Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: Overview of phase I and phase II clinical trials

Pathophysiologic processes common to both vascular (multi-infarct) dementia and dementia of the Alzheimer type may include microglial activation with resultant generation of inflammatory cytokines and neurotoxic free radicals , decreased secretion of nerve growth factor by astrocytes, excess release of glutamate with associated neurotoxicity, and loss of cholinergic neurons . The functional benefits and neuroprotective effects of propentofylline (P PF) stem from its interference with these overlapping pathways of neurodege neration. The clinical pharmacology and safety of PPF were studied in a num ber of phase I studies in healthy young and elderly adults and in patients with renal or hepatic impairment. These studies have shown that PPF 300 mg t.i.d. is safe and well tolerated when taken on an empty stomach 1 h before meals. In a randomized, double-blind phase II study involving 190 elderly subjects with clinically and psychometrically documented mild to moderate d ementia, 12 weeks of PPF therapy produced significantly greater improvement s than placebo in Gottfries-Brane-Steen (GBS) scores, Mini-Mental State Exa mination (MMSE) scores, and Clinical Global Impression (CGI) ratings. A sub sequent phase II study using positron emission tomography (PET) revealed th at cortical glucose metabolism improved significantly in patients with vasc ular dementia after 12 weeks of PPF treatment but deteriorated significantl y with placebo. A third phase II study, which enrolled patients with Alzhei mer-type dementia, demonstrated that PPF significantly enhanced functional reserve, as reflected by increases in regional cerebral glucose metabolism after stimulation with a verbal memory task. In contrast, patients randomiz ed to placebo exhibited a significant decline in functional activation and significant worsening in their MMSE scores over the course of this 12-week study. Propentofylline proved to be safe, well tolerated, and free of sever e side effects in all three of these phase II trials. Phase I trial results suggest that significant food interactions occur with PPF, indicating that the drug should be taken on an empty stomach 1 h before meals. Phase II tr ial results indicate that PPF yields clinically measurable improvements in the symptoms of dementia and prevents loss of stimulation-related increases in glucose metabolism over a treatment period of 3 months. Whether these r esults indicate that PPF can slow the progression of dementia can be determ ined only by long-term trials specifically designed to determine the drug's effect on disease progression.