William K. Summers

ORAL TETRAHYDROAMINOACRIDINE IN LONG-TERM TREATMENT OF SENILE DEMENTIA, ALZHEIMER TYPE

We treated 17 patients who had moderate to severe Alzheimers disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimers Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimers disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

Tacrine in the Treatment of Alzheimer’s Disease

The initial report of the effectiveness of tacrine or tetrahydroaminoacridine (THA) in the treatment of some patients with Alzheimers disease has been confirmed by further study of additional subjects and by preliminary reports from other investigators. The major side effect, elevation of liver enzymes, is shown to be reversible, dose-dependent and without significant hepatic pathology. Therapeutic serum concentrations of THA vary between 7 and 20 ng/ml. In addition to its presumed action as an acetylcholinesterase inhibitor, data are presented demonstrating marked effects on other brain neurotransmitters in animal models.

Complex Antioxidant Blend Improves Memory in Community-Dwelling Seniors

One hundred thirteen community dwelling subjects between the ages of 50 and 75 without dementia were recruited. A blind administrator randomly assigned 54 subjects to placebo and 59 to active treatment groups. The active treatment consisted of four months treatment with a complex antioxidant blend. Placebo treatment was an identical gel and bottle administered for four months. Forty-eight active subjects and 38 placebo subjects completed the study. Memory testing with a 50 part paired association test and a 20-word immediate recall test were significantly improved, p=0.015 and p=0.005 respectively. A secondary study of serum homocysteine was completed in 25 active treatment subjects and 17 placebo subjects. Significant reduction in serum homocysteine levels was seen in the active treatment subjects (p=0.005). A complex antioxidant blend taken over four months improves performance on two difficult memory tests in community dwelling elderly subjects. Furthermore, the antioxidant significantly reduced the serum homocysteine level in treatment group.

Alzheimer's disease, oxidative injury, and cytokines.

Alzheimers disease is infrequently a genetically driven disease. Rather it is the product of free radical injury inflicted over decades after an initial insult to the central nervous system (CNS). The brain is uniquely sensitive to oxidative injury. A variety of insults to the CNS are now associated with Alzheimers disease. These include hypertension, diabetes, and head trauma. These then cause a cytokine cascade and microlocalized inflammation in the CNS, that in time results in clinical Alzheimers disease. By the ninth decade of life over half of the population manifests Alzheimers disease. Prevention or reversal of this pathophysiology will lie in administration of effective antioxidant therapy with specific treatments when etiologies are known.

Comparison of seven psychometric instruments used for evaluation of treatment effect in Alzheimer's dementia.

Standards of assessment of treatment effect in Alzheimers disease have been wanting. We report here a comparison of seven methods of assessment of the severity of Alzheimers disease used in demented subjects (n = 18) and in nondemented controls (n = 18). The instruments tested were the Names Learning test, the Orientation test, the Mini-Mental State Examination, the Alzheimers Staging Scale (the AZSS), the Global Deterioration Scale, the Clinical Dementia Rating Scale, and the Alzheimers Deficit Scale (ADS). Two examiners did the testing per telephone methodology, and test/retest design. Results showed all tests to be reliable. A ceiling and/or basement effect was noted in all but the AZSS and the ADS.

Tacrine, and Alzheimer's treatments*

The story of the development of tacrine began from its synthesis as an intravenous antiseptic in 1940 by Adrian Albert in Australia. In the 1970s William Summers began using tacrine in treating drug overdose coma and delirium. He felt it might have application in Alzheimers based on work done in England by Peter Davies. In 1981, Summers et al. gave intravenous tacrine to Alzheimers patients showed measurable improvement. Between 1981 and 1986, Summers worked with Art Kling and his group at UCLA to demonstrate usefulness of oral tacrine in treatment of Alzheimers patients. The average length of tacrine use in 14 completing patients was 12.6 months and improvement was robust. This sparked controversy in the field. In 1993, after larger studies replicated the positive effect of tacrine, it was approved by the US Food and Drug Administration for treatment of Alzheimers disease.

Bismuth Toxicity Masquerading as Alzheimer's Dementia

A 76-year old white married female had rapid onset dementia with myoclonus and was admitted to an HMO hospital where she was initially diagnosed as Alzheimers disease. The physician- husband suggested that the condition might be due to the Pepto-Bismol which she had taken chronically to control her irritable bowel syndrome. An elevated serum bismuth level of 242 &mgr;g/L (normal is 5 &mgr;g/L) established bismuth toxicity as the cause of the dementia. With treatment the patient returned to a normal mental state. The possibility of bismuth encephalopathy needs to be considered in the differential diagnosis of possible Alzheimers dementia.