A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia.

This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761 (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer's disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.

The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.

In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test-Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as established by QPEEG measurements, in the CNS similar to those previously established in healthy, young subjects. The type of CNS effects produced by EGb (as established by HZI's CEEG psychotropic drug database) in elderly dementia patients were similar to those induced by tacrine responders as well as those seen after the administration of other "cognitive activators" (pramiracetam, vinpocetine, BMY-21502, suloctidil, and lisuride) and anti-dementia drugs approved in the United States or Europe (tacrine, donepezil, nimodipine, piracetam, and oxiracetam) from our database. The results also showed that 240 mg of EGb has typical cognitive activator CEEG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). Because of the small sample size, we could not test the hypothesis that subjects who showed cognitive activator-type pharmacological response to the first Test-Dose of EGb or tacrine also exhibit more therapeutic effects (compared to nonresponders) when drugs are administered chronically.

Computer-analyzed EEG (CEEG) and dynamic brain mapping in AIDS and HIV related syndrome: a pilot study.

In a group of HIV positive young male patients without any significant neuropsychiatric signs, computer-analyzed EEG (CEEG) and Dynamic Brain Mapping evaluations were conducted. These patients, who only had micro-neuropsychiatric symptoms, demonstrated CEEG profiles that more closely resemble those of patients diagnosed as suffering from mild dementia than age-related normals from our CEEG data base. The CEEGs of patients diagnosed as having Acquired Immune Deficiency Syndrome (AIDS), compared to patients with HIV positive, showed greater similarity in CEEG patterns to severely demented patients than to normal control groups. The findings of this pilot study suggest that CEEG may be useful for early determination of the Central Nervous System's (CNS) involvement with the AIDS virus and monitoring the progress of the illness.

Discrimination of mode of action of anxiolytics using an integrated computer data bank and Dynamic Brain Mapping (CNS effects of diazepam and lorazepam).

In a double-blind, placebo-controlled, crossover study, the CNS effects of intravenously administered diazepam and lorazepam were investigated in anxious subjects through the quantitative pharmaco-EEG (QPEEG) method. For up to 4 1/2 hours following administration the effects of each substance on brain function were measured using computer analyzed EEG recordings (CEEG) and a new technique called Dynamic Brain Mapping. The following observations were made: 1. Both active drugs produce statistically significant CNS effects as measured by CEEG changes. These changes were observed earlier with diazepam than with lorazepam. 2. Although both compounds are classified as anxiolytic by the routine computer EEG data base, the detailed brain mapping technology indicated that the CNS effects of diazepam and lorazepam were quantitatively and qualitatively different. 3. Clinical CNS side-effects (sedation) were seen more frequently with lorazepam than with diazepam. This was consistent with the EEG slowing producing properties of lorazepam. The EEG fast activity which is characteristic for all anxiolytics was established more with diazepam than lorazepam.

The significance of pharmacodynamic measurements in the assessment of bioavailability and bioequivalence of psychotropic drugs using CEEG and dynamic brain mapping.

There are a variety of problems in evaluating the bioavailability of psychotropic drugs. Psychotropics have many metabolites; there are discrepancies between peripheral plasma levels and therapeutic effects, and psychotropics must penetrate the blood-brain barrier to have an effect on their target organ. Therefore, "classical" pharmacokinetic evaluation may not be sufficient to determine the bioavailability and bioequivalence of these drugs. Additional and more precise information may be obtained by adding pharmacodynamic procedures to these evaluations. Quantitative pharmaco-EEG (QPEEG), which uses the computer-analyzed electroencephalogram (CEEG), may be the method of choice for determining the pharmacodynamic profiles of psychotropic drugs at the central nervous system (CNS) level. The difficulties in evaluating the bioavailability of psychotropics, as well as the results of several studies that confirm the significance of CEEG as a pharmacodynamic measure, are discussed.

CNS pharmacology and clinical therapeutic effects of oxiracetam.

Oxiracetam, a new substance found to be a nootropic in experimental pharmacological studies, was tested in three clinical trials: a single rising dose tolerance and dose-finding study with quantitative pharmaco-electroencephalogram (pharmaco-EEG) and quantitative pharmacopsychology in healthy volunteers; a dose-finding study, at three dose levels for 3 months, with quantitative pharmaco-EEG in mild to moderate dementia patients; and a safety and efficacy study with increasing dosages for 12 weeks with subjective and objective tests in elderly patients with dementia. In single and repeated oral dosages up to 2,400 mg, oxiracetam is a safe compound. According to HZI Data Bank Classification Systems, oxiracetam is a vigilance-enhancing compound with some effects on spontaneous memory. The therapeutic effect of oxiracetam can be discriminated from placebo, and in comparison with piracetam, oxiracetam exhibits greater improvement in memory factor.

The effects of mesterolone, a male sex hormone in depressed patients (a double blind controlled study).

Based on computer EEG (CEEG) profiles, in high doses, antidepressant properties of mesterolone, a synthetic androgen, were predicted. In a double-blind placebo controlled study, the clinical effects of 300-450 mg daily mesterolone were investigated in 52 relatively young (age range 26-53 years, mean 42.7 years) male depressed outpatients. During 6 weeks of mesterolone treatment, there was a significant improvement of depressive symptomatology. However, since an improvement was also established during the placebo treatment, no statistically appreciable difference in the therapeutic effects of mesterolone was established compared to placebo. Mesterolone treatment significantly decreased both plasma testosterone and protein bound testosterone levels. Patients with high testosterone levels prior to treatment seem to have had more benefit from mesterolone treatment than patients with low testosterone levels. The degree of improvement weakly correlated to the decrease of testosterone levels during mesterolone treatment.

CNS effects of citalopram, a new serotonin inhibitor antidepressant (a quantitative pharmaco-electroencephalography study).

Citalopram, a new phthalane derivative and a specific serotonin re-uptake inhibitor in animal pharmacological tests, was evaluated in a double-blind, crossover, quantitative pharmaco-EEG (QPEEGTM) study in healthy human volunteers. The CNS effects of citalopram are linear, dose- and time-related, can statistically be differentiated from placebo, and indicate a rapid onset of effects with short duration. According to the Computer Data Bank, citalopram has a mode of action similar to mood elevators (antidepressants) with fewer sedative properties. Thus the therapeutic action of citalopram is predicted to be similar to desipramine and protriptyline from the tricyclics, and fluvoxamine from non-tricyclics. According to data bank assessment, it is hypothesized that the single antidepressant dose of citalopram is to be more than 25 mg, which should be given t.i.d. in clinical trials.

Central mechanisms of clonidine and propranolol in man. Quantitative Pharmaco-EEG with antihypertensive compounds.

Direct CNS effects of clonidine (0.2 mg) and propranolol (40 mg and 80 mg) were established in healthy young male subjects within three hours after oral administration. They were demonstrated in two studies using procedures of the Quantitative Pharmaco-EEG (QPEEG) method. Quantitatively, the greatest CNS effects were attained with 0.2 mg clonidine followed by 80 mg, and finally by 40 mg propranolol. Based on the computer-analyzed EEG (CEEG) profiles obtained and using the HZI Research Center CEEG data base, the psychotropic properties of these compounds were predicted. Propranolol, in the 40-mg dose, showed a similarity to vigilance-enhancing compounds, whereas the 80-mg dose and the 0.2-mg dose of clonidine were established as primarily similar to mood-elevating (sedative antidepressant) drugs. However, despite some overall similarities in the mode of action between the high dose of propranolol and the clonidine, some differences in their CNS effects were detected based on their secondary effects (anxiolytic and sedative effects, respectively).