To compare the efficacy and tolerability of dehydroepiandrosterone (DHEA) vs placebo in AD.
Fifty-eight subjects with AD were randomized to 6 month's treatment with DHEA (50 mg per os twice a day; n = 28) or placebo (n = 30) in a multi-site, double-blind pilot trial. Primary efficacy measures assessed cognitive functioning (the AD Assessment Scale-Cognitive [ADAS-Cog]) and observer-based ratings of overall changes in severity (the Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus]). At baseline, 3 months, and 6 months, the ADAS-Cog was administered, and at 3 and 6 months, the CIBIC-Plus was administered. The 6-month time point was the primary endpoint.
Nineteen DHEA-treated subjects and 14 placebo-treated subjects completed the trial. DHEA was relatively well-tolerated. DHEA treatment, relative to placebo, was not associated with improvement in ADAS-Cog scores at month 6 (last observation carried forward; p = 0.10); transient improvement was noted at month 3 (p = 0.014; cutoff for Bonferroni significance = 0.0125). No difference between treatments was seen on the CIBIC-Plus at either the 6-month or the 3-month time points.
DHEA did not significantly improve cognitive performance or overall ratings of change in severity in this small-scale pilot study. A transient effect on cognitive performance may have been seen at month 3, but narrowly missed significance.
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"A trial in mild-to-moderate AD of atorvastatin enrolled 98 participants, of whom 15 withdrew consent prior to random assignment 'primarily to participate in other trials' . Similarly, the ADCS trial of dihydroepiandrosterone initially recruited 58 participants, but only 33 completed the 12-month trial . Fifty-three percent of subjects randomly assigned to placebo dropped out of the study prior to completion, and the authors hypothesized that the high rate of dropout may have been the result of the widespread availability of FDA-approved AChEI therapies during study conduct . "
[Show abstract][Hide abstract] ABSTRACT: Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them.
Alzheimer's Research and Therapy 12/2010; 2(6):34. DOI:10.1186/alzrt58 · 3.98 Impact Factor
"No studies of DHEA replacement on healthy elderly populations, either acute administration or chronic (up to 12 months) supplementation, have shown a benefit in memory with treatment (Wolf et al. 1997, 1998; Wolf and Kirschbaum 1999; Arlt et al. 2001; Grimley Evans et al. 2006; Kritz- Silverstein et al. 2008), and some have even observed a negative effect on memory (Wolf et al. 1998; Parsons et al. 2006). DHEA supplementation has also shown no benefit in the treatment of Alzheimer's disease (Wolkowitz et al. 2003). "
[Show abstract][Hide abstract] ABSTRACT: In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
Age 09/2009; 32(1):61-7. DOI:10.1007/s11357-009-9113-4 · 3.45 Impact Factor
"DHEA is widely consumed as a drug for a wide range of expected therapeutic actions, including androgen synthesis , improvement of degenerative diseases  and the treatment of overweight and obesity [12,13]. The rapid absorption and disposal of oral DHEA  has generated a number of studies and patents focussed on the maintenance of plasma DHEA levels within a therapeutic range in spite of its rapid metabolism/excretion. "
[Show abstract][Hide abstract] ABSTRACT: Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels.
Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver.
The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females.