Weitbrecht and Jansen (1986) studied the effects of Ginkgo Biloba Extract 761 (120mg/day) compared with placebo and ergot alkaloids (5.94mg/day) in patients suffering from mild to moderate primary degenerative dementia. This randomized trial was double-blind with respect to Ginkgo Biloba Extract 761 and placebo, and the reference substance was given to a third treatment group under open conditions. Sixty patients (average age 72.4±4.6; Hachinski score<7) were treated for 3 months with Ginkgo Biloba Extract 761, placebo, or ergot alkaloids, 20 patients each. Efficacy was measured on the psychopathological level from the patient’s self-assessment, the physician’s global assessment and the Sandoz Clinical Assessment — Geriatric. Objective assessment of performance was carried out by applying the Wechsler digit symbol substitution test and the digit span test. Flicker fusion frequency and reaction time were tested to provide insight into functional-dynamic effects, and the Crichton scale was employed for assessment of behaviour closely related to activities of daily living. After only 4 weeks of treatment, the EGb 76 l-treated group showed statistically significant improvements in both psychometric test performance and clinical assessments. After 3 months of Ginkgo Biloba Extract 761 treatment, a mean improvement of 23.5% as compared to baseline was found on the Crichton scale. Pre/post differences were significantly higher in the active treatment group as compared with the placebo group after 3 months (p<0.0001; U-test). The SCAG total score improved by approximately 33% in comparison to baseline values (p<0.0001 for pre/post differences vs. placebo; Fig. 1). According to the physician’s global assessment and the patients’ self-assessment, the patients’ state of health improved significantly under Ginkgo Biloba Extract 761 treatment, but not under placebo. Both the digit span and digit symbol substitution test demonstrated significantly greater improvements in actively treated patients compared with placebo-treated patients. The same was true for flicker fusion frequency and reaction time. Treatment with ergot alkaloids gave also a significantly better outcome than placebo treatment. There were no significant differences at any time between the reference substance and Ginkgo Biloba Extract 761. No adverse reactions were reported (2 patients in the placebo-group dropped out for reasons unrelated to treatment). To summarize, the results of this study indicate the effectiveness of Ginkgo Biloba Extract 761 in treatment of mild to moderate primary degenerative dementia.

Wesnes et al. (1987) included 58 elderly patients (mean age 71 years) who were living at home and suffering from mild dementia manifesting itself as an impairment of everyday functioning (Crichton score >14). After a washout period of 1-3 weeks, 27 patients were treated with Ginkgo Biloba Extract 761 (120mg/day), and 27 were given placebo. Duration of treatment was 12 weeks. Efficacy was assessed by an extensive cognitive test battery comprising computerized as well as pencil and paper tests of memory function, attention, and information processing. Quality of life was measured by a behavioural questionnaire applied before and after the study. Improvements could be detected in both groups, but the improvement at week 12 was significantly more pronounced in the Ginkgo Biloba Extract 761-treated group than in the placebo group in most of the single tests, and also when the accuracy scores from all the 8 tests were combined (p<0.05). The most important finding in this study, however, emerged from the quality of life scale. While there was no difference between the treatment groups with respect to the number of activities still practised, the number of activities carried out with “high interest” increased significantly in the Ginkgo Biloba Extract 761-treated group (p<0.05) but not in the placebo group. One adverse event (constipation) was reported in the actively treated group which was not considered to be related to the treatment.

Figure 1 Development of SCAG Total Scores During 12 Weeks Treatment with Ginkgo Biloba Extract 761 and Placebo; mean values and standard deviations; *: p<0.0001 for inter-group comparison of pre/ post differences.

In 50 outpatients suffering from mild dementia (uncomplicated senile dementia, presenile dementia and arteriosclerotic dementia) according to ICD-9, Halama (1991) studied the effects of Ginkgo biloba special extract LI 1370 on cognitive functioning and psychopathology. Patients were treated for 12 weeks with 150mg/day of LI 1370 or placebo, 25 patients each. A symptom scale comprising 11 typical symptoms of early dementia, the SKT-test, the digit connection test ZVT and global ratings by patients and the physician were employed to measure the therapeutic outcome. LI 1370 was found to be significantly superior to placebo concerning 7 out of 11 typical symptoms and the SKT total score. There was also a more pronounced decrease in ZVT processing time on active treatment which did not reach statistical significance. Global ratings of therapeutic success by both the patients and the physician significantly favoured LI 1370. Three adverse events were reported in this study: 1 patient receiving placebo suffered from headache and nausea; out of 2 patients under active substance, 1 reported an allergic skin reaction, the other complained of a pain in the kidney region.

Twenty patients with dementia of the Alzheimer type according to DSM-III-R and NINCDS/ADRDA criteria were enrolled in a study by Ihl et al. (1992). Treatment duration was 3 months. As primary efficacy measure, the sum score of the SKT-test was defined. Secondary efficacy measures were further psychometric tests: the ZVT and the Alzheimer’s Disease Assessment Scale, the Clinical Global Impressions, and electrophysiological parameters (topographic EEG). During treatment, SKT-scores changed in the Ginkgo biloba group from 19.67 to 16.78 (mean values) and from 18.11 to 18.89 in the placebo group (p=0.013 for differences). The superiority of Ginkgo biloba was also observed in the secondary variables, CGI change (p=0.069) and EEG (increase of mean amplitudes). There were no adverse drug reactions. The most important finding in this study was that the efficacy of Ginkgo Biloba Extract 761 could be clearly demonstrated by objective cognitive testing and global rating in patients suffering from relatively severe cerebral impairment in moderately severe dementia of the Alzheimer type, which rapidly progressed in placebo-treated patients.

Forty inpatients (aged 50 to 75 years) with a clinical diagnosis of mild senile dementia of the Alzheimer type, were studied by Hofferberth (1994). Diagnosis was based on common clinical criteria together with a CT-scan and the Hachinski Ischemic Score. Patients received, after random allocation, either Ginkgo Biloba Extract 761 (240mg/day) or placebo for 3 months. Inclusion criteria were described as follows: Blessed Dementia Scale (Blessed et al., 1968): sum Part A: 0-16, sum Part B: 9.5-30.5; Ischemic Score according to Rosen et al. (1980) <4; normal or diffuse and possibly asymmetrically atrophic CT findings. The severity of the disease was determined by the SKT-test (a brief cognitive test battery for the measurement of memory and attention; Kim et al., 1993) the total score of which was 17 in the Ginkgo Biloba Extract 761 group and 15 in the placebo group, both consistent with a moderately severe cognitive impairment. Exclusion criteria were: advanced Alzheimer dementia, i.e. necessity of special accommodation and constant care; intellectual deterioration or state of confusion and/or dementia syndrome of another origin, pseudodementia; significant depression with a HAMD total score >15; pronounced sensory or motor disturbances; severe organic illness. Treatment with vasoactive agents, nootropics, psychotonics, tranquilizers and/or antidepressants was prohibited throughout the study. The SKT-test was predefined as the primary outcome measure. Secondary variables were the Saccade Test, Vienna Determination Test, the Sandoz Clinical Assessment — Geriatric and electroencephalography (particularly the theta/alpha quotient). Memory and attention, as measured by the SKT, improved significantly in the verum group already after 1 month (inter-group differences at p<0.001), as did psychopathology, psychomotoric performance, and functional dynamic variables as measured by the procedures mentioned above. After 3 months of Ginkgo Biloba Extract 761 treatment, the mean SKT total score had decreased by 5 points whereas an increase of 2 points was found in the placebo group, resulting in a highly significant inter-group difference in favour of the active treatment (p<0.001). This was confirmed on the psychopathological level by a mean decrease of 29 points in the SCAG total score after Ginkgo Biloba Extract 761, compared with a negligible change during placebo application. At month 3, the theta/alpha quotient in the active-treatment group had decreased from 79.4% to 61.9%, indicating enhanced vigiliance. Significant superiority of the Ginkgo biloba special extract was also demonstrated as regards choice reaction time and both latency and speed of saccadic eye movements. No adverse events were observed. In this methodologically adequate trial, again, the clinical relevance of treatment-selected effects could be demonstrated by highly consistent results on 3 levels of assessment. Improvement in test performance measured by objective procedures was in accordance with a decrease in psychopathology and changes towards normal in functional dynamic measures.

Haase et al. (1996) enrolled 40 patients, aged 68±12.5 years, suffering from moderate dementia of the Alzheimer type, vascular dementia, and mixed forms according to DSM-III-R criteria (American Psychiatric Association, 1987) into a short-term study. Psychopathology corresponded to stages IV or V of the Global Deterioriation Scale of Reisberg e£ a/. (1982); patients showing any signs consistent with another type of dementia or suffering from severe somatic disease had to be excluded. Treatment duration was 4 weeks. Patients received either intravenous infusions of Ginkgo Biloba Extract 761 (200mg active substance/250ml saline) on 4 days of each week or placebo infusions having the same appearance. Clinical efficacy was assessed by the Nuremberg Gerontopsychological Observation Scale for Activities-of-Daily-Living which reflects the patient’s ability to perform activities of daily living as observed by a relative or a caregiver; by the change in the patient’s overall condition as realized by the psychiatrist (CGI, Item 2; National Institute of Mental Health, 1976); and by objective cognitive testing. In the actively treated group, a mean decrease of 3.6 in the NAB total score was found after 4 weeks treatment, thus reflecting a meaningful improvement in patients with moderate dementia. Only a minimal decrease of 0.3 points was seen in the placebo group. The resulting inter-group difference was highly significant (p<0.01). According to the CGI, 85% of actively treated patients and 35% of those who received placebo were judged as having improved (p<0.0001). The cognitive test revealed an improvement in general IQ in 45% of the patients treated with Ginkgo Biloba Extract 761 and in 5 patients who were given placebo (p<0.05). No adverse events occurred during Ginkgo Biloba Extract 761 treatment. As this trial was designed in accordance with the most recent published recommendations of the German Federal Health Authority, efficacy was assessed — and established — on the psychopathologic and the psychometric plane, and the plane of activities of daily living. It was thus possible to demonstrate that treatment-related improvements of psychopathology and cognitive test performance do in fact result in a gain of competence in coping with the demands of everyday life.

A very convincing study has been published by Kanowski et al. (1996). The objective was to prove the clinical efficacy of Ginkgo biloba special extract Ginkgo Biloba Extract 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Diagnoses were established by DSM-III-R  criteria with support from CT-scans and the Ischemic Score according to Rosen et al. (1980). Patients were included if they scored between 13 and 25 in the Mini-Mental State Examination and between 6 and 18 in the SKT-test , which is compatible with mild to moderate dementia. Patients suffering from any other significant psychiatric or somatic disease, or taking any drugs possibly interfering with efficacy assessment were excluded. 216 patients aged over 55 years were randomized to receive either Ginkgo biloba special extract Ginkgo Biloba Extract 761 (240mg/day) or placebo. A run-in period of 4 weeks was followed by a treatment period of 24 weeks. Three primary variables were selected according to the recommended multi-dimensional approach for proving the efficacy of nootropic and/or anti-dementia drugs; these were the CGI (Item 2) as a global rating on the psychopathological level, the SKT for objective assessment of syndrome-relevant cognitive performance, and the Nuremberg Gerontopsychological Observation Scale for Activities-of-Daily-Living (NAB; Oswald and Fleischmann, 1995). Per-protocol analysis was based on the data from 156 patients (Ginkgo Biloba Extract 761: 79; placebo: 77) and carried out as a multiple-responder analysis according to pre-specified rules. Only those improvements considered clinically meaningful were accepted as being a response, i.e. a judgement of “much improved” or “very much improved”, with respect to the patient’s condition, in the CGI; a decrease of at least 4 points in the SKT total score; and a decrease of at least 2 points in the NAB total score. A response in at least 2 of the three primary variables was considered a treatment response. After 24 weeks, 28% of the patients treated with Ginkgo Biloba Extract 761 were found to be treatment responders, whereas only 10% of placebo patients showed multiple response (p<0.005, Fisher’s Exact Test). When considering only those patients who showed response in all of the 3 primary variables, Ginkgo Biloba Extract 761 was again found to be significantly superior to placebo (p<0.05, descriptive). When reviewing the single variables, improvements in CGI-scores termed “better” or “much better” were found in 32% of Ginkgo Biloba Extract 761-treated patients and in 17% of patients in the placebo group (p<0.05). Decreases in SKT total scores by at least 4 points were documented in 38% of the actively treated patients and in 18% of the placebo patients (p<0.005). Improvements in the NAB of at least 2 points were found in 33% of cases in the Ginkgo Biloba Extract 761 group and 23 % of cases in the placebo group (p<0.1). An additional intent-to-treat analysis of the data from 205 patients led to noticeably similar results. Exploratory analyses of prospectively defined subgroups did not reveal any relevant differences in efficacy in the context of the dementia type (Alzheimer or vascular). There were 5 adverse events in the Ginkgo Biloba Extract 761 group which were judged as possibly treatment-related by the investigators (allergic skin reactions, gastrointestinal complaints, headache). A comparison of all adverse events observed in 216 patients exposed to study medication (Ginkgo Biloba Extract 761 or placebo) shows, however, that allergic skin reactions were the only type of event that occurred more frequently in the actively treated group. The opposite was the case for gastrointestinal complaints; and headaches were virtually equally distributed between the groups.

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