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Background: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. Objectives: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. Methods: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale--Cognitive Subscale (ADAS-cog) and Clinician's Interview--Based Impression of Change including caregiver information (CIBIC plus). Results: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P [is less than] .001); 0.3 and 0.4 units for CIBIC plus (P [is less than or equal to] .008); and 1.0 and 1.3 units for Mini-Mental State Examination (P [is less than or equal to] .004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean ([+ or -] SEM) donepezil plasma concentrations at study end point were 25.9 [+ or -] 0.7 ng/mL and 50.6 [+ or -] 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean ([+ or -] SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% [+ or -] 0.9% and 74.7% [+ or -] 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the [EC.sub.50] (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P [is less than] .001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P [is less than] .001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. Conclusion: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease. Arch Intern Med. 1998;158:1021-1031

The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended‐release dosage form (ER‐lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER‐lovastatin either 10, 20 or 40 mg in a three‐way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration–time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed‐ and extended‐release characteristics at each dose. Mean (±) values for the Cmaxof lovastatin were 1.04±0.43, 2.03±0.65 and 4.03±3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC0–48 hof lovastatin were 14.6±7.8, 34.1 ±13.7, and 53.9±35.6 ng h/ml. The same tendency was also found for Cmaxand AUC0−48 hvalues of lovastatin acid. Results from this study demonstrated as the dose of ER‐lovastatin increased from 10 to 40 mg, the Cmaxand AUC0−48 hvalues of lovastatin as well as lovastatin acid appeared to increase linearly. Copyright © 2002 John Wiley & Sons, Ltd.

The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three‐period crossover study following a single oral dose of lovastatin extended‐release (ER) tablets and lovastatin immediate‐release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets under fasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed‐ and extended‐release characteristics. The relative bioavailabilitv, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.

• Fifty-nine children were enrolled in an open trial of aztreonam, a monocyclic β-lactam, therapy for serious gram-negative infections. Thirty-six infections were microbiologically evaluable and received five or more days of therapy. Patients' ages ranged from 3 days to 12 years, and diagnoses included pyelonephritis or cystitis (20), deep soft tissue or joint infection (seven), septicemia (four), pneumonia (three), peritonitis, and epiglottitis. Causative bacteria included Escherichia coli and other Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus influenzae. The standard regimen was 30 mg/kg every six or eight hours intravenously. All isolates were aztreonam-susceptible and were eradicated during therapy. Two patients had microbiologic relapses: a patient with Salmonella choleraesuis meningitis who was initially treated for only ten days and a patient with E coli pyelonephritis. Clinical cure was achieved in 31 of 36 children. Pharmacokinetic studies performed in six children demonstrated no difference in serum concentrations or pharmacokinetic variables between day 1 and day 7 of therapy. Although several patients had transient eosinophilia (eight), elevated levels of aminotransferase (seven), or thrombocytosis (ten), no clinically significant adverse effects were noted. In this initial, uncontrolled study, aztreonam was effective and safe in the treatment of a variety of serious gram-negative infections in children.(AJDC 1986;140:1147-1151)

The membrane potential of the human platelet was investigated using the membrane potential probes 3,3-dipropyl-2,2'-thiadicarbocyanine iodide and tritiated triphenylmethylphosphonium bromide. The membrane potential in physiologic buffer was estimated to be 52-60 mV inside negative. The membrane was depolarized when extracellular potassium or hydrogen ion concentrations were increased. Changes in extracellular sodium, chloride, or calcium ion concentration had no measurable effect on membrane potential. Elevated extracellular potassium has been shown to increase platelet sensitivity to the aggregating agent, adenosine diphosphate. Our results show that changes in extracellular ion concentrations that depolarize platelets increase platelet sensitivity to aggregating agents. These results suggest that membrane potential changes may play a role in modulating the response of platelets to aggregating agents.

SQ 28,668 is a structural analog of thromboxane A2. It inhibits the effects of thromboxane in vitro. Fifty-six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg. Plasma drug concentrations increased in a dose-dependent manner. The shape of the plasma drug concentration-time curve was consistent with enterohepatic recirculation. The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2with a platelet receptor dissociation constant (estimated by Schild analysis) of about 19 nmol/L. Approximately 94% occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time. Dose-ranging studies of antithrombotic drugs are difficult and expensive. For this reason, a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin.

Clinical trials for Alzheimer disease drugs have an exceptionally high failure rate, discouraging investment in the field despite the unmet medical need. Drug developers need to more effectively harness existing and emerging data and digital technologies to improve the likelihood of success.

The deposition of ß-amyloid (Aß) in neuronal plaques is believed to be crucial for the initiation and progression of Alzheimer's disease (AD). Studies in vitro have shown that inhibiting cholesterol metabolism with lovastatin, or its active metabolite lovastatin acid, lowers Aß production. To examine the effects of lovastatin on Aß in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized, placebo-controlled study with 10, 20, 40 or 60 mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Aß concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Aß concentrations showed a dose-dependent decrease, and analysis of variance indicated that treatment was statistically significant (p < 0.0348). Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p = 0.05).