Effective decision-making: progressing compounds through clinical development.

In today's drug-development environment, companies are under increasing pressure to improve efficiency and maintain returns on investment. Tomorrow's environment is likely to be harsher still, and companies that survive and prosper will be those that are already responding by re-inventing their structures and culture to meet the challenges that lie ahead. In this review, we explore some of the strategies and issues that are central to this process, with particular reference to decision-making in drug development.

The effects of sertraline on psychomotor performance in elderly volunteers.

The psychopharmacologic effects of sertraline, a new antidepressant drug, are reviewed. A double-blind, placebo-controlled crossover study was conducted, investigating the effects of 9 days' administration of sertraline and mianserin on cognitive and psychomotor performance of elderly volunteers. The two antidepressants were given on a rising dose schedule for the first five days of treatment (sertraline 100 mg Day 1 and 2, 150 mg Days 3 and 4, and 200 mg Day 5; mianserin 10 mg Days 1 and 2, 20 mg Days 3 and 4, and 30 mg Day 5) with the highest dose (mianserin 30 mg and sertraline 200 mg) being intended for the rest of the study. To assess the effect of concomitant alcohol administration, alcohol (0.5 g/kg body weight) was given 6 hours after the last dose of each treatment. There was a severe intolerance to the effects of mianserin in this group of patients even at the lowest dose and, as many subjects were withdrawn, there was no formal analysis because of the missing data. However, the available evidence showed the expected sedative effects on a number of psychometric tests. Single or multiple doses of sertraline did not affect objective measures of performance. The addition of alcohol did not affect these results. The results indicate that sertraline has a neutral psychomotor profile in the elderly and appears to have no additive depressant effects when taken with moderate amounts of alcohol.

Erythromycin A oxime 11,12-carbonate and its oxime ethers.

Erythromycin A oxime 11,12-carbonate (5a) and its oxime ethers 5b approximately 5p have been prepared and their antibacterial activities compared with those of erythromycin A (1) and its 11,12-carbonate 2. The oxime 5a and many of its oxime ether derivatives showed good activity in vitro against Gram-positive and the more permeable Gram-negative organisms, in some cases being even more active than the carbonate 2.

Biological properties of ER 42859, a novel erythromycin derivative.

The antimicrobial activity of a new semi-synthetic oral erythromycin derivative, ER 42859, was evaluated in vitro and in vivo in comparison with erythromycin, spiramycin, josamycin, oleandomycin and the newer semi-synthetic derivatives flurithromycin, roxithromycin and A-56268. MIC values of ER 42859 were superior to those of roxithromycin, oleandomycin, josamycin and spiramycin but generally 2-fold poorer than those of erythromycin. The activity equalled that of erythromycin against Haemophilus influenzae and was superior to that of roxithromycin and A-56268 against this organism. MIC values of the compound were greatly influenced by pH due to the dibasic nature of the molecule. ER 42859 had markedly superior activity to erythromycin, spiramycin, josamycin, oleandomycin and flurithromycin against experimental infections in mice and similar activity to roxithromycin and A-56268. Blood and tissue levels were high and prolonged in rodents. In volunteers, blood levels were prolonged but inferior to those of erythromycin.

9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A.

A series of 9,11-cyclic acetal derivatives of (9S)-9-dihydroerythromycin A (4) have been prepared and their antibacterial activities compared to those of erythromycin A and 9-dihydroerythromycin A. Many of the cyclic acetal derivatives showed better antibacterial activity than their parent 4. In particular, the acetaldehyde acetal (9-O,11-O-ethylidene-9-dihydroerythromycin A) (8b) showed good antibacterial activity in comparison with erythromycin A but was not sufficiently improved in vivo to warrant progression.

Erythromycin A 11,12-methylene acetal.

Erythromycin A 11,12-methylene acetal (5) and the corresponding 9-methoxime, 9-dihydro, and 8-hydroxy derivatives have been prepared and their antibacterial activities compared with those of erythromycin A and its 11,12-cyclic carbonate. The simple methylene acetal 5 showed excellent activity against Gram-positive organisms in vitro.

An investigation of the effects of lofepramine, nomifensine, amitriptyline and placebo on aspects of memory and psychomotor performance related to car driving.

Ten healthy, female volunteers took part in a double-blind, placebo-controlled study to investigate the effects of lofepramine 70 mg, lofepramine 140 mg, nomifensine 100 mg, amitriptyline 50 mg and placebo on psychomotor performance related to driving. One subject failed to complete the study for reasons unrelated to the medications. Each subject received each of the treatments in random order at weekly intervals and was then assessed for psychomotor performance, sedation and quality of sleep. Amitriptyline 50 mg served as a positive control producing results consistent with its known sedative properties. In contrast, lofepramine 70 mg and 140 mg and nomifensine 100 mg were generally free from any significant effect on psychomotor performance.