A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HIV dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2× 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HIV-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection. Human immunodeficiency virus type 1 (HIV-1)-associated dementia complex(HIV dementia) occurs in 15 to 20% of acquired immunodeficiency syndrome(AIDS) patients and is characterized by cognitive impairment, motor dysfunction, and behavioral changes.1-5 The cognitive impairment includes mental slowing, forgetfulness, and poor concentration. Motor symptoms include loss of fine motor control, clumsiness, unsteady gait, and tremor. Behavioral changes include apathy, lethargy, and depression.2,3,6 HIV dementia is usually a rapidly progressive disorder with a mean survival of about 6 months,2 although recently, patients with slower progression or a stable course have been identified.7 HIV-1-associated minor cognitive motor disorder, a milder syndrome, is estimated to occur in 25% of patients with symptomatic HIV infection.8 Few available antiretroviral agents have been studied for the treatment of HIV dementia. Open label studies with zidovudine (ZDV) in demented patients showed improvements in clinical functioning, neuropsychological performance, and neuroimaging studies.9 ZDV, in a placebo-controlled blinded study, also improved neuropsychological function in AIDS or AIDS-related complex patients without dementia.10 The only placebo-controlled trial of ZDV in HIV dementia demonstrated the greatest neurocognitive improvement only with very high dosages (i.e., 2,000 mg/day).11 Unfortunately, the response to ZDV treatment may be short-lived or associated with intolerable side effects and therefore often unsatisfactory. There is very limited information about the therapeutic effects of other antiretroviral medications (e.g., dideoxynucleosides)12 or protease inhibitors. Neurotoxins from HIV-infected activated macrophages or microglia interacting with astrocytes may play a central pathogenetic role in HIV dementia.13,14 Putative neurotoxins include cytokines (tumor necrosis factor alpha [TNF-α]) and oxygen radicals.2,15 Both TNF-α and hydroxyl free radicals may stimulate apoptosis (programmed cell death), and apoptotic neurons have been demonstrated in the cerebral cortex and basal ganglia of both children and adults with HIV encephalitis.16,17 We hypothesized that these indirect mechanisms of neuronal injury could be modified by deprenyl and thioctic acid to improve or even prevent HIV-associated cognitive impairment. Deprenyl, a selective monoamine oxidase type B inhibitor, at very low dosages in in vitro and in vivo systems has a trophic effect on injured neurons.18-21 Thioctic acid is a naturally occurring enzymatic cofactor for pyruvate dehydrogenase and alpha oxoglutarate dehydrogenase and scavenges harmful hydroxyl radicals and other reactive oxygen species.22,23 We conducted a randomized, double-blind, placebo-controlled clinical trial of deprenyl and thioctic acid to assess their safety and tolerability and to assess their impact on HIV-associated cognitive impairment in HIV seropositive (HIV+) patients

Clinical confirmation of the American Academy of Neurology algorithm for HIV-1-associated cognitive/motor disorder

Objective: Our goal was to put into operation the American Academy of Neurology (AAN) algorithm for the definition of minor cognitive/motor disorder and human immunodeficiency virus type 1 (HIV-1)-associated dementia complex (ADC) and examine the neuropsychological, neurologic, psychiatric, and functional deficits in affected subjects. Design: Two hundred seventy-one HIV-positive men and women with CD4 count of <200 or demonstrated cognitive impairment were recruited from three sites (Columbia University, The Johns Hopkins University, and the University of Rochester) and underwent standardized assessments. Results: Sixty-five subjects met criteria for ADC (cognitive, functional, and neurologic or behavioral), 56 met criteria for minor cognitive/motor disorder, and 150 met criteria for neither. Seventy-eight subjects met neuropsychological and neurologic/behavioral criteria but did not demonstrate functional impairment. Those with ADC performed significantly worse on speeded motor and verbal memory tests and demonstrated more extrapyramidal signs and behavioral symptoms than did the other two groups. Both ADC and minor cognitive/motor disorder were independently predictive of poor physical function, after adjustment for age, gender, years of education, log (CD4 count), hemoglobin, number of HIV diagnoses and medications, and depression. Conclusions: The operationalization of AAN criteria demonstrates that it is rare to have both cognitive and functional impairment without associated neurologic and/or behavioral deficits. Functional impairment in isolation is also rare. Dementia is an independent predictor of physical function. NEUROLOGY 1996;47: 1247-125

Safety and tolerability of the antioxidant OPC-14117 in HIV-associated cognitive impairment

Cognitive impairment is a common and disabling complication of advanced HIV infection. Antiretroviral agents are the only proven therapies currently used for the treatment of HIV dementia, but the response to these agents is frequently unsatisfactory, short-lived, or complicated by intolerable side effects. We hypothesized that OPC-14117, a lipophilic antioxidant that acts to scavenge superoxide anion radicals, might ameliorate the toxic interactions between HIV infected macrophages and neurons. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the safety and tolerability of OPC-14117 240 mg per day. All 30 patients enrolled(15 per group) had cognitive impairment based on performance on neuropsychological tests. The primary outcome was tolerability of the study drug as measured by the proportion of subjects able to complete the study on their assigned dosage of experimental medication. Overall OPC-14117 was as well tolerated as placebo. Five subjects withdrew because of adverse experiences (two placebo, three OPC-14117). The OPC-14117-treated group had better scores on a clinical global impression scale, compared with the placebo group. There were trends toward improvement in the cognitive test scores; however, these changes were not statistically significant. These results demonstrate that this antioxidant intervention is well tolerated in cognitively impaired patients with advanced HIV infection, and suggest that a larger efficacy trial to assess the impact of OPC-14117 on cognitive performance is warranted