Single‐Dose Pharmacokinetics, Safety, and Tolerance of Linopirdine (DuP 996) in Healthy Young Adults and Elderly Volunteers

Abstract

The pharmacokinetics, safety, and tolerance of linopiridine ([3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one]; DuP 996) a potential therapeutic agent for Alzheimer's disease, were assessed in double-blind, placebo-controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopirdine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopirdine disposition was characterized by rapid absorption (mean Tmax, < 1 hr) and elimination (mean t1/2, 0.4-3.2 hr). Urinary excretion of unchanged drug was negligible. The pharmacokinetic parameters showed large inter- and intrasubject variability. Linopirdine was well-tolerated in both young and elderly volunteers. The most frequently reported adverse event was headache. The subjects who received linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations.

KCNQ Modulators Reveal a Key Role for KCNQ Potassium Channels in Regulating the Tone of Rat Pulmonary Artery Smooth Muscle

“…In our study, systemic pressure was unchanged or even decreased at the highest dose of linopirdine. We cannot explain the discrepancy, but our findings concur with reports that linopirdine does not affect blood pressure in humans (Saletu et al, 1989;Pieniaszek et al, 1995).…”

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

“…It was well tolerated and the most frequent adverse event was headache. Results of electroencephalograms, ECGs, and clinical laboratory evaluations were not affected (Pieniaszek et al, 1995). Another study administering single oral doses of 30 mg linopirdine observed electroencephalography changes suggesting vigilance-improving properties and no abnormalities in ECG or laboratory evaluations, indicating a good tolerability (Saletu et al, 1989).…”

Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

“…It has been reported that linopirdine was well tolerated in patients and did not appreciably alter measured cardiovascular parameters in human volunteers (Pieniaszek et al, 1995). It was also relatively ineffective as a cognition enhancer in patients with AD (Rockwood et , 1997).…”