Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: Overview of phase I and phase II clinical trials
R. Mielke
Bok Engelsk 1998
| Utgitt | 1998
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| Omfang | Side S29- S35
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| Opplysninger | Pathophysiologic processes common to both vascular (multi-infarct)dementia and dementia of the Alzheimer type may include microglialactivation with resultant generation of inflammatory cytokines andneurotoxic free radicals, decreased secretion of nerve growth factorby astrocytes, excess release of glutamate with associatedneurotoxicity, and loss of cholinergic neurons. The functionalbenefits and neuroprotective effects of propentofylline (PPF) stemfrom its interference with these overlapping pathways ofneurodegeneration. The clinical pharmacology and safety of PPF werestudied in a number of phase I studies in healthy young and elderlyadults and in patients with renal or hepatic impairment. Thesestudies have shown that PPF 300 mg t.i.d. Is safe and well toleratedwhen taken on an empty stomach 1 h before meals. In a randomized,double-blind phase II study involving 190 elderly subjects withclinically and psychometrically documented mild to moderate dementia,12 weeks of PPF therapy produced significantly greater improvementsthan placebo in Gottfries-Brane-Steen (GBS) scores, Mini-Mental StateExamination (MMSE) scores, and Clinical Global Impression (CGI)ratings. A subsequent phase II study using positron emissiontomography (PET) revealed that cortical glucose metabolism improvedsignificantly in patients with vascular dementia after 12 weeks ofPPF treatment but deteriorated significantly with placebo. A thirdphase II study, which enrolled patients with Alzheimer-type dementia,demonstrated that PPF significantly enhanced functional reserve, asreflected by increases in regional cerebral glucose metabolism afterstimulation with a verbal memory task. In contrast, patientsrandomized to placebo exhibited a significant decline in functionalactivation and significant worsening in their MMSE scores over thecourse of this 12-week study. Propentofylline proved to be safe, welltolerated, and free of severe side effects in all three of thesephase II trials. Phase I trial results suggest that significant foodinteractions occur with PPF, indicating that the drug should be takenon an empty stomach 1 h before meals. Phase II trial results indicatethat PPF yields clinically measurable improvements in the symptoms ofdementia and prevents loss of stimulation-related increases inglucose metabolism over a treatment period of 3 months. Whether theseresults indicate that PPF can slow the progression of dementia can bedetermined only by long-term trials specifically designed todetermine the drug's effect on disease progression.
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