Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.

SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present study was designed to assess the safety and tolerability of higher doses of ENA 713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs, range 45-90) were assigned to a fixed, nine-week dose escalation schedule in which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20) or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose escalation for the bid and tid ENA 713 groups was identical, beginning with 2 mg/day on Days 1 to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses through 12 mg/day were well tolerated. Most adverse events were mild to moderate in severity and of limited duration, most commonly headache, nausea, dizziness, and diarrhea. Three of forty patients on ENA 713 discontinued, all due to adverse events. Two experienced nausea and vomiting; the third experienced an unrelated mild atrial fibrillation.

The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease.

Xanomeline tartrate (active ingredient xanomeline) is a muscarinic agonist that has demonstrated specificity for the M1 receptor in preclinical studies and has been well tolerated at dosages up to 50 mg three times a day in healthy elderly subjects. To define the maximum tolerated dose (MTD) of xanomeline tartrate in patients with Alzheimer's disease, 48 patients (20 men, 28 women) with probable Alzheimer's disease were enrolled in a double-blind, placebo-controlled inpatient study to determine the safety and tolerability of 8 fixed dosages of xanomeline tartrate (25, 35, 50, 60, 75, 90, 100, and 115 mg, all three times a day) given for 7 days. For each dosage the treatment panel consisted of six patients (four taking xanomeline tartrate and two taking placebo). With the discontinuation of two patients because of severe intolerable adverse events, a minimum intolerated dose was reached at 115 mg three times a day, and 100 mg three times a day was defined as the MTD. This MTD in patients was two-fold greater than the MTD previously determined in healthy elderly volunteers.

Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.

OBJECTIVE: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. METHODS: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. RESULTS: A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml). CONCLUSIONS: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.

Effects of the cholinomimetic SDZ ENS-163 on scopolamine-induced cognitive impairment in humans.

Scopolamine-induced cognitive impairment was used in healthy men to evaluate the central nervous system activity of the new cholinomimetic SDZ ENS-163. Eighteen subjects were treated in a crossover design with oral placebo/intravenous saline, 50 mg of oral SDZ ENS-163/intravenous saline, oral placebo/0.4 mg of intravenous scopolamine, and 50 mg of oral SDZ ENS-163/0.4 mg of intravenous scopolamine. The administration of placebo with scopolamine caused significant cognitive impairment, as assessed by the Computerized Neuropsychological Test Battery (CNTB), and also decreased salivation and heart rate. In contrast, SDZ ENS-163 with saline had no effect on CNTB scores, increased salivation, and increased heart rate. Despite the observed cholinomimetic effects of SDZ ENS-163 when administered with saline, the changes in CNTB scores, heart rate, and salivation were indistinguishable between placebo/scopolamine and SDZ ENS-163/scopolamine. Thus, 50 mg of oral SDZ ENS-163 has cholinomimetic activity in normal men, but this dose is insufficient to reverse the muscarinic effects of 0.4 mg of intravenous scopolamine.

Orthostasis in Alzheimer disease: a retrospective analysis.

Vitiello et al. (1993) recently reported statistically significant decreases in systolic blood pressure upon standing in patients with Alzheimer disease (AD) (n = 60) as compared with healthy elderly controls (n = 20), which would suggest a possible autonomic dysfunction associated with AD. To investigate this issue, we conducted a retrospective analysis of blood pressures and heart rates of 31 patients 55-85 years of age (mean 69.6) who met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable AD. The patients were selected from a pool of placebo-treated patients with AD in five inpatient phase I clinical trials. All patients met rigorous entrance criteria and thus were in excellent physical health except for AD. Blood pressure and pulse were assessed after 3-5 min of lying down and after 1-3 min of standing. Systolic and diastolic blood pressures showed decreases upon standing of 12 mm Hg (8.6%) and 6 mm Hg (8.2%), respectively, on day 1 and decreases of 10 mm Hg (7.6%) and 4 mm Hg (5.7%), respectively, on day 7 of hospitalization (p < 0.05). Pulse rates increased upon standing by 17% and 13% on days 1 and 7, respectively (p < 0.05). Our data support the finding of Vitiello et al. of significant postural decreases in systolic blood pressure in patients with AD. Well-controlled, prospective studies of orthostasis in AD and healthy elderly subjects should be conducted to determine its prevalence in both populations and to determine whether the orthostatic changes seen in AD differ from those in normal aging.

The safety and efficacy of ipsapirone vs. lorazepam in outpatients with generalized anxiety disorder (GAD): single site findings from a multicenter trial.

We report the findings of a randomized, double-blind, placebo-controlled, parallel, generalized anxiety disorder (GAD) outpatient study. The purpose of the study was to compare the efficacy, safety, and tolerability of ipsapirone, an azapirone and 5-HT1A agonist, given at a total daily dose of 10 mg to 30 mg, with a total daily dose of 2 mg to 6 mg of lorazepam or placebo in 90 outpatients with GAD of moderate or greater severity. At baseline, all patients had a Hamilton Anxiety Scale (HAM-A) score of > or = 18 and Covi anxiety score of > or = 8. After a 1-week single-blind washout, patients entered a 4-week double-blind period with an optional extension for another 4 weeks, followed by a 2-week single-blind placebo washout. Ipsapirone and lorazepam ratings on the HAM-A and Clinical Global Impressions (CGI) were significantly (p < .05) superior to placebo at the end of the acute and maintenance periods of the trial, with a 50 percent HAM-A reduction on active drugs vs. 20 percent on placebo. The anxiety of patients receiving lorazepam, but not ipsapirone, rebounded during the final placebo washout.