Continuous ICV infusion of scopolamine impairs sustained attention of rhesus monkeys.

Systemic administration of anticholinergic agents impairs cognitive performance in animals and man. The anticholinergic, scopolamine, has profound effects on peripheral and central cholinergic function, making interpretation of its effects on cognitive performance difficult. To circumvent this problem, scopolamine was administered directly to the central nervous system of rhesus monkeys using a subcutaneously implanted infusion pump connected to a cannulae directed toward the right lateral ventricle. Intracerebroventricular (ICV) infusion of scopolamine (0.004, 0.012, 12.5, and 40.0 micrograms/kg/h) produced a dose-dependent decrease in the number of responses on a continuous performance task. Response decrements produced by scopolamine were seen mainly during the last half of the test session and at short stimulus durations. These data suggest that scopolamine produces a deficit in sustained attention or slowing of information processing that is mediated through direct central cholinergic blockade in the rhesus monkey.

Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group.

Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 +/- 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22; mean age, 68 +/- 2 yr) and autopsied AD brains (n = 11; mean age, 73 +/- 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to [3H]quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [3H]pirenzepine binding as an index of M1 cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in [3H]quinuclidinyl benzilate binding or [3H]pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or ChAT activity in the biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebroventricular bethanechol chloride infusion in Alzheimer's disease. Results of a collaborative double-blind study.

The use of intracerebroventricular bethanechol chloride infusion in patients with Alzheimer's disease was first reported in 1984. An initial trial in four patients demonstrated the feasibility of this approach for cholinergic drug delivery to the brain, but objective improvement in cognitive function was not documented. A collaborative placebo-controlled double-blind crossover study has now been carried out in 49 patients with biopsy-documented Alzheimer's disease. The results demonstrate a statistical improvement in Mini-Mental State scores and significantly slower performance on Trails A testing during drug infusion. Other neuropsychological test scores were not similarly affected. The degree of improvement was not sufficient to justify further treatment of Alzheimer's disease patients by intracerebroventricular infusion of bethanechol chloride. The drug delivery system used in the study was well tolerated, with two irreversible complications in more than 50,000 patient days.

Direct cerebrospinal fluid infusion of bethanechol chloride in Alzheimer's disease: use of an implantable continuous infusion device.

Recently, investigation into an experimental treatment for patients with Alzheimer's disease has begun utilizing surgical implantation of a continuous infusion device to deliver a muscarinic agonist, bethanechol chloride, directly into the cerebrospinal fluid (CSF). The nurse research assistant has been very active in this study being involved in patient evaluation, preoperative and postoperative patient education, collection of data, and refill of the infusion device. The neurosurgical nurse also plays an active role in patient education, immediate preoperative and postoperative care, and careful observation and recording of patient behavior and general well-being. Success of continued research based on this protocol will be enhanced by the contributions of the nurse research assistant and neurosurgical nurse familiar with the study and with her/his anticipated role.

Preliminary report: intracranial cholinergic drug infusion in patients with Alzheimer's disease.

After toxicity studies in dogs, a preliminary feasibility trial of the continuous intracranial infusion of a muscarinic agonist was begun in four patients with biopsy-documented Alzheimer's disease. During the last 8 months, a totally implantable infusion system has been used to deliver bethanechol chloride into the cerebrospinal fluid of these patients at doses of 0.05 to 0.7 mg/day. Complications have been few and resolved spontaneously or were easily reversible. The subjective response to this treatment has been encouraging, with reports of improved cognitive and social function during drug infusion and a return to base line function with single-blind saline placebo infusions. Obviously, further evaluation will be necessary to demonstrate the efficacy of this treatment, and a double-blind placebo-controlled crossover trial is now being done. However, we think the preliminary results are encouraging and warrant the consideration of this approach as a potential treatment in patients with Alzheimer's disease.

Continuous drug delivery by an implantable pump.

Continuous infusion of drugs via an implantable infusion system offers advantages that are not available with other methods of drug delivery. For patients who require frequent drug injections, a continuous drug level, or high local concentrations, an implantable pump may assure compliance, comfort, and an improved therapeutic response. This method of drug delivery has been shown to be reliable and well tolerated by patients in numerous clinical trials. For hospice care professionals, familiarity with the mechanism of drug delivery and the various approved and experimental uses of the implantable pump will in all likelihood become increasingly important. At the present time regional infusion chemotherapy and intraspinal narcotic infusion for cancer pain seem to be most frequently encountered in a hospice setting. However, other uses for these implantable infusion systems are rapidly being developed, and this means of drug delivery probably will become more common in the next few years. One of the goals of continuous drug infusion by implantable pumps--optimal medical care without confining the patient to a hospital bed--is eminently compatible with the philosophy of hospice care.