Imipramine (50 mg), nomifensine (50 mg) or placebo was administered early morning, late morning, and mid-afternoon to normal volunteers. The program of hourly tests included: the Digit Symbol Substitution, Perceptual Reversal, Time Estimation Test, and Simple and Complex Continuous Performances tests both of which required recognition of briefly exposed letters of the alphabet. It was found that relative to placebo or nomifensine, imipramine had a clearly detracting effect on most of the tests. Drowsiness was reported more often in the imipramine group than in the placebo and nomifensine groups combined.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate), an oral anticholinesterase, enhances memory in rodents and may be useful in treating Alzheimer's disease (AD). To assess adverse events in relation to dosage and plasma drug levels, 24 hospitalized AD subjects were randomly assigned to receive placebo or HP 029 for 10 days in a double-blind, sequential escalation study. Maximum daily dosages were 450 mg (group 1), 300 mg (group 2), and 225 mg (group 3), divided into three doses per day. The group 1 trial was discontinued on day 5 because one subject, 6 hours following the second of three scheduled 150-mg doses, had a tonic seizure after protracted vomiting and hyperventilation; adverse events in other patients included nausea, vomiting, abdominal cramps, diarrhea, dizziness, and syncope. Adverse events were generally less severe in group 2, but only two of six HP 029 subjects could complete the trial at 300 mg/day. All group 3 subjects completed the trial at 225 mg/day with drug related, mild adverse events (nausea, vomiting, lacrimation, rhinorrhea) in only two subjects. Although mean plasma drug levels were related to adverse events across dosage groups, they did not adequately predict the occurrence or severity of adverse events in individual subjects. The 225 mg/day dose appears to be safe for use in multicenter outpatient trials of HP 029 efficacy in AD. Further patient studies are ongoing to determine the relation of specific subject characteristics to the metabolic profile of HP 029 and biological response.

A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.

Dosage and tolerance are critical issues in successful drug therapy for patients with Alzheimer's disease (AD). A clear distinction among patient populations and AD patient subpopulations is necessary to ensure a thorough assessment of new central nervous system-active compounds. Phase I inpatient trials, in which tolerance and safety are evaluated under double-blind conditions in the target population, provide valuable information for use in planning multicenter outpatient trials. In similar studies, even those involving the elderly, tolerance and safety outcomes in healthy volunteers are not always predictable. An early trial of the effects of velnacrine in healthy, elderly, male volunteers was followed by a trial in the target population. A group of volunteers, aged 60 to 74 years who did not have AD, received 300 mg of velnacrine each day. This dosage was well tolerated for 28 days. Diarrhea, generally of moderate severity, was the only reported adverse effect. No subjects were required to discontinue taking velnacrine. In contrast, a similar trial showed a dosage of 300 mg of velnacrine each day intolerable among patients with AD. Adverse reactions to dosages greater than 225 mg/day included dizziness, fainting, nausea and/or vomiting, headache, and severe diarrhea. A velnacrine dosage of 225 mg/day appeared to be safe and well tolerated in a small population of healthy patients with AD. Based on the inpatient experience with AD subjects, a maximum dose of 225 mg/day was adopted for outpatient studies. Although factors that may contribute to drug sensitivity in patients with AD vary beyond conclusive parameters, the observed sensitivity within the target AD group may indicate a safety/tolerance study as a worthwhile antecedent to multicenter efficacy trials.