on attention and memory with modest effect sizes (Nathan et al, 2013). A larger follow study (over 190 mild/moderate Alzheimer's cases) reported GSK239512, up-titrated over 4 weeks (10-20-40-80 mg) followed by a 12-week maintenance phase, compared with sham controls, although it did not display improvement in working memory and other cognitive outcomes, however, it exhibited improved episodic memory, with a reasonable safety profile (Grove et al, 2014).…”

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

“…Interestingly, GSK-239512 has completed phase 1 clinical trial, and the results suggest a modest efficacy in mild-moderate AD patients (ClinicalTrials.gov trial registration number: NCT00675090). This compound completed phase 2 trials in patients with multiple sclerosis with no disclosure of the results yet (ClinicalTrials.gov trial registration number: NCT01772199) ( Figure 10, Table 1&4) [97,98]. However, further larger scale testing is required to clarify its effectiveness [98].…”

“…This compound completed phase 2 trials in patients with multiple sclerosis with no disclosure of the results yet (ClinicalTrials.gov trial registration number: NCT01772199) ( Figure 10, Table 1&4) [97,98]. However, further larger scale testing is required to clarify its effectiveness [98]. CEP-26401 (irdabisant) is a different potent H3R antagonist which has been shown to improve performance in the rat social recognition model of short-term memory and showed wake-promoting effects [99][100][101].…”

Neuronal histamine and cognitive symptoms in Alzheimer's disease

“…Another trial on the efficacy of GSK239512 to improve cognitive function in a small sample of Alzheimer patients with mild to moderate symptoms used an ascending dose titration regimen in order to find the optimal dose for individual patients. The results suggest that GSK239512 was well tolerated and had beneficial effects on measures of attention and memory with moderate effect sizes between 0.56 and 1.37 (Nathan et al, 2013). Although, these preliminary findings using a titration regimen appear promising, they await replication in a much larger sample.…”

“…Pathological changes in the neuronal histaminergic system seem to be correlated with cognitive deficits in Alzheimer's disease patients. However, the clinical trials performed so far with the histamine-related drugs that are at hand suggest that these compounds have either no effect or only minor beneficial effects on cognitive performance in patients suffering from Alzheimer disease (Grove et al, 2014;Nathan et al, 2013). Recent findings have implicated the neuronal histaminergic system in neurogenesis in the hippocampus and sub-ventricular zone/olfactory bulb (Ambree et al, 2014;Bernardino et al, 2012).…”