Cerebrolysin A Review of its Use in Dementia

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks' duration in patients with Alzheimer's disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer's disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia. Pharmacological Properties Several in vitro and in vivo studies have shown that Cerebrolysin has neurotrophic effects similar to those of endogenous neurotrophic factors. Cerebrolysin improved the viability of cultured neurons in vitro and rescued medial septal cholinergic neurons following intraperitoneal administration in rats after transections of fimbria-fornix in the brain. Peripheral administration of Cerebrolysin also produced neuroprotective effects, limiting neuronal dysfunction and maintaining the structural integrity of neurons under detrimental conditions in preclinical studies in animal models. In addition, Cerebrolysin showed effects as a synaptic modulator, potentially improving the integrity of neuronal circuits in a transgenic mouse model of Alzheimer's disease (mThy 1-hAPP751), and various in vitro and in vivo studies showed that Cerebrolysin promotes neurogenesis. Behavioural effects, including amelioration of performance deficits in transgenic mice (mThy1-hAPP751), have also been demonstrated with Cerebrolysin. Although its mechanism of action at a molecular level has not been fully elucidated, a potentially significant effect of Cerebrolysin is that of reduced phosphorylation of the amyloid precursor protein and amyloid-beta peptide production via modulation of kinases GSK3 beta and CDK5. Taken together, preclinical and radiolabelling studies indicate that, following peripheral administration, Cerebrolysin crosses the blood-brain barrier in sufficient concentrations to produce pharmacodynamic effects in the CNS. Therapeutic Efficacy Several randomized, double-blind, placebo-controlled studies of up to 28 weeks' duration in patients with Alzheimer's disease have demonstrated that, compared with placebo, intravenously administered Cerebrolysin produced a consistent, statistically significant improvement on global measures, as assessed by Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) or Clinical Global Impression (CGI) of severity or change (CGIS/C). Several of these studies also showed statistically significant improvements on cognition, as assessed by the Alzheimer's Disease Assessment Scale (ADAS-cog) or its extended version (ADAS-cog-plus). Beneficial effects of Cerebrolysin on these co-primary outcomes were observed in patients with mild to moderate disease as well as in subgroups of patients with greater cognitive impairment at baseline, and when outcomes were measured at the end of the treatment period or several weeks after the final dose. A large, randomized, 28-week comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures (CIBIC-plus scores) and cognition (ADAS-cog-plus scores) for all three treatment groups compared with baseline. Although effects on cognitive improvement were most pronounced with combination therapy (-2.339), followed by Cerebrolysin (-1.708) then donepezil (-1.258), there were no statistically significant differences between groups. The proportions of CIBIC responders in the respective treatment groups were 62.7%, 64.1% and 37.8%. Beneficial effects of Cerebrolysin on other outcomes, including behaviour (as assessed by the Neuropsychiatric Inventory), were shown in some trials. In patients with vascular dementia, Cerebrolysin was superior to placebo, as assessed by CIBIC-plus and ADAS-cog (co-primary endpoints) in a large, well designed, 24-week trial. Other studies with Cerebrolysin in patients with vascular dementia have also demonstrated beneficial effects on global outcomes and cognition. Tolerability Tolerability data from studies in patients with dementia indicate that Cerebrolysin was generally well tolerated in all clinical trials. The incidence of any treatment-emergent adverse event was 43.4-64% with Cerebrolysin compared with 38.0-73% with placebo in three larger, placebo-controlled trials in patients with Alzheimer's disease. Commonly reported adverse events with both Cerebrolysin and placebo included dizziness (or vertigo), headache, increased sweating, nausea, urinary tract infection, depression and fever, although there was marked variability between studies in terms of the type and incidence of adverse events. The incidence of adverse events in the large, active-comparator trial was generally similar between Cerebrolysin, donepezil and combination therapy arms. The most frequently reported adverse events with Cerebrolysin-containing regimens included aggression, agitation, anorexia, arthralgia, delusion, dizziness, headache, hypokinesia, insomnia and urinary tract infection. Donepezil was most frequently associated with diarrhoea, dysthymic disorder, muscle spasms and nausea. In general, adverse events reported with Cerebrolysin in patients with Alzheimer's disease were broadly similar to those reported in patients with vascular dementia.